EP4753708A1 - Combination of niraparib and abiraterone for use in the treatment of metastatic castration-resistant prostate cancer - Google Patents

Abstract

The present disclosure relates to a drug product with at least one approved indication, wherein said drug product comprises niraparib and abiraterone acetate.

Description

DRUG PRODUCT FOR THE TREATMENT OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. TECHNICAL FIELD OF THE INVENTION The present disclosure relates to methods of treating metastatic castration-resistant prostate cancer (mCRPC) with an approved drug product containing niraparib and abiraterone acetate. The present disclosure relates to an approved drug product with at least one indication for use in treating mCRPC. Also disclosed are methods of selling or offering for sale an approved drug product containing niraparib and abiraterone acetate, wherein the approved drug product is approved for at least one indication. The present disclosure relates to methods of treating metastatic castration-resistant prostate cancer (mCRPC) with a drug product containing niraparib and abiraterone acetate. The present disclosure relates to a drug product with at least one indication for use in treating mCRPC. Also disclosed are methods of selling or offering for sale a drug product containing niraparib and abiraterone acetate, wherein the drug product is approved for at least one indication. BACKGROUND OF THE INVENTION Worldwide, prostate cancer is the second most common cancer and the fifth leading cause of cancer death in men, accounting for 1.4 million (14.1%) new cancer cases and 375,304 (6.8%) cancer deaths in 2020. While patients with localized prostate cancer may be cured with current therapies, development of metastases heralds a lethal disease. Over the spectrum of disease, prostate cancers are dependent on androgen-mediated signaling for their growth and survival. For many decades, initial (first-line) treatment for metastatic prostate cancer has been surgical castration by bilateral orchiectomy or chemical castration with androgen deprivation therapy (ADT). Generally, there is an initial benefit with ADT, however, resistance to ADT inevitably occurs. In addition to androgen dependence, in approximately 25-30% of patients with metastatic prostate cancer, DNA-repair anomalies have been identified. Examples of these homologous recombination repair (HRR) gene alterations include those HRR alterations in BRCA1, BRCA2, CDK12, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or ATM genes. Several lines of evidence suggest that HRR gene alterations act as a second oncogenic driver in patients with mCRPC, as evidenced by a worse oncologic outcome in these patients. Patients with mCRPC and HRR gene defects have a shorter life expectancy (median cause-specific survival [CSS] from mCRPC of 23.3 months) compared to patients with mCRPC and no HRR gene defects (median CSS from mCRPC of 33.2 months). Clinical trials with Poly (ADP-ribose) polymerase inhibitors (PARPi) are being run but not without hurdles. For example, clinical trials with veliparib and pamiparib have been discontinued. This data makes clear that the path to safer and more efficacious patient treatments for mCRPC remains complex and unpredictable to this day. In the pharmaceutical industry, the path from drug discovery to reaching an approved product is long and riddled with uncertainty. For a prostate cancer product, the average time from Phase 1 to approval is 9.3 years. To date, only the ClinicalTrials.gov site has registered 5,927 clinical studies in prostate cancer, and the likelihood of regulatory approval from Phase 1 is less than 5% for a prostate cancer product. The final path to approval is also not a certainty nor inevitable as failures continue as late as from Phase 3 to approval, with a 50% average probability of a prostate cancer drug advancing from Phase 3. This is not only due to the high unpredictability and uncertainty regarding how a pharmaceutical product will impact human biology, but often human behavior is unpredictable in how data is interpreted by regulatory agencies and whether the data warrants approving a study drug as an approved product for use in commerce. The Magnitude study is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of niraparib 200 mg in combination with abiraterone acetate (AA) 1,000 mg plus prednisone 10 mg daily, compared with placebo and abiraterone acetate plus prednisone (AAP) in subjects with mCRPC. The Magnitude study has been run for several years, involved 318 study locations worldwide, and enrolled 765 patients so far. In a first Interim Analysis 1 (IA1), no detrimental effect on overall survival (OS) was observed in Cohort 1 with treatment with niraparib + AAP in patients with mCRPC and having HRR gene alterations, obtaining a Hazard Ratio (HR) equal to 0.938, with a 95% Confidence Interval (CI) (0.648, 1.358), and a p value of 0.7333. The boundary for significance for OS at this first interim analysis was 0.0005. Medians were not reached for either treatment group. A pre- specified analysis of subjects with all HRR excluding ATM alterations, showed a HR of 0.910, 95% CI (0.608, 1.362) for OS. Another prespecified analysis of subjects with all HRR alterations but excluding both ATM and CDK12 alterations showed a HR of 0.883, 95% CI (0.586, 1.330) for OS in favor of niraparib + AAP. OS analysis for the non-BRCA subgroup showed a HR of 0.91795% CI (0.547, 1.536) and nominal p = 0.7407, whilst OS analysis for the BRCA subgroup showed a HR of 0.96195% CI (0.565, 1.633) and nominal p = 0.8819. Additional follow up and further analysis of OS was needed to understand the impact of individual genes and co-occurring mutations. At IA2 a HR of 0.881 was observed for OS in the BRCA subgroup. The median OS for treatment with niraparib + AAP was 29.27 months with 95% CI (27.7, not estimable) and the median in the placebo + AAP treated subjects was 28.6 months with 95% CI (23.8, 32.95). The multivariate analysis, which accounts for imbalances in subject baseline characteristics, indicated that treatment with niraparib + AAP was associated with a favorable survival with a HR=0.682; 95% CI: 0.445, 1.046. Additionally, the data remained immature as there was still a high number of censored subjects at IA2. The overall survival endpoint is generally defined as the average length of time patients are alive after the start of treatment. Overall survival is usually considered the “gold standard” (or ideal) primary endpoint in oncology because patients with cancer often want to take medications that can help them live longer. However, showing an overall survival advantage in a clinical trial can be lengthy, costly and otherwise challenging. For that reason, researchers use other clinical endpoints to show patient benefit like overall response rate and progression- free survival. Thus, there is a need to demonstrate the benefit, through overall survival data, of administering niraparib 200 mg in combination with abiraterone acetate (AA) 1,000 mg plus prednisone 10 mg daily, to patients with mCRPC and HRR gene alterations. There is a need for approved drug products that provide more efficacious and safer treatment options for patients with mCRPC and HRR gene alterations, or that overcome the potential therapeutic deficiencies of existing therapies. There is a need for drug products that provide more efficacious and safer treatment options for patients with mCRPC and HRR gene alterations, or that overcome the potential therapeutic deficiencies of existing therapies. The present disclosure has solved these needs by demonstrating an improved overall survival in a BRCA mutated subgroup of mCRPC patients vis-à-vis those OS data obtained at IA1 and IA2. The disclosed approved drug products, methods of treatment using these approved drug products, and medical uses thereof are directed to these and other important needs. The disclosed drug products, methods of treatment using these drug products, and medical uses thereof are directed to these and other important needs. SUMMARY OF THE INVENTION An objective of the present invention is to provide drug products or approved drug products with at least one indication or approved indication, wherein said drug product or approved drug product comprises niraparib and abiraterone acetate. An objective of the present invention is to provide a drug product or an approved drug product, wherein the drug product or approved drug product is indicated with prednisone for the treatment of a patient with deleterious or suspected deleterious BReast Cancer-mutated (BRCAm) mCRPC, as detected by a test or an approved test. An objective of the present invention is to provide drug products or approved drug products, wherein said drug products or approved drug products elicit a median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test or an approved test. An objective of the present invention is to provide drug products or approved drug products, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from Prostate-Specific Antigen (PSA), Lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) grade, bone lesion number, and Visceral Disease. An objective of the present invention is to provide a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering the drug product or approved drug product as defined herein, in combination with prednisone, to said patient. An objective of the present invention is to provide a drug product or an approved drug product as defined herein, for use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone. An objective of the present invention is to provide a drug product or an approved drug product comprising niraparib and abiraterone acetate, for use with prednisone or prednisolone in a method for the treatment of an adult patient with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated; wherein positive BRCA status is established with a validated test method; wherein the single daily dose of the drug product or approved drug product is 200 mg of niraparib and 1,000 mg of abiraterone acetate, and the daily dose of prednisone or prednisolone is 10 mg, until disease progression or unacceptable toxicity; characterized in that the treatment comprises an improvement of the median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120). FIGURES Figure 1: Kaplan-Meier plot of Overall Survival for BRCA+ patients (Cohort 1), one arm receiving niraparib and abiraterone acetate plus prednisone, and the other arm receiving placebo and abiraterone acetate plus prednisone. Figure 2: Forest Plot of Overall Survival for Subgroups Defined by Baseline Clinical Disease Characteristics Cohort 1 BRCA Figure 3a: Kaplan-Meier plot of Time to Symptomatic Progression (TSP) for BRCA+ patients (Cohort 1), one arm receiving niraparib and abiraterone acetate plus prednisone, and the other arm receiving placebo and abiraterone acetate plus prednisone. Patients receiving niraparib and abiraterone acetate plus prednisone had delayed TSP. NE: not estimable. Figure 3b: Kaplan-Meier plot of Time to initiation of Cytotoxic Chemotherapy (TCC) for BRCA+ patients (Cohort 1), one arm receiving niraparib and abiraterone acetate plus prednisone, and the other arm receiving placebo and abiraterone acetate plus prednisone. Patients receiving niraparib and abiraterone acetate plus prednisone had delayed TCC. NE: not estimable. Figure 4: Kaplan-Meier Plot of BICR assessed radiologic progression-free survival in the BRCA population (MAGNITUDE, primary analysis) Figure 5: Kaplan-Meier Plot of Radiographic Progression-free Survival by Central Review in BRCAm mCRPC patients in MAGNITUDE Cohort 1 Figure 6: Kaplan-Meier Plot of BICR Assessed Radiographic Progression-Free Survival in the BRCAm Population (MAGNITUDE, primary analysis) Figure 7: Kaplan-Meier Plot of Overall Survival in the BRCAm Population (MAGNITUDE, final analysis) Figure 8: Method of administration. Press and hold Figure 9: Method of administration. Pull out Figure 10: Packaging indications. Fold over to close Figure 11: Packaging indications. Flip open DETAILED DESCRIPTION The disclosed drug products or approved drug products, methods, and uses may be understood more readily by reference to the following detailed description. It is to be understood that the disclosed drug products or approved drug products, methods, and uses are not limited to the specific drug products or approved drug products, methods, and uses described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed drug products or approved drug products, methods, and uses. Unless specifically stated otherwise, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed drug products or approved drug products, methods, and uses are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement. Throughout this text, the descriptions refer to drug products or approved drug products, methods, and uses. Where the disclosure describes or claims a feature or embodiment associated with a drug product or an approved drug product, such a feature or embodiment is equally applicable to the methods and uses. Likewise, where the disclosure describes or claims a feature or embodiment associated with the methods or uses, such a feature or embodiment is equally applicable to the drug products or approved drug products. The entire disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference. Definitions As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings. In the present disclosure the singular forms “a,”, “an,” and “the” include the plural reference, and reference to a given numerical value includes at least that value, unless the context clearly indicates otherwise. Thus, for example, a reference to “an ingredient” is a reference to one or more of such ingredients and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when indicating that a certain element “may be” X, Y, or Z, it is not intended by such usage to exclude in all instances other choices for the element. When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as including ranges “1 to 4”, “1 to 3”, “1- 2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included.” The term “acceptable” with respect to a pharmaceutical formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the human being treated. The term “AAP” refers to abiraterone acetate plus prednisone or prednisolone. The term “androgen-deprivation therapy (ADT)” refers to the use of surgery or medicines to reduce androgen levels made by the testicles in a prostate cancer patient to castrated levels of testosterone (< 50 ng/dL). Such treatments can include orchiectomy or the use of gonadotropin- releasing hormone agonists or antagonists. ADT includes surgical castration (orchiectomy) and/or the administration of luteinizing hormone-releasing hormone (“LHRH”) agonists to a human. Examples of LHRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin palmoate. Physicians can prescribe LHRH agonists in accordance with instructions, recommendations and practices. This may include about 0.01 mg to about 20 mg of goserelin over a period of about 28 days to about 3 months, preferably about 3.6 mg to about 10.8 mg of goserelin over a period of about 28 days to about 3 months; about 0.01 mg to about 200 mg of leuprolide over a period of about 3 days to about 12 months, preferably about 3.6 mg of leuprolide over a period of about 3 days to about 12 months; or about 0.01 mg to about 20 mg of triptorelin over a period of about 1 month, preferably about 3.75 mg of triptorelin over a period of 1 month. About 50 mg of histrelin acetate over a period of 12 months of histrelin acetate or about 50 µg per day of histrelin acetate. The term “approved” when referring to a drug product and at least one medical indication means a pharmaceutical product that contains one or more active pharmaceutical ingredients that has been approved for marketing by a governmental authority for the treatment of at least one medical indication, said governmental authority including without being limited to, the Food and Drug Administration (FDA), the European Medicines Agency (EMA), Health Canada, the National Medical Products Administration (NMPA) in China, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, or the similar authority in other countries. The present disclosure is also directed to an approved drug product by the EMA, FDA or Health Canada, or the similar authority in other countries, comprising niraparib an abiraterone acetate, wherein the at least one indication is prostate cancer. The term “drug product” means a pharmaceutical product that contains one or more active pharmaceutical ingredients that is marketed for at least one indication, for example, prostate cancer. The term “ARi” refers to an androgen receptor inhibitor. The term “BM” refers to biomarker. The term “BPI-SF” refers to the Brief Pain Inventory–Short Form. The terms “BRCA+”, “BRCAm”, “positive BRCA status”, or the like, refer to the BReast Cancer genes BRCA1 and BRCA2 in a mutated or altered form, whether germline and/or somatic, which forms are deleterious or suspected deleterious in prostate cancer. BRCA+, BRCAm, or positive BRCA status, is established or detected by an approved or validated test method. The term “cancer” as used herein refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The term “chemotherapy naive metastatic castration-resistant prostate cancer” refers to metastatic castration-resistant prostate cancer that has not been previously treated with a chemotherapeutic agent. The term “clinically effective amount” means an amount of the niraparib and abiraterone acetate drug product or approved drug product that provides for the achievement of the improved overall survival, delay progression, control the growth, prolonging the onset of distant metastasis, amelioration of symptoms or growth of prostate cancer in a patient, or improvement in quality of life in prostate cancer patients as measured with BPI-SF (Brief Pain Inventory Short Form) pain scores, and as confirmed by efficacy data secured through a clinical trial. The terms "co-administration" or the like, as used herein, encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. The term “CRPC” as used herein refers to castration-resistant prostate cancer. CRPC is prostate cancer that continues to grow despite the suppression of male hormones that fuel the growth of prostate cancer cells. The transitional terms “comprising,” “consisting essentially of,” and “consisting” are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of” excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents), also provide, as embodiments, those which are independently described in terms of “consisting of” and “consisting essentially of”. When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.” The term “ECOG PS” refers to the Eastern Cooperative Oncology Group performance status. The term “HRR+” or “HRRm” refers to a gene of the homologous recombination repair family of genes in a mutated or altered form, which forms are deleterious or suspected deleterious in prostate cancer. The terms “excipient” and carrier” are used interchangeably in the present disclosure. The European Pharmacopoeia (Ph. Eur.) defines an excipient as “any component, other than the active substance(s), present in a medicinal product or used in the manufacture of the product. The intended function of an excipient is to act as the carrier (vehicle or basis) or as a component of the carrier of the active substance(s) and, in so doing, to contribute to product attributes such as stability, biopharmaceutical profile, appearance and patient acceptability and to the ease with which the product can be manufactured. Usually, more than one excipient is used in the formulation of a medicinal product.” The terms vehicle and basis are further defined in the same pharmacopoeia: “A vehicle is the carrier, composed of one or more excipients, for the active substance(s) in a liquid preparation” and “A basis is the carrier, composed of one or more excipients, for the active substance(s) in semi-solid and solid preparations.” As used herein, a “fixed-dose combination” (FDC) are pharmaceutical formulations or compositions that include abiraterone acetate and niraparib and any pharmaceutically acceptable salt, solvate, and hydrate forms thereof, for example niraparib tosylate monohydrate, in a single oral dosage form. A “free-dose combination” (FrDC) refers to pharmaceutical formulations or compositions that include two or more active ingredients that are administered to a human as separate dosage forms. For example, 1) a tablet comprising abiraterone acetate; and 2) a separate tablet comprising niraparib, and any pharmaceutically acceptable salt, solvate, and hydrate forms thereof, for example niraparib tosylate monohydrate. The terms “kit” and “article of manufacture” are used as synonyms. “Label” or “approved product label” refers to human prescription drug labeling (1) that contains a summary of the essential scientific information needed for the safe and effective use of the drug; and (2) includes the Prescribing Information, FDA-approved patient labeling (Medication Guides, Patient Package Inserts, and/or Instructions for Use), and/or carton and container labeling. In some embodiments, the label or approved product label identifies niraparib and abiraterone acetate, or its tradename Akeega®, and provides instructions for its use in a patient. “Prescribing Information” or “United States Prescribing Information (USPI)”, reflects a regulatory authority’s (for example, FDA, EMA) finding regarding the safety and effectiveness of the human prescription drug under the labeled conditions of use. The PI is written for the healthcare professional and must: 1. Contain a summary of the essential scientific information needed for the safe and effective use of the human prescription drug, 2. Be informative and accurate and neither promotional in tone nor false or misleading, and 3. Be updated when new information becomes available that causes labeling to become inaccurate, false, or misleading. “Medication Guide” is patient labeling that is part of the FDA-approved prescription drug labeling for certain prescription drugs when the FDA determines that: ^ Patient labeling could help prevent serious adverse reactions ^ The drug has serious risk(s) (relative to benefits) of which patients should be made aware because information concerning the risk(s) could affect patients' decision to use, or to continue to use, the product, or ^ Patient adherence to directions for use is crucial to the drug’s effectiveness. Patient Package Insert contains information that is intended for patients and may be required as part of the approved drug product’s label. Instructions for Use (IFU) is: a form of prescription drug labeling that is generally created for drug products that have complicated or detailed patient-use instructions that is reviewed and approved by FDA under an NDA, BLA, or ANDA and is generally provided to patients when drug product is dispensed. Under European Law (article 54 of the Council Directive 2001/83/EEC), the following particulars shall appear on the outer packaging of medicinal products or, where there is no outer packaging, on the immediate packaging: (a) the name of the medicinal product followed by its strength and pharmaceutical form, and, if appropriate, whether it is intended for babies, children or adults; where the product contains up to three active substances, the international non-proprietary name (INN) shall be included, or, if one does not exist, the common name; (b) a statement of the active substances expressed qualitatively and quantitatively per dosage unit or according to the form of administration for a given volume or weight, using their common names; (c) the pharmaceutical form and the contents by weight, by volume or by number of doses of the product; (d) a list of those excipients known to have a recognized action or effect and included in the detailed guidance published pursuant to Article 65. However, if the product is injectable, or a topical or eye preparation, all excipients must be stated; (e) the method of administration and, if necessary, the route of administration. Space shall be provided for the prescribed dose to be indicated; (f) a special warning that the medicinal product must be stored out of the reach and sight of children; (g) a special warning, if this is necessary for the medicinal product; (h) the expiry date in clear terms (month/year); (i) special storage precautions, if any; (j) specific precautions relating to the disposal of unused medicinal products or waste derived from medicinal products, where appropriate, as well as reference to any appropriate collection system in place; (k) the name and address of the marketing authorisation holder and, where applicable, the name of the representative appointed by the holder to represent him; (l) the number of the authorization for placing the medicinal product on the market; (m) the manufacturer's batch number; (n) in the case of non-prescription medicinal products, instructions for use; (o) for medicinal products other than radiopharmaceuticals referred to in Article 54a(1), safety features enabling wholesale distributors and persons authorised or entitled to supply medicinal products to the public to: — verify the authenticity of the medicinal product, and — identify individual packs, as well as a device allowing verification of whether the outer packaging has been tampered with. The term “metastatic castration-resistant prostate cancer” or “mCRPC” refers to castration- resistant prostate cancer that has metastasized to other parts of the human body, e.g., the bone, lymph nodes or other parts of the body in a male. The term "metastatic castration-sensitive prostate cancer" refers to cancer that has spread (metastasized) to other areas of the body, e.g., the bone, lymph nodes or other parts of the body in a male, and that is responsive to androgen-deprivation therapy (ADT). The term “offering for sale” means the proposal of a sale by a seller to a buyer for a drug product, e.g., a pharmaceutical composition and an oral dosage form. The term “overall survival” is defined as the average length of time patients are alive after the start of treatment. The term “PFS” refers to progression free survival. The term “pharmaceutically acceptable,” as used in connection with compositions described herein, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a human. The term “pharmaceutically acceptable” also means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “placebo” as used herein means administration of a pharmaceutical composition comprising abiraterone acetate and prednisone that does not include niraparib. “Progression-free survival on first subsequent therapy” (PFS2) is defined as time from randomization to the date of progression (radiographic, clinical, or PSA progression) on the first subsequent therapy or death from any cause, whichever occurs first. General rules for PFS2 event and censoring: 1. For patients who initiated a subsequent anti-cancer therapy: a. If there is a disease progression on 1^st subsequent anti-cancer therapy or death, this is a PFS2 event, date of PFS2 = minimum of disease progression date and death date. b. If no disease progression on 1st subsequent anticancer therapy and no death prior to start of 2^nd subsequent anti-cancer therapy, this is not a PFS2 event, the subject will be censored at start date of 2nd subsequent anti-cancer therapy – 1 day. c. If no disease progression on 1st subsequent anticancer therapy and no death and no start of 2^nd subsequent anti-cancer therapy, this is not a PFS2 event, the subject will be censored at last known alive date. 2. For patients who did not receive any subsequent anti-cancer therapy: a. If a patients died, this is a PFS2 event with death date as date of PFS2. b. If a patient did not die, this is not a PFS2 event, the subject will be censored at last known alive date. The term “prostate cancer” as used herein refers to histologically or cytologically confirmed adenocarcinoma of the prostate. . The term “PSA” refers to the prostate-specific antigen. The term “PSA50 response” as used herein means a decline of serum prostate-specific antigen by 50% from baseline. The term “radiographic progression-free survival” (rPFS) is defined as the time interval from the date of randomization to the first date of radiographic progression or death due to any cause, whichever occurs first. Radiographic progression is determined by first occurrence of progression by bone scan (according to PCWG3 criteria) or progression of soft tissue lesions by CT or MRI (according to RECIST 1.1 criteria). Radiographic progression should be evaluated as follows: ^ Progression of soft tissue lesions measured by CT or MRI as defined by RECIST 1.1. ^ Progression by bone lesions observed by bone scan and based on PCWG3. Under these criteria, any bone progression must be confirmed by a subsequent scan ≥6 weeks later. The Week 8 scan (first post-treatment scan) should be used as the baseline to which all subsequent scans are compared to determine progression. Bone progression is defined as one of the following: 1. Patient whose Week 8 scan is observed to have ≥2 new bone lesions would fall into one of the 2 categories below: a. Patient whose confirmatory scan (which is performed ≥6 weeks later) shows ≥2 new lesions compared to the Week 8 scan (ie, a total of ≥4 new lesions compared to baseline scan) will be considered to have bone scan progression at Week 8. b. Patient whose confirmatory scan did not show ≥2 new lesions compared to the Week 8 scan will not be considered to have bone scan progression. The Week 8 scan will be considered as the baseline scan to which subsequent scans are compared. The FIRST scan timepoint that shows ≥2 new lesions compared with the Week 8 scan will be 5 considered as the bone scan progression timepoint if these new lesions are confirmed by a subsequent scan ≥6 weeks later. 2. For a patient whose Week 8 scan does not have ≥2 new bone lesions compared to baseline scan, the FIRST scan timepoint that shows ≥2 new lesions compared with the Week 8 scan will be considered as the bone scan progression timepoint if these new lesions are confirmed by a 10 subsequent scan ≥6 weeks later. Patients without radiographic progression or death will be censored at the last disease assessment date if they never start subsequent anti-cancer therapy or censored at the last disease assessment date prior to the start of the subsequent anti-cancer therapy if they started subsequent anti-cancer therapy. Key censoring rules are summarized below. Scenario Censoring Rule No disease assessment at baseline Censored on the date of randomization or No disease assessment after baseline Patients who are lost to follow-up or Censored on the date of the last disease withdraw from study assessment Patients who receive new systemic Censored on the date of the last disease anticancer therapy known or intended for the assessment prior to the start of the new systemic anti-cancer therapy treatment of mCRPC during the study prior to documented disease progression or death Patients with no evidence of radiographic Censored on the date of the last disease progressive disease or death assessment Patients who miss ≥2 consecutive planned Censored on the date of the last disease radiographic scans or has ≥2 consecutive assessment before the missed/unevaluable unevaluable scans before progression or scans death No postbaseline assessment and death Censored on the date of randomization occurred after missed 2 or more planned disease assessments 15 The term “randomization” as it refers to a clinical trial design is the time when the patient is confirmed eligible for the clinical trial and gets assigned to a treatment arm. The term “Reference Listed Drug (RLD)” is an approved drug product to which new generic versions are compared to show that they are bioequivalent (21 CFR 314.3(b)). It is also a medicinal product that has been granted marketing authorization by a Member State of the European Union or by the Commission on the basis of a completed dossier, i.e., with the submission of quality, pre-clinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which the application for marketing authorization for a generic/hybrid medicinal product refers, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies. In the United States, a company seeking approval to market a generic equivalent must refer to the RLD in its Abbreviated New Drug Application (ANDA). For example, an ANDA applicant relies on the FDA’s finding that a previously approved drug product, i.e., the RLD, is safe and effective, and must demonstrate, among other things, that the proposed generic drug product is the same as the RLD in certain ways. Specifically, with limited exceptions, a drug product for which an ANDA is submitted must have, among other things, the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the RLD. The RLD is the listed drug to which the ANDA applicant must show its proposed ANDA drug product is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use, among other characteristics. In the electronic Orange Book, there will is a column for RLDs and a column for reference standards. In the printed version of the Orange Book, the RLDs and reference standards are identified by specific symbol. In Europe, Applicants identify in the application form for its generic/hybrid medicinal product, which is the same as a ANDA or sNDA drug product, the reference medicinal product (product name, strength, pharmaceutical form, Marketing Authorization Holder (MAH), first authorization, Member State/Community), which is synonymous with a RLD, as follows: 1. The medicinal product that is or has been authorized in the European Economic Area (EEA), used as the basis for demonstrating that the data protection period defined in the European pharmaceutical legislation has expired. This reference medicinal product, identified for the purpose of calculating expiry of the period of data protection, may be for a different strength, pharmaceutical form, administration route or presentation than the generic/hybrid medicinal product. 2. The medicinal product, the dossier of which is cross-referred to in the generic/hybrid application (product name, strength, pharmaceutical form, MAH, marketing authorization number). This reference medicinal product may have been authorized through separate procedures and under a different name than the reference medicinal product identified for the purpose of calculating expiry of the period of data protection. The product information of this reference medicinal product will, in principle, serve as the basis for the product information claimed for the generic/hybrid medicinal product. 3. The medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the bioequivalence study(ies) (where applicable). The different abbreviated approval pathways for drug products under the FD&C Act are described in sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C.355(j) and 21 U.S.C. 23355(b)(2), respectively). According to the FDA (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC M579751.pdf, the contents of which is incorporated herein by reference), NDAs and ANDAs can be divided into the following four categories: (1) A “stand-alone NDA” is an application submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use. (2) A 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. (3) An ANDA is an application for a duplicate of a previously approved drug product that was submitted and approved under section 505(j) of the FD&C Act. An ANDA relies on FDA’s finding that the previously approved drug product, i.e., the reference listed drug (RLD), is safe and effective. An ANDA generally must contain information to show that the proposed generic product (a) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product. (4) A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient) and for which FDA has determined, in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act (suitability petition), that studies are not necessary to establish the safety and effectiveness of the proposed drug product. A scientific premise underlying the Hatch-Waxman Amendments is that a drug product approved in an ANDA under section 505(j) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling. In contrast to an ANDA, a 505(b)(2) application allows greater flexibility as to the characteristics of the proposed product. A 505(b)(2) application will not necessarily be rated therapeutically equivalent to the listed drug it references upon approval. The term “safe and effective amount” refers to an amount of an active ingredient that elicits the desired biological or medicinal response in a subject’s biological system without the risks outweighing the benefits of such response in accordance with the Federal Food, Drug, and Cosmetic Act, as amended (secs.201–902, 52 Stat.1040 et seq., as amended; 21 U.S.C. §§ 321–392). Safety is often measured by toxicity testing to determine the highest tolerable dose or the optimal dose of an active pharmaceutical ingredient needed to achieve the desired benefit. Studies that look at safety also seek to identify any potential adverse effects that may result from exposure to the drug. Efficacy is often measured by determining whether an active pharmaceutical ingredient demonstrates a health benefit over a placebo or other intervention when tested in an appropriate situation, such as a tightly controlled clinical trial. In some embodiments, administration of the drug product or of the approved drug product results in no more than a grade 2 adverse event. In other embodiments, administration of the drug product or approved drug product results in no more than a grade 3 adverse event. In other embodiments, administration of the drug product or approved drug product results in no more than a grade 4 adverse event. The terms “sale” or “selling” means transferring title of a drug product or an approved drug product in an arms-length transaction from a seller to a buyer. The term “subject” and “patient” and “human” are used interchangeably. Usually the subject, patient, or human is a male subject, patient, or human. The term “survival benefit” as used herein means an increase in survival of the patient from time of randomization on the trial of administered drug to death. In some embodiments, the survival benefit is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 80, about 100 months or greater than 100 months. The terms “treat,” “treating” and “treatment” refer to the achievement of the improved overall survival, delay progression, control the growth, prolonging the onset of distant metastasis, amelioration of symptoms or growth of prostate cancer in a patient, or improvement in quality of life in prostate cancer patients as measured with BPI-SF (Brief Pain Inventory Short Form) pain scores. The delay of progression of cancer includes inhibition of the progress of cancer, a reduction in the rate of progress of cancer, or a halt in the rate of progress of cancer. The term “time to initiation of cytotoxic chemotherapy” or “time to cytotoxic chemotherapy” (TCC) is defined as the time from randomization to initiation of a new cytotoxic chemotherapy being administered to the subject (e.g., survival follow-up CRF). Time to initiation of cytotoxic chemotherapy for subjects who do not start a cytotoxic chemotherapy is censored on the date of last contact. Surprisingly, the administration of the drug product or approved drug product of the disclosure in accordance with the product label provides treatment of mCRPC as measured by time to cytotoxic chemotherapy. “Time to initiation of subsequent therapy” regarding clinical trial design is defined as the time from the date of randomization to the date of initiation of subsequent anticancer therapy for prostate cancer. Patients who did not initiate subsequent anticancer therapy at the time of the analysis will be censored on last visit date prior to or on last known alive date. Subsequent anticancer therapy for prostate cancer will include categories of chemotherapy, hormone therapy, PARPi and any other kind of therapy for prostate cancer. The “time to PSA progression” regarding clinical trial design is defined as the time from randomization to the first date of documented PSA progression per PCWG3 criteria. There will be a PSA progression when after decline from baseline: PSA increase ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value ≥ 3 weeks later (i.e., a confirmed rising trend); and when no decline from baseline: PSA increase ≥25% and ≥ 2 ng/mL from baseline beyond 12 weeks. Patients with no PSA progression at the time of analysis will be censored on the last known date with no progression. Patients without a baseline PSA or without any post baseline values will be censored at randomization date. PSA response rate is the proportion of subjects achieving a PSA decline of ≥50% and confirmed at 3-4 weeks later according to PCWG3 criteria by Week 12 and during treatment period. “Time-to-pain progression” regarding clinical trial design is defined as the time from date of randomization to the date of the first observation of pain progression. Pain progression is defined as an average increase by 2 points from baseline in the BPI-SF worst pain intensity (item 3) observed at 2 consecutive evaluations ≥3 weeks apart. Subjects with no pain progression at the time of analysis will be censored at last date of BPI-SF pain score collection. The term “time to symptomatic progression” (TSP) in regard to clinical trial design is defined as the time from randomization to the first of any of the following events: (i) external beam radiation therapy (EBRT) for skeletal symptoms; (ii) tumor-related orthopedic surgical intervention; (iii) other cancer-related procedures, for example: nephrostomy insertion, bladder catheter insertion, or surgery for tumor symptoms other than skeletal; (iv) initiation of a new systemic anti-cancer therapy because of cancer pain; (v) having cancer-related morbid events, for example: fracture, symptomatic and/or pathologic cord compression, urinary obstructive events. Usually these events are documented in the Case Report Form (CRF) and may be reported as (1) development of a skeletal-related event (SRE) like pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to the bone; (2) pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anti-cancer therapy; or (3) development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy. Administration of the drug product or approved drug product of the disclosure provides improved treatment of mCRPC as measured by time to symptomatic progression. Embodiments of the disclosure The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, wherein said drug product or approved drug product comprises niraparib and abiraterone acetate. The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, wherein said drug product or approved drug product comprises niraparib and abiraterone acetate, wherein the at least one indication or approved indication is metastatic castration resistant prostate cancer (mCRPC). The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, wherein said drug product or approved drug product comprises niraparib and abiraterone acetate, wherein the drug product or approved drug product is packaged, and wherein the package includes a label that identifies the drug product or approved drug product as indicated with prednisone for the treatment of a patient with deleterious or suspected deleterious BReast Cancer-mutated (BRCAm) mCRPC, as detected by a test or an approved test. The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, wherein the drug product or approved drug product is indicated with prednisone for the treatment of a patient with deleterious or suspected deleterious BReast Cancer-mutated (BRCAm) mCRPC, as detected by a test or an approved test. The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, that treats prostate cancer using a daily dosage of 200 mg of niraparib, 1,000 mg of abiraterone acetate, and 10 mg of prednisone, wherein niraparib and abiraterone acetate are administered in a fixed dose combination drug product or as free-dose combination drug products. The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, wherein said drug product or approved drug product is administered to deliver orally once daily a dosage of 200 mg of niraparib, 1,000 mg of abiraterone acetate, and is administered in combination with a daily dose of 10 mg of prednisone. The present disclosure relates to a drug product or an approved drug product with at least one indication or approved indication, wherein said drug product or approved drug product is administered orally once daily reduced dosage of 100 mg of niraparib, 1,000 mg of abiraterone acetate, (and 10 mg of prednisone), in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. The drug product or approved drug product is administered on an empty stomach. In one embodiment food is not eaten two hours before and one hour after taking the drug product or approved drug product. The patient receiving the drug product or approved drug product should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently, or the patient should have had bilateral orchiectomy. The GnRH analog used as ADT may be selected, without being limited to, triptorelin, nafarelin, goserelin, leuprorelin or leuprolide, histrelin, gonadorelin, and buserelin. The drug product or approved drug product is not administered in a patient with moderate or severe hepatic impairment. The drug product or approved drug product is not co-administered with the CYP3A4 inducer rifampicin. The present disclosure relates to a drug product or an approved drug product, wherein said drug product or approved drug product comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and i. 100 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (regular strength); or ii. 50 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (lower strength). The present disclosure relates to a drug product or an approved drug product, wherein said drug product or approved drug product elicits a median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test or an approved test. The present disclosure relates to a drug product or an approved drug product, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from Prostate-Specific Antigen (PSA), Lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) grade, bone lesion number, and Visceral Disease. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product elicits an improved median Time to Symptomatic Progression (TSP) with a HR of 0.562 (95% CI: 0.371, 0.849) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test or an approved test, when compared to a patient receiving placebo and abiraterone acetate plus prednisone. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product elicits an improved median Time to Cytotoxic Chemotherapy (TCC) with a HR of 0.598 (95% CI: 0.387, 0.924) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test or an approved test, when compared to a patient receiving placebo and abiraterone acetate plus prednisone. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product elicits a median radiographic Progression Free Survival (rPFS) of 19.5 months with a HR of 0.553 (95%: 0.392, 0.782) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test or an approved test. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product comprises 159.40 mg niraparib tosylate monohydrate equivalent to 100 mg niraparib free base as the active ingredient, and 500 mg of abiraterone acetate. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product comprises 79.70 mg niraparib tosylate monohydrate equivalent to 50 mg niraparib free base as the active ingredient, and 500 mg of abiraterone acetate. The present disclosure relates to a drug product or an approved drug product, wherein the pharmaceutical composition is an oral dosage form selected from a film-coated tablet, a tablet, a capsule, granules, and a sachet. In an embodiment, the pharmaceutical composition is a film-coated tablet further comprising colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, and sodium lauryl sulfate; and a film-coating. In an embodiment, the film-coated tablet comprises 100 mg niraparib and 500 mg abiraterone acetate; and the film-coating comprises iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. In an embodiment, the film-coated tablet comprises 50 mg niraparib and 500 mg abiraterone acetate; and the film-coating comprises iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. In an embodiment, the pharmaceutical composition is a capsule comprising 100 mg niraparib and 500 mg abiraterone acetate, and a pharmaceutically acceptable carrier comprising crospovidone, hypromellose, sodium lauryl sulfate (SLS), lactose monohydrate, and magnesium stearate. In an embodiment, the pharmaceutical composition is a capsule comprising 50 mg niraparib and 500 mg abiraterone acetate, and a pharmaceutically acceptable carrier comprising crospovidone, hypromellose, sodium lauryl sulfate, lactose monohydrate, and magnesium stearate. These capsule formulations may contain the active ingredients (niraparib and abiraterone acetate) in the form of granules. Crospovidone may be replaced by a suitable disintegrant; hypromellose may be replaced by a suitable binder, SLS may be replaced by a suitable wetting agent, lactose monohydrate may be replaced by a suitable diluent or filler, and magnesium stearate may be replaced by a suitable lubricant. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product is approved for marketing in the European Economic Area (EEA), Canada, US, Japan, China, and any other country. The present disclosure relates to a drug product or an approved drug product, wherein the drug product or approved drug product is a generic, an ANDA, a sNDA, an NDA product, or a 505(b)(2) drug product. The present disclosure further relates to a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering the drug product or approved drug product, in combination with prednisone, to said patient. The present disclosure further relates to a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering the drug product or approved drug product, in combination with prednisone, to the patient in an amount and manner that is described in the drug product label or approved drug product label for the drug product or approved drug product. The method for treating BRCAm mCRPC of the disclosure further comprises administering orally once daily the drug product or approved drug product that contains 200 mg of niraparib and 1,000 mg of abiraterone acetate, along with a separate daily dose of 10 mg of prednisone, until disease progression or unacceptable toxicity. The method for treating BRCAm mCRPC of the disclosure further comprises administering orally once daily a reduced dosage of the drug product or approved drug product that contains 100 mg of niraparib and 1,000 mg of abiraterone acetate, along with a separate daily dose of 10 mg of prednisone, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non- hematological grade 3 or 4 adverse reactions. The method for treating BRCAm mCRPC of the disclosure further comprises the improvement of the median OS to 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). In one embodiment, the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. The method for treating BRCAm mCRPC of the disclosure further comprises the improvement of median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). The method for treating BRCAm mCRPC of the disclosure further comprises the improvement of median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). The method for treating BRCAm mCRPC of the disclosure further comprises the improvement of median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). The present disclosure further relates to a method of selling a drug product or an approved drug product comprising niraparib and abiraterone acetate as defined herein, said method comprising selling such drug product or approved drug product. In one embodiment, the drug product or approved drug product is generic, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product. In one embodiment, the reference listed drug for such drug product or approved drug product improves OS, rPFS, TCC, TSP, or TPP. In one embodiment, in the method of selling a drug product or an approved drug product of the disclosure, the median OS is 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). In one embodiment, in the method of selling a drug product or an approved drug product of the disclosure, the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. In one embodiment, in the method of selling a drug product or an approved drug product of the disclosure, the median TSP is improved with a HR of 0.562 (95% CI: 0.371, 0.849). In one embodiment, in the method of selling a drug product or an approved drug product of the disclosure, the median TCC is improved with a HR of 0.598 (95% CI: 0.387, 0.924). In one embodiment, in the method of selling a drug product or an approved drug product of the disclosure, the median rPFS is 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). The present disclosure further relates to a method of offering for sale a drug product or an approved drug product comprising niraparib and abiraterone acetate as defined herein, said method comprising offering for sale such drug product or approved drug product. In one embodiment, the drug product or approved drug product is a generic, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product. In one embodiment, the reference listed drug for such drug product or approved drug product improves OS, rPFS, TCC, TSP, or TPP. In one embodiment within the method of offering for sale a drug product or an approved drug product of the disclosure, the median OS data is 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). In one embodiment, the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. In one embodiment, the median TSP data is improved with a HR of 0.562 (95% CI: 0.371, 0.849). In one embodiment, the median TCC data is improved with a HR of 0.598 (95% CI: 0.387, 0.924). In one embodiment, the median rPFS is 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). The present disclosure further relates to a drug product or an approved drug product as defined herein, for use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone. The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the method for treating comprises administering orally once daily a dosage of 200 mg of niraparib and 1,000 mg of abiraterone acetate of the drug product or approved drug product, and 10 mg of prednisone, until disease progression or unacceptable toxicity. The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the method for treating comprises administering orally once daily a reduced dosage of 100 mg of niraparib and 1,000 mg of abiraterone acetate of the drug product or approved drug product, and 10 mg of prednisone, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the method for treating comprises the improvement of the median OS to 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the treatment comprises the improvement of median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the treatment comprises the improvement of median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). The present disclosure relates to the drug product or approved drug product as defined herein, for the use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test or an approved test, the method comprising administering said drug product or approved drug product, in combination with prednisone, wherein the treatment comprises the improvement of median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). The present disclosure further relates to a drug product or an approved drug product comprising niraparib and abiraterone acetate, for use with prednisone or prednisolone in a method for the treatment of an adult patient with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated; wherein positive BRCA status is established with a validated test method; wherein the single daily dose of the drug product or approved drug product is 200 mg of niraparib and 1,000 mg of abiraterone acetate, and the daily dose of prednisone or prednisolone is 10 mg, until disease progression or unacceptable toxicity; characterized in that the treatment comprises an improvement of the median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120). In one embodiment, the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. In one embodiment, the treatment comprises an improvement of the median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). In one embodiment, the treatment comprises an improvement of the median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). In one embodiment, the treatment comprises an improvement of the median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). Niraparib Niraparib is an orally available highly selective poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. The preparation of niraparib is described in U.S. Patent Nos. 8,071,623 and 8,436,185, both of which are incorporated herein by reference. As used herein, the compound (2-[4-[(3S)- piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), a salt form, including pharmaceutically acceptable salts, of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide (e.g., 4- methylbenzenesulfonic acid; 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), and/or a solvated form, including a hydrated form, thereof (e.g., 2-[4-[(3S)-piperidin-3- yl]phenyl]-2H-indazole-7-carboxamide tosylate monohydrate). Such forms may be individually referred to as “niraparib free base”, “niraparib tosylate” and “niraparib tosylate monohydrate”, respectively. The term “niraparib eq.” or “niraparib equivalent” refers to the free base dose amount of niraparib. In any of the embodiments presented herein regarding the drug product or approved drug product, methods of treatment with the drug product or approved drug product, or medical uses thereof, niraparib is in the salt form of tosylate monohydrate. Other niraparib salt forms are also encompassed in the present disclosure provided these salt forms of niraparib are bioequivalent to niraparib tosylate monohydrate. Examples of such forms are sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate. Abiraterone Acetate Abiraterone acetate is a compound of formula: and is a prodrug of orally active inhibitor of the key enzyme in testosterone synthesis, 17α-hydroxylase-C17,20-lyase, also known as steroid 17α- monooxygenase inhibitor or Human Cytochrome P45017α. Suppression of testosterone synthesis has been demonstrated with abiraterone acetate in patients with prostate cancer. The compound was disclosed in WO 93/20097 (A1) and is available commercially through the brand Zytiga® for example. Abiraterone acetate plus prednisone or prednisolone is approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone-sensitive prostate cancer (mHSPC). Abiraterone acetate tablets are currently on the market as 250 or 500 mg oral tablets. Prednisone Where a particular reference is made to “prednisone” in the present disclosure, one of ordinary skill will recognize that prednisone may be substituted with a different glucocorticoid, such as prednisolone, hydrocortisone, methyl prednisolone, or dexamethasone. The person skilled in the art will know how to exchange prednisone with these other drugs and adjust their dosage, if necessary. Particular suitable glucocorticoids include but are not limited to, (1) dexamethasone (e.g., Decadron, oral; Decadron-LA injection, etc.), (2) prednisolone (e.g., Delta-CORTEF^®, prednisolone acetate (ECONOPRED^®), prednisolone sodium phosphate (HYDELTRASOL^®), prednisolone tebutate (HYDELTRA-TBA^®, etc.)), (3) prednisone (DELTASONE^®, etc.), or (4) methylprednisolone (e.g., MEDROL^®), and combinations thereof. See, e g., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th edition 2001. Test or Approved test In any of the embodiments presented herein regarding the drug product or approved drug product, methods of treatment with the drug product or approved drug product, or medical uses thereof, the germline and/or somatic HRR gene alteration(s), and in particular the deleterious or suspected deleterious BRCA-mutated (BRCAm) genes, are determined by means of a 5 validated test method. The BRCA genes refer to BRCA1 and BRCA2 genes. Examples of Commercially Available Germline Genetic Tests and Somatic Tests for Prostate Cancer are provided herein below: A) Germline testing Test Company ^S Prostate-specific panel t_y ^a p^mple s or e hereditary cancer panels Multi-gene prostate panel: 14 genes USA) /saliva MSH6, NBN, PALB2, PMS2, RAD51D, and TP53) Color Color Genomics 30-gene panel including BRCA1, Hereditary (Burlingame, CA, Blood BRCA2, MLH1, MSH2, MSH6, Cancer Test USA) PMS2, EPCAM, CHEK2, TP53, ATM, and NBN Invitae Corpor Multi-gene prostate panel: 12 genes Invitae Prostate ation r Panel (San Fra Blood (ATM, BRCA1, BRCA2, CHEK2, Cance ncisco, CA, USA) /saliva EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PMS2, and TP53) Multi-gene prostate panel: 11 genes Prostate Gene ^G (_C ^e aⁿ m^eH b_r ^e i^a d^l g^th (BRCA1, BRCA2, HOXB13, MLH1, e_{, UK)} Blood MSH2, MSH6, PMS2, EPCAM, FoundationOne Foundation Medic Tumor 14 HRR pathway genes within 324 CDx ine Inc. (Cambridge, MA) biopsy gene panel FoundationOne Foundation Liquid CDx Medicine Inc. _Blood ^{14 prostate specific genes within 324} (Cambridge, MA) _{gene panel} Caris Molecular Caris Life Sciences Tumor Intelligence (Irving, TX) _biopsy ^NA Guardant Health Blood/ Guardant360 Inc. (Redwood Circulating tumo 70+ genes City, CA) r DNA The test or approved test may determine homologous recombination deficiency (HRD) positive biomarker status. HRD is also referred to as homologous recombination repair (HRR) gene defects or alterations and can result from DNA repair gene defects (DRD) in certain DNA repair genes. HRD or HRR gene alterations encompass DRD and also those gene mutations or alterations outside of the DNA-repair pathway. Said HRD –or HRR gene defects or deleterious alterations– positive status may be detected by evaluating monoallelic or biallelic, germline and/or somatic alterations in one or more DNA repair genes, or by evaluating genome-wide loss of heterozygosity (LOH), or homozygous deleterious changes in DNA repair genes. HRD –or HRR gene defects or alterations– positive status is also a synonym for PARP biomarker positive status. The deleterious or suspected deleterious DNA repair genes include, without being limited to, mutated BRCA2 (Breast Cancer gene 2), mutated BRCA1 (Breast Cancer gene 1), mutated ATM (ataxia-telangiectasia mutated), mutated BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1 gene), mutated CHEK2 (Checkpoint Kinase 2 gene), mutated FANCA (Fanconi Anemia Complementation Group A gene), mutated HDAC2 (Histone deacetylase 2), mutated PALB2 (Partner and Localizer of BRCA2 gene), or mutated CDK12 (Cyclin Dependent Kinase 12). The germline and/or somatic HRR gene alteration is determined by using a validated test method. HRR status may be preferably evaluated by either a plasma- (Resolution Bioscience) or tissue-based test (Foundation Medicine), particularly by detecting circulating plasma DNA or circulating tumor cells. A list of tests for determining germline and/or somatic HRR gene alterations is provided herein above and below. Gene expression profile analysis and protein biomarkers may also be used to risk-stratify patients with prostate cancer to guide treatment decisions. Commercially available tests include Prolaris® (Myriad Genetics, Salt Lake City, UT); OncotypeDx^® Prostate Cancer Assay (Genomic Health, Redwood City, CA); ProMark™ Protein Biomarker Test/ProMark™ Risk Score (Metamark Genetics, Cambridge, MA); FoundationOne^® CDx (Foundation Medicine, Cambridge, MA); FoundationOne^® Liquid CDx (Foundation Medicine, Cambridge, MA); Caris Molecular Intelligence (Caris Life Sciences, Irving, TX); Guardant360 (Guardant Health Inc., Redwood City, CA); ProstateNext® (Ambry Genetics, Aliso Viejo, CA); Color Hereditary Cancer Test (Color Genomics, Burlingame, CA); Invitae Prostate Cancer Panel (Invitae Corp., San Francisco, CA); Prostate Gene (GeneHealth, Cambridge, UK); Myriad myRisk® Hereditary Cancer Test (Myriad Genetics Inc., Salt Lake City, UT) and Decipher^® Prostate Cancer Test (GenomeDx Biosciences, San Diego, CA), this latter based on the expression pattern of 22 RNA markers in biopsy or radical prostatectomy specimens. Prolaris®, OncotypeDx^®, and Decipher^® are tissue-based gene expression tests. The test or approved test is run with samples obtained from prostate cancer patients. These samples may be circulating tumor cells (CTC), circulating tumor DNA, blood, tissue samples, tumor biopsies. Methods of Treatment and Medical Uses The methods for treating a prostate cancer, in particular BRCAm mCRPC, as determined by a test or an approved test, of the drug product or approved drug product comprise, consist of and/or consist essentially of, administering to a patient in need thereof administering the disclosed drug product or approved drug product to the patient in an amount and manner that is described in a drug product label or an approved drug product label for the product or approved product. It is to be understood that the method of treatment embodiments described herein encompass the use of a drug product or an approved drug product for the manufacture of a medicament and the drug product or approved drug product for use in a method of treatment. Thus, also described herein are uses of the drug product or approved drug product in the manufacture of a medicament for the treatment of BRCAm mCRPC in a patient, as determined by a test or an approved test, wherein the medicament is administered in an amount that is described in the drug product label or approved drug product label for said drug product or approved drug product. The methods for treating a prostate cancer, in particular BRCAm mCRPC, or the medical uses of the drug product or approved drug product comprise, consist of and/or consist essentially of, administering to a patient in need thereof the drug product or approved drug product, plus a glucocorticoid, for example prednisone or prednisolone in a clinically effective amount. Also disclosed are dosage regimens of the oral dosage forms disclosed herein, said dosage regimens comprising, consisting of and/or consisting essentially of, administering the two-drug combination, the dual combination, or FDC of niraparib and abiraterone acetate, plus a glucocorticoid, for example prednisone or prednisolone, in a total amount that is clinically effective for the treatment of prostate cancer in a human. The subject may be surgically castrated or chemically castrated. The patient may have undergone one or more other types of treatment for the prostate cancer prior to the first dose of the drug product or approved drug product plus prednisone. For example, the patient may have undergone taxane-based chemotherapy prior to administering the drug product or approved drug product plus prednisone. Additionally or alternatively, the patient may have undergone at least one line of androgen receptor-targeted therapy, such as apalutamide and/or enzalutamide, prior to administering the drug product or approved drug product plus prednisone. In an aspect, the patient does not respond initially or becomes refractory to previous treatments, prior to administering the drug product or approved drug product plus prednisone. The drug product or approved drug product plus prednisone may be administered once daily, at least 1 hour before a meal or at least two hours after a meal, in 2 tablets or 2 capsules comprising the two-drug combination, the dual combination, or FDC of niraparib and abiraterone acetate, and prednisone in a separate dosage form. In an aspect, 2 tablets or 2 capsules comprising the two-drug combination, the dual combination, or FDC of niraparib and abiraterone acetate are administered once daily, with water, on an empty stomach at least 1 hour before a meal or at least two hours after meal. In an aspect a glucocorticoid is administered once or twice daily. In an aspect prednisone or prednisolone tablets or capsules are administered once or twice daily. In an aspect, 1 or 2 tablets or capsules comprising the two-drug combination, the dual combination, or FDC of niraparib and abiraterone acetate are administered once daily and 1 or 2 tablets or capsules of a glucocorticoid, for example prednisone is administered once or twice daily. The regular once daily dosage of the drug product or approved product is about 200 mg of niraparib, about 500 mg of the abiraterone acetate, and about 10 mg of prednisone. The regular strength oral dosage form of the drug product or approved drug product comprises about 100 mg of niraparib and about 500 mg of the abiraterone acetate. As such, two oral dosage forms of the drug product or approved drug product are taken once daily, plus 10 mg of prednisone. These two oral dosage forms may be a film-coated tablet, a tablet, a capsule, a granule composition, or a sachet. Preferably, the oral dosage form is a film-coated tablet. For dose reduction in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non- hematological grade 3 or 4 adverse reactions; the once daily dosage of the drug product or approved drug product is reduced to about 100 mg of niraparib, about 1,000 mg of the abiraterone acetate, and about 10 mg of prednisone. The lower strength oral dosage form of the drug product or approved drug product comprises about 50 mg of niraparib and about 500 mg of the abiraterone acetate. As such, two oral dosage forms of the drug product or approved drug product are taken once daily, plus 10 mg of prednisone. These two oral dosage forms may be a film-coated tablet, a tablet, a capsule, a granule composition, or a sachet. Preferably, the oral dosage form is a film-coated tablet. The drug product or approved drug product of the present disclosure, and a separately administered glucocorticoid (e.g., prednisone, a prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or a prednisolone) may be administered to a patient having metastatic prostate cancer. In particular, the two-drug combination, the dual combination, or FDC drug product or approved drug product of the present disclosure, and a separately-administered glucocorticoid (e.g., prednisone, a prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or a prednisolone) may be administered to a patient having mCRPC, such as first-line (L1) mCRPC (e.g., subjects who have not been treated with any therapy in the metastatic castrate- resistant setting, except for ADT and a limited exposure to abiraterone acetate plus prednisone). The patient is positive for HRR alterations, preferably the patient is positive for BRCA alterations, as determined by a test or an approved test. The metastatic prostate cancer may be confirmed by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI). The patient may have castrate levels of testosterone ≤ 50 ng/dL and may be under ADT. The patient may continue with ADT. The patient may have an Eastern Cooperative Oncology Group Performance Score (ECOG PS) Grade of 0 or 1. The patient may be able to continue ADT therapy during the treatment with the drug product or approved drug product plus prednisone (or a prednisolone), if not surgically castrated (i.e., subjects who has not undergone bilateral orchiectomy). The patient may have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to 1. Also disclosed herein are kits including the drug product or approved drug product that comprises niraparib and abiraterone acetate, and optionally a separate composition that comprises prednisone or prednisolone, in particular BRCAm mCRPC, as determined by a test or an approved test. The instructions may provide instructions for administering the respective compositions once daily. For example, the instruction print may provide instructions for administering the drug product or approved drug product comprising niraparib and abiraterone acetate to a human patient having prostate cancer or BRCAm mCRPC on a once daily basis, and for administering the composition comprising prednisone or prednisolone to the human patient on a single or twice daily basis. The present disclosure further relates to a method for determining the bioequivalence of a test fixed-dose combination (FDC) formulation of niraparib and abiraterone acetate, relative to a drug product or an approved drug product of the present disclosure, said method comprising i) measuring a bioequivalence parameter of the test FDC formulation and optionally measuring a bioequivalence parameter of the drug product or approved drug product of the present disclosure, and ii) comparing the bioequivalence parameter of the test FDC formulation to the corresponding bioequivalence parameter of the drug product or approved drug product of the present disclosure. In an aspect, the bioequivalence parameter is selected from AUC(0-t), AUC(0-∞), residual area, Cmax and tmax, AUC(0-72h), terminal rate constant (λz), t1/2, AUC(0-τ), Cmax,ss, tmax,ss, Ae(0-t), and Rmax, which bioequivalence parameters are well known to the person skilled in the arts of bioequivalence and pharmacokinetics. Methods of Selling and Methods of Offering For Sale a Drug Product or an Approved Drug Product Provided herein are methods of selling a drug product or an approved drug product as disclosed herein, said method comprising selling such drug product or approved drug product, wherein a drug product label or an approved drug product label for a reference product for such drug product or approved drug product includes instructions for treating adult patients with BRCAm mCRPC, as determined with a test or an approved test. In some embodiments, the methods of selling comprise selling the generic, wherein a drug product or an approved drug product label for a reference product for the generic includes instructions for treating adult patients with BRCAm mCRPC, as determined with a test or an approved test. In another aspect, described herein are methods of selling the drug product or approved drug product of the disclosure comprising, consisting of, or consisting essentially of placing the drug product or approved drug product into the stream of commerce wherein said drug product or approved drug product is accompanied with a package insert that contains instructions for safely and effectively treating prostate cancer or BRCAm mCRPC using the drug product or approved drug product. Also provided herein are methods of offering for sale a drug product or an approved drug product, said method comprising offering for sale such drug product or approved drug product, wherein a drug product label or an approved drug product label for a reference product for such drug product or approved drug product includes instructions for treating adult patients with BRCAm mCRPC, as determined with a test or an approved test. In some embodiments, the methods of offering for sale comprise offering for sale the generic, wherein a drug product label or an approved drug product label for a reference product for the generic includes instructions for treating adult patients with BRCAm mCRPC, as determined with a test or an approved test. In still further aspects, described herein are methods of offering for sale the drug product or approved drug product comprising, consisting of, or consisting essentially of offering to place the drug product or approved drug product into the stream of commerce wherein said drug product or approved drug product is accompanied with a package insert that contains instructions for safely and effectively treating BRCAm mCRPC using the drug product or approved drug product. In some embodiments, the methods of selling comprise methods of selling a kit comprising a generic, said method comprising selling the generic, wherein a drug product label or an approved drug product label for a reference product for the generic includes instructions for treating a patient with BRCAm mCRPC, as determined by a test or an approved test. The disclosure further provides methods of offering for sale a kit comprising niraparib and abiraterone acetate, said method comprising offering for sale such kit, wherein the drug product label or approved drug product label for a reference product for niraparib and abiraterone acetate includes instructions for treating a patient with BRCAm mCRPC, as determined by a test or an approved test. Also described herein are methods comprising selling a kit comprising a generic or the drug product or approved drug product, wherein the drug product label or approved drug product label for a generic or the drug product or approved drug product comprises overall survival data, adjusted OS data, TSP, TCC, or rPFS data. Further embodiments Embodiment 1. An approved drug product with at least one indication approved by at least one of FDA, EMA, and Health Canada, wherein said approved drug product comprises niraparib and abiraterone acetate. Embodiment 2. The approved drug product of embodiment 1, wherein the at least one approved indication is metastatic castration resistant prostate cancer (mCRPC). Embodiment 3. The approved drug product of embodiment 1 or 2, wherein the approved drug product is indicated with prednisone for the treatment of a patient with deleterious or suspected deleterious BReast Cancer-mutated (BRCAm) mCRPC, as detected by an approved test. Embodiment 4. The approved drug product of embodiment 3, wherein the approved drug product is administered to deliver orally once daily a dosage of 200 mg of niraparib and 1,000 mg of abiraterone acetate, and is administered in combination with a daily dose of 10 mg of prednisone. Embodiment 5. The approved drug product embodiment 3, wherein the approved drug product is administered orally once daily with a reduced dosage of 100 mg of niraparib and 1,000 mg of abiraterone acetate, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. Embodiment 6. The approved drug product of any one of embodiments 3-5, wherein the approved drug product is administered on an empty stomach. Embodiment 7. The approved drug product of any one of embodiments 3-6, wherein food is not eaten two hours before and one hour after taking the approved drug product. Embodiment 8. The approved drug product of any one of embodiments 3-7, wherein the patient concurrently receives a gonadotropin-releasing hormone (GnRH) analog, or the patient has had bilateral orchiectomy. Embodiment 9. The approved drug product of embodiment 8, wherein the GnRH analog is selected from triptorelin, nafarelin, goserelin, leuprorelin or leuprolide, histrelin, gonadorelin, and buserelin. Embodiment 10. The approved drug product of any one of embodiments 3-9, wherein the approved drug product is not administered to a patient with moderate or severe hepatic impairment. Embodiment 11. The approved drug product of any one of embodiments 3-10, wherein the approved drug product is not co-administered with the CYP3A4 inducer rifampicin. Embodiment 12. The approved drug product of any one of the preceding embodiments, wherein said approved drug product comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and (i) 100 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (regular strength); or (ii) 50 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (lower strength). Embodiment 13. The approved drug product of any one of embodiments 4-12, wherein said approved drug product elicits a median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by an approved test. Embodiment 14. The approved drug product of embodiment 13, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from Prostate-Specific Antigen (PSA), Lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) grade, bone lesion number, and Visceral Disease. Embodiment 15. The approved drug product of any one of embodiments 4-14, wherein the approved drug product elicits an improved median Time to Symptomatic Progression (TSP) with a HR of 0.562 (95% CI: 0.371, 0.849) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by an approved test, when compared to a patient receiving placebo and abiraterone acetate plus prednisone. Embodiment 16. The approved drug product of any one of embodiments 4-15, wherein the approved drug product elicits an improved median Time to Cytotoxic Chemotherapy (TCC) with a HR of 0.598 (95% CI: 0.387, 0.924) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by an approved test, when compared to a patient receiving placebo and abiraterone acetate plus prednisone. Embodiment 17. The approved drug product of any one of embodiments 4-16, wherein the approved drug product elicits a median radiographic Progression Free Survival (rPFS) of 19.5 months with a HR of 0.553 (95%: 0.392, 0.782) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by an approved test. Embodiment 18. The approved drug product of any one of embodiments 1-17, wherein the approved drug product comprises 159.40 mg niraparib tosylate monohydrate equivalent to 100 mg niraparib free base as the active ingredient, and 500 mg of abiraterone acetate. Embodiment 19. The approved drug product of any one of embodiments 1-17, wherein the approved drug product comprises 79.70 mg niraparib tosylate monohydrate equivalent to 50 mg niraparib free base as the active ingredient, and 500 mg of abiraterone acetate. Embodiment 20. The approved drug product of any one of embodiments 12-19, wherein the pharmaceutical composition is an oral dosage form selected from a film-coated tablet, a tablet, a capsule, granules, and a sachet. Embodiment 21. The approved drug product of embodiment 20, wherein the pharmaceutical composition is a film-coated tablet further comprising colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, and sodium lauryl sulfate; and a film-coating. Embodiment 22. The approved drug product of embodiment 21, wherein the film-coated tablet comprises100 mg niraparib and 500 mg abiraterone acetate; and the film-coating comprises iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. Embodiment 23. The approved drug product of embodiment 21, wherein the film-coated tablet comprises 50 mg niraparib and 500 mg abiraterone acetate; and the film-coating comprises iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. Embodiment 24. The approved drug product of any one of the preceding embodiments, wherein the approved drug product is approved for marketing in the European Economic Area (EEA), or Canada. Embodiment 25. The approved drug product of any one of the preceding embodiments, wherein the approved drug product is a generic, an ANDA, a sNDA, an NDA product, or a 505(b)(2) drug product. Embodiment 26. A method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by an approved test, the method comprising administering the approved drug product as defined in any one of the preceding embodiments, in combination with prednisone, to said patient. Embodiment 27. The method for treating mCRPC of embodiment 26, wherein the method for treating comprises administering orally once daily the approved drug product that contains 200 mg of niraparib and 1,000 mg of abiraterone acetate, along with a separate daily dose of 10 mg of prednisone, until disease progression or unacceptable toxicity. Embodiment 28. The method for treating mCRPC of embodiment 26, wherein the method for treating comprises administering orally once daily a reduced dosage of the approved drug product that contains 100 mg of niraparib and 1,000 mg of abiraterone acetate, along with a separate daily dose of 10 mg of prednisone, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. Embodiment 29. The method for treating mCRPC of any one of embodiments 26-28, wherein the method for treating comprises the improvement of the median OS to 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). Embodiment 30. The method for treating mCRPC of embodiment 29, wherein the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. Embodiment 31. The method for treating mCRPC of any one of embodiments 26-30, wherein the treatment comprises the improvement of median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). Embodiment 32. The method for treating mCRPC of any one of embodiments 26-31, wherein the treatment comprises the improvement of median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). Embodiment 33. The method for treating mCRPC of any one of embodiments 26-32, wherein the treatment comprises the improvement of median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). Embodiment 34. A method of selling an approved drug product comprising niraparib and abiraterone acetate as defined in any one of embodiments 1-25, said method comprising selling such approved drug product. Embodiment 35. The method of selling of embodiment 34, wherein the approved drug product is a generic, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product. Embodiment 36. The method of selling of embodiment 34 or 35, wherein the reference listed drug for such approved drug product improves OS, rPFS, TCC, TSP, or TPP. Embodiment 37. The method of selling of embodiment 36, wherein the median OS is 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). Embodiment 38. The method of selling of embodiment 37, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. Embodiment 39. The method of selling of any one of embodiments 36-38, wherein the median TSP is improved with a HR of 0.562 (95% CI: 0.371, 0.849). Embodiment 40. The method of selling of any one of embodiments 36-39, wherein the median TCC is improved with a HR of 0.598 (95% CI: 0.387, 0.924). Embodiment 41. The method of selling of any one of embodiments 36-40, wherein the median rPFS is 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). Embodiment 42. A method of offering for sale an approved drug product comprising niraparib and abiraterone acetate as defined in any one of embodiments 1-25, said method comprising offering for sale such approved drug product. Embodiment 43. The method of offering for sale of embodiment 42, wherein the approved drug product is a generic, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product. Embodiment 44. The method of offering for sale of embodiment 42 or 43, wherein the reference listed drug for such approved drug product improves OS, rPFS, TCC, TSP, or TPP. Embodiment 45. The method of offering for sale of embodiment 44, wherein the median OS is 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). Embodiment 46. The method of offering for sale of embodiment 45, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. Embodiment 47. The method of offering for sale of any one of embodiments 44-46, wherein the median TSP is improved with a HR of 0.562 (95% CI: 0.371, 0.849). Embodiment 48. The method of offering for sale of any one of embodiments 44-47, wherein the median TCC is improved with a HR of 0.598 (95% CI: 0.387, 0.924). Embodiment 49. The method of offering for sale of any one of embodiments 44-48, wherein the median rPFS is 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). Embodiment 50. An approved drug product as defined in any one of preceding embodiments 1-25, for use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by an approved test, the method comprising administering said approved drug product, in combination with prednisone. Embodiment 51. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of embodiment 50, wherein the method for treating comprises administering orally once daily a dosage of 200 mg of niraparib and 1,000 mg of abiraterone acetate of the approved drug product, and 10 mg of prednisone, until disease progression or unacceptable toxicity. Embodiment 52. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of embodiment 50, wherein the method for treating comprises administering orally once daily a reduced dosage of 100 mg of niraparib and 1,000 mg of abiraterone acetate of the approved drug product, and 10 mg of prednisone, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. Embodiment 53. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of any one of embodiments 50-52, wherein the method for treating comprises the improvement of the median OS to 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). Embodiment 54. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of embodiment 53, wherein the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. Embodiment 55. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of any one of embodiments 50-54, wherein the treatment comprises the improvement of median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). Embodiment 56. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of any one of embodiments 50-55, wherein the treatment comprises the improvement of median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). Embodiment 57. The approved drug product as defined in any one of preceding embodiments 1-25, for the use in a method of any one of embodiments 50-56, wherein the treatment comprises the improvement of median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). Embodiment 58. An approved drug product comprising niraparib and abiraterone acetate, for use with prednisone or prednisolone in a method for the treatment of an adult patient with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated; wherein positive BRCA status is established with a validated test method; wherein the single daily dose of the approved drug product is 200 mg of niraparib and 1,000 mg of abiraterone acetate, and the daily dose of prednisone or prednisolone is 10 mg, until disease progression or unacceptable toxicity; characterized in that the treatment comprises an improvement of the median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120). 59. The approved drug product for the use of embodiment 58, wherein the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. 60. The approved drug product for the use of embodiments 58 or 59, wherein the treatment comprises an improvement of the median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). 61. The approved drug product for the use of any one of embodiments 58-60, wherein the treatment comprises an improvement of the median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). 62. The approved drug product for the use of any one of embodiments 58-61, wherein the treatment comprises an improvement of the median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). The present disclosure is further defined in the following examples which include unexpected and advantageous results. It should be understood that these examples, while indicating preferred embodiments of the disclosure, are given by way of illustration only, and should not be construed as limiting the appended claims. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions. EXAMPLES Example 1 – Final Analysis of the MAGNITUDE study with efficacy results for the Cohort 1 BRCA subgroup (comprised of 225 subjects: 113 subjects in the niraparib + AAP group and 112 subjects in the placebo + AAP group) and safety results for the Cohort 1 All HRR population. Updated Cohort 3 results are also summarized in this Example. STUDY DESIGN The MAGNITUDE study was a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of niraparib 200 mg in combination with abiraterone acetate (AA) 1,000 mg plus prednisone 10 mg daily, compared with placebo and abiraterone acetate plus prednisone (AAP) in subjects with metastatic castration-resistant prostate cancer (mCRPC). Subjects were prospectively enrolled into Cohort 1 or Cohort 2 based on the presence or absence of homologous recombination repair (HRR) gene alterations. In addition, after completion of enrollment into Cohorts 1 and 2, a separate open-label cohort, Cohort 3, was enrolled to obtain clinical experience with the fixed dose combination (FDC) tablet formulation of niraparib and AA given with prednisone. Study population Male subjects over the age of 18 years with mCRPC with or without HRR gene alterations who had not been treated in the metastatic castration-resistant setting, except for limited exposure to AAP and ongoing ADT, were eligible for the study. • Cohort 1: Subjects with HRR gene alterations - Alterations in BRCA1, BRCA2, ATM, BRIP1, CDK12, CHEK 2, HDAC2, FANCA, or PALB2 genes. • Cohort 2: Subjects without HRR gene alterations - This cohort met futility criteria as described below. • Cohort 3: Subjects with HRR gene alterations - Same gene alterations as listed for Cohort 1. All subjects were enrolled after testing for HRR gene alterations using the Foundation One CDx tissue assay, Resolution HRD plasma assay, Amoy Dx blood and tissue assay (China only), or an accredited local laboratory biomarker test with central review demonstrating a pathogenic germline or somatic alteration. Randomization Subjects were randomly assigned in a 1:1 ratio to receive niraparib + AAP or placebo + AAP and stratified by: past taxane-based chemotherapy exposure (yes versus no); past AR-targeted therapy exposure in the mHSPC or nmCRPC setting (enzalutamide or apalutamide versus no exposure); and prior AAP use in mCRPC (yes versus no). Cohort 1 was additionally stratified by gene mutation group (BRCA1 or BRCA2 versus all other HRR gene alterations). Treatment duration / Trial duration The study consisted of a Prescreening Phase for biomarker evaluation only, a Screening Phase, a Treatment Phase, and a Follow-up Phase for collection of secondary endpoints. Treatment was continuous until unequivocal clinical progression, unacceptable toxicity, death, or sponsor termination of the study. Treatment could be discontinued upon determination of radiographic progression per central radiology review. Primary Objective: ^ To evaluate the effectiveness of niraparib and AAP compared to AAP and placebo Secondary Objectives: ^ To assess the clinical benefit of niraparib and AAP compared to AAP and placebo ^ To characterize the safety profile of niraparib when given with AAP compared to AAP with placebo Primary efficacy variable Radiographic progression-free survival (rPFS) assessed by blinded central review (BICR), defined as the time interval from the date of randomization to the first date of radiographic progression by BICR or death due to any cause, whichever occurs first. Major secondary efficacy variables ^ Time to symptomatic progression (TSP) defined as the time from randomization to the first of any of the following: o external beam radiotherapy (EBRT) o tumor-related orthopedic surgical intervention o cancer-related procedures (e.g., nephrostomy insertion, or surgery for tumor symptoms other than skeletal) o initiation of a new systemic anti-cancer therapy because of cancer pain o cancer-related morbid events (e.g., fracture, cord compression, urinary obstruction) ^ Time to cytotoxic chemotherapy (TCC) ^ Overall survival (OS) Primary analysis set for efficacy Data from randomized subjects in Cohort 1 were used in the efficacy analysis for Cohort 1. Study Drug Information All study treatments were provided directly by the Sponsor. For Cohorts 1 and 2, niraparib was provided as 100 mg capsules for oral administration. Placebo for niraparib was provided as a capsule formulation and was matched in size, color, and shape to maintain the study blind. AA was provided as 250 mg tablets for oral administration, and prednisone was provided as 5 mg tablets for oral administration. For Cohort 3, niraparib/AA FDC was provided as regular strength tablets containing 100 mg niraparib/500 mg AA per tablet. Prednisone was provided as 5 mg tablets for oral administration. Low strength (LS) FDC tablets containing 50 mg/500 mg niraparib/AA per tablet were also available if dose modifications for niraparib were needed. For subjects needing to discontinue 1 of the drugs due to toxicity, single dose niraparib was available as 100 mg capsules and AA was available as 250 mg tablets, both for oral administration. Dosage and Administration Subjects in Cohorts 1 and 2 were randomized in a 1:1 ratio to receive either 200 mg niraparib, 1,000 mg AA, and 10 mg prednisone (nira+AAP) and or matching placebo, 1,000 mg AA, and 10 mg prednisone (PBO+AAP) daily. Subjects in Cohort 3 received 200 mg niraparib/1,000 mg AAP (referred to hereafter as FDC) and 10 mg prednisone daily (FDC+P). The study treatments were to be taken in the morning on an empty stomach without food being consumed for at least 2 hours before and for at least 1 hour after dosing. The study treatments were swallowed whole with water. Study treatments were administered together, except for prednisone, which was taken twice daily. If a subject forgot to take the study treatment(s) at the regular time, then the missed dose(s) were only to be replaced if remembered within the same day. Background therapy with a GnRHa for patients who had not previously undergone surgical castration was mandatory to maintain castrate concentrations of testosterone (≤50 ng/dL). The choice of GnRHa was at the discretion of the investigator. Dose and dose schedule (without interruption) were to be consistent with the prescribing information for the GnRHa agent that was used and were only to be adjusted if clinically indicated to maintain castrate concentrations of testosterone. Prohibited Concomitant Medications The following medications/therapies were prohibited during the study: • Investigational agents other than the study treatments • Other anti-cancer therapies • Other agents that targeted the androgen axis (eg, antiandrogens such as enzalutamide and apalutamide, or CYP17 inhibitors such as ketoconazole) • Testosterone • Radiotherapy for tumor progression. Subjects may had received palliative radiotherapy in selected cases after discussion with Sponsor. • Chemotherapy • Immunotherapy • Diethylstilbestrol or similar estrogen receptor agonists • Pomegranates and pomegranate juice • Spironolactone • Radiopharmaceuticals such as radium-223, strontium, or samarium • Strong inducers of CYP3A4 (e.g., rifampin) Restricted Concomitant Medications Based on the drug interaction potential of niraparib/AAP, use of the following medications was restricted: • Substrates of CYP2D6: Caution was advised when AA was to be administered with medicinal products activated by or metabolized by CYP2D6, particularly with medicinal products that had a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that were metabolized by CYP2D6 were to be considered. • Substrates of CYP2C8: In a CYP2C8 drug-drug interaction study in healthy subjects, the AUC of pioglitazone was increased by 46% when pioglitazone was administered with a single dose of 1,000 mg AA. Although no clinically meaningful increases in exposure were demonstrated when AA was combined with drugs that were predominantly eliminated by CYP2C8, subjects were to be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with AA. Inclusion Criteria Subjects were required to meet the following key inclusion criteria: 1. Had HRR gene alteration status (as identified by the Sponsor’s required assays or local testing for HRR gene alteration) as follows: a. Cohort 1: positive for HRR gene alteration b. Cohort 2: not positive for HRR gene alteration (i.e., no HRR gene alteration) c. Cohort 3: positive for HRR gene alteration 2. Had metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI. 3. Had metastatic prostate cancer in the setting of castrate levels of testosterone ≤50 ng/dL on a GnRHa or bilateral orchiectomy as evidenced by PSA progression or radiographic progression. 4. Were able to continue GnRHa during the study if not surgically castrate. 5. Had ECOG Performance Score Grade of 0 or 1. 6. Had score of ≤3 on the BPI-SF Question #3 (worst pain in last 24 hours). 7. Clinical laboratory values at Screening: a. ANC ≥1.5 x 10⁹/L. b. Hemoglobin ≥9.0 g/dL, independent of transfusions for at least 30 days. c. Platelet count ≥100 x 10⁹/L. Exclusion Criteria Subjects were not to be enrolled into the study if it was determined upon pre-study examination that they met any of the following key exclusion criteria: 1. Had prior treatment with a PARP inhibitor. 2. Had systemic therapy (i.e., novel second generation AR targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or more than 4 months of AAP prior to randomization) in the mCRPC setting; or AAP outside of the mCRPC setting. 3. Subjects who had received 2 to 4 months of AAP prior to randomization for the treatment of mCRPC should have had no evidence of progression by PSA (per PCWG3) during screening. These potential subjects were required to have 2 PSA values during the Prescreening and Screening Phases. The second PSA value was to be within 2 weeks of randomization and PSA rise was thought to be due to flare, the Investigator was to confirm that there was no radiographic progression. 4. Had presence of uncontrolled hypertension (persistent systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg). Subjects with a history of hypertension were allowed if BP was controlled to within these limits by anti-hypertensive treatment. 5. Subjects who had the following ≤ 28 days prior to randomization: a. A transfusion (platelets or red blood cells). b. Hematopoietic growth factors. c. An investigational agent for prostate cancer. d. Major surgery (Sponsor should be consulted regarding what constitutes major surgery). e. Radiation therapy Expected effect size and planned sample size Cohort 1: Approximately 400 subjects with mCRPC and HRR gene alterations were to be randomized 1:1 to receive nira+AAP or PBO+AAP in order to observe approximately 220 rPFS events and to provide 87% power to detect a difference at a 2-sided level of significance of 0.05, assuming a HR of 0.65. Approximately 50% of subjects were to have BRCA1 or BRCA2 (BRCA) alterations to yield, approximately 102 rPFS events in the BRCA subgroup and provide 93% power to detect difference assuming a HR of 0.50 at a 2-sided level of significance of 0.05. Cohort 2: Approximately 600 subjects with mCRPC and without an HRR gene alteration were to be randomized 1:1 to receive nira+AAP or PBO+AAP if futility was not met. The pre- planned futility analysis for this cohort wasperformed with 247 subjects enrolled (the 14 subjects with CDK12 alterations were excluded from the futility analyses). Enrollment into Cohort 2 was stopped as futility was met. Subjects were unblinded (except for the 14 subjects with CDK12 alterations) and given the opportunity to either continue nira+AAP, niraparib (if AAP was discontinued due to toxicity) or discontinue nira+AAP and receive AAP alone, per the Principal Investigator’s discretion based on a benefit and risk assessment.. Cohort 3: Approximately 100 subjects with HRR gene alterations (with approximately half having BRCA alterations) were to be enrolled into cohort 3. Futility analysis for Cohort 2 The pre-planned futility analysis for Cohort 2 was performed on 13 August 2020 with 247 subjects enrolled and when 113 composite progression events (the first of either PSA progression or radiographic progression or death) had been observed (40 rPFS events and 73 PSA events). With an HR = 1.087, 95% CI (0.751, 1.571) for the composite progression endpoint, the pre-specified criteria for futility of HR > 1 was met and futility was declared for this cohort. At the time of futility analysis, time to PSA progression analysis (83 PSA events, HR = 1.03295% CI (0.671, 1.588) and rPFS analysis were also performed (65 rPFS events, HR = 1.027, 95% CI (0.631, 1.671). The Independent Data Monitoring Committee (IDMC) recommended that “therapy/registration for this cohort of subjects may be discontinued.” The Sponsor committee accepted the IDMC’s recommendation, enrollment was stopped, and the Cohort was unblinded. Subjects in Cohort 2 who had CDK12 mutations were excluded from the futility analysis and remained blinded. These subjects were to be included in sensitivity analysis with those prospectively randomized to Cohort 1 as part of amendment 3. Subjects who were unblinded were given the option to continue niraparib or continue with AAP alone. Subjects continued to be followed for safety. Statistical Testing Strategy of the Primary Endpoint The primary endpoint of the study, rPFS, is defined as the time interval from the date of randomization to the first date of radiographic progression as assessed by blinded independent central review (BICR) or death due to any cause, whichever occurs first. BICR was evaluated using chest, abdomen, and pelvis CT or MRI scans and whole-body bone scans (^99mTc). Given that Cohort 2 met futility, the overall statistical approach was to test the primary endpoint of rPFS with full alpha of 0.05 in Cohort 1. Within Cohort 1, rPFS was to be tested in the BRCA subgroup of Cohort 1 first at alpha=0.05 (2-sided). If the result was statistically significant, then rPFS in the full Cohort 1 was to be tested at alpha = 0.05 (2-sided) based on the pre- defined testing hierarchy. The analysis of rPFS for the non-BRCA subgroup in Cohort 1 was pre-planned in the SAP although no formal statistical testing procedure was implemented with alpha allocation to this analysis. Interim analysis for Secondary Endpoints Two interim analyses (IAs) and one final analysis were planned for the major secondary endpoints through a group sequential design method: overall survival (OS), time to symptomatic progression (TSP) defined as the need to initiate: EBRT for skeletal symptoms, tumor-related orthopedic surgical intervention, other cancer-related procedures (for example: nephrostomy insertion, bladder catheter insertion, EBRT, or surgery for tumor symptoms other than skeletal), new systemic anti-cancer therapy because of cancer pain or having cancer- related morbid events (for example: fracture, symptomatic and/or pathologic, cord compression, urinary obstructive events) and time to cytotoxic chemotherapy (TCC) in Cohort 1. If the result of rPFS in Cohort 1 was statistically significant, then the three secondary endpoints were to be tested simultaneously allowing for alpha recycling through the group sequential design method. Analysis Methods Estimates of the time-to-event endpoints were obtained using the Kaplan-Meier estimates of the survival distributions and a stratified Cox model was used to obtain the HR along with the associated 95% confidence intervals. The testing of these other efficacy endpoints was based on the stratified log rank test. ORR and PSA response rate was summarized by descriptive statistics (count and percentage) by the treatment group. The relative risk will be reported along with the corresponding two- sided 95% CI. The two treatment groups were compared by using the chi-square test; Fisher’s exact test could be used if the expected counts in some of the cells are less than 5. STUDY RESULTS Summary of Interim Analyses 1 (IA1) and 2 (IA2) At the primary analysis of rPFS (IA1 for secondary endpoints; clinical cut-off (CCO) date of 8 October 2021, median follow-up: 18.6 and 16.7 months for Cohort 1 and the BRCA subgroup, respectively), both the pre-defined BRCA subgroup and All HRR population (Cohort 1) demonstrated statistically significant and clinically meaningful improvement in rPFS with niraparib + AAP. At IA2 (CCO 17 June 2022, median follow-up: 26.8 and 24.8 months for Cohort 1 and the BRCA subgroup, respectively), a statistically significant and clinically meaningful prolongation in TSP was observed in the All HRR population, as well as a clinically meaningful prolongation of TSP in the BRCA subgroup. Treatment with niraparib + AAP also resulted in a prolongation in TCC in the All HRR population and BRCA subgroup. (Table 1). Table 1: Results for rPFS, TSP and TCC at PA-IA1 and IA2 for All HRR and BRCA Placebo+AAP Niraparib+AAP Analysis Timepoint Event/N Median Median HR (95% CI)^* P-value^** rPFS All HRR PA-IA1 217/423 13.7 16.5 0.729 (0.556, 0.956) 0.0217^# IA2 264/423 13.7 16.7 0.760 BRCA PA-IA1 109/225 10.9 16.6 0.533 IA2 135/225 10.9 19.5 0.553 TSP All HRR PA-IA1 116/423 NE NE 0.686 IA2 137/423 30.6 NE 0.596 BRCA PA-IA1 67/225 19.8 NE 0.683 IA2 82/225 23.6 NE 0.544 (0.347,0.853) 0.0071^## TCC All HRR PA-IA1 97/423 26.0 NE 0.588 (0.389,0.889) 0.0108 IA2 134/423 NE NE 0.666 (0.471,0.942) 0.0206 BRCA PA-IA1 55/225 26.0 NE 0.578 (0.332,1.006) 0.0495^## IA2 72/225 27.3 NE 0.558 (0.346,0.900) 0.0152^## OS All HRR IA2 179/423 32.2 29.3 1.010 (0.751,1.357) 0.9480 BRCA IA2 92/225 28.6 29.3 0.881 (0.582,1.335) 0.5505^{## * **} HR estimates are from Stratified Cox Proportional Hazard model. ^# P-values are based on stratified log-rank test. ^## Statistically significant Nominal p-value As shown in Table 1 above, at IA2 a HR of 0.881 was observed for OS in the BRCA subgroup. The multivariate analysis, which accounts for imbalances in subject baseline characteristics, indicated that treatment with niraparib + AAP is associated with a favorable survival with a HR=0.682; 95% CI: 0.445, 1.046. Data in the All HRR population remained confounded by imbalances in baseline characteristics, with the multivariate analysis (HR=0.815; 95% CI: 0.603, 1.101) strongly suggesting no detriment in OS with niraparib + AAP treatment. Summary of Final Analysis (FA) for OS (CCO date: 15 May 2023) The pre-specified final analysis as per the SAP occurred when approximately 246 OS events (deaths) in Cohort 1 were observed. Given BICR for scans was discontinued after IA2, rPFS analyses were not updated at FA but all the secondary endpoints were evaluated in the All HRR population and the BRCA subgroup with more mature data. Analyses of PROs for the BRCA subgroup are also presented in this report as are the updated safety data. All p-values are 2-sided per SAP, and p-values for the analyses of the secondary endpoints at FA in the BRCA population are nominal. Cohort 1, Final Efficacy Analysis (BRCA Subgroup) At the time of the FA CCO (15 May 2023), the median duration of follow-up for BRCA subjects in Cohort 1 was 35.9 months (11.1 additional months of follow-up since IA2).240 deaths were observed in the Cohort 1 All HRR population (98% of the planned number of events for the FA per the SAP), with 130 deaths in the BRCA subgroup. BRCA subjects in the niraparib + AAP group received a median of 20.5 months of treatment vs a median of 14.4 months in the placebo + AAP group. As no formal statistical testing had been planned for secondary endpoints in the BRCA subgroup, nominal p-values are presented for descriptive purposes. Overall Survival (OS) for the BRCA Subgroup In the BRCA subgroup, more deaths were observed in the placebo + AAP group (70/112, 62.5%) compared to the niraparib + AAP group (60/113, 53.1%). The OS at FA demonstrates a strong trend (p=0.1828) toward improved OS with niraparib + AAP treatment in subjects with BRCA alterations (HR=0.788; 95% CI: 0.554, 1.120), with clear separation of the Kaplan Meier curves between the treatment groups with longer follow-up (Figure 1). Median OS was 30.4 months in the niraparib + AAP group and 28.6 months in the placebo + AAP group. Multivariate Analysis of OS for the BRCA Subgroup Imbalance of baseline characteristics between treatment groups: As noted in the IA2 Clinical Study Report (CSR), several key baseline factors known to be predictors for survival (Armstrong 2020; Halabi 2014; Lin 2009) were imbalanced between the treatment groups, potentially disadvantaging the niraparib + AAP group. These imbalances include: ^ A higher proportion of subjects with baseline ECOG PS score of 1 in the niraparib + AAP group (38.7%) compared to the placebo + AAP group (30.8%) ^ A higher proportion of subjects ≥75 years of age in the niraparib + AAP group (29.7%) compared to the placebo + AAP group (23.2%) ^ A higher proportion of subjects with bone lesions at the time of randomization in the niraparib + AAP group (86.3%) compared to the placebo + AAP group (80.6%) ^ A higher proportion of subjects with visceral disease at the time of randomization in the niraparib + AAP group (24.1%) compared to the placebo + AAP group (18.5%) The validated prognostic model developed by Halabi et al (2014) utilizing 8 identified prognostic factors (opioid use, disease site, ECOG performance score, LDH, albumin, hemoglobin, alkaline phosphatase, and PSA) was used to calculate a composite risk score for each subject. The median scores along with the interquartile ranges, presented in Table 2 below, show consistently higher risk scores for subjects in the niraparib + AAP group in the BRCA subgroup, confirming the imbalance of prognostic factors disfavoring niraparib + AAP. This analysis highlights the importance of a multivariate analysis that adjusts for important prognostic factors. Table 2: Summary of Halabi Prognostic Risk Score Population Median Risk Score (IQR) Cohort 1 – BRCA (N=225) Placebo + AAP Niraparib + AAP 0.69 (0.56, 0.89) 0.75 (0.58, 1.08) Multivariate Analysis results A prespecified multivariate Cox regression analysis of OS in the BRCA subgroup adjusting for externally validated, clinically relevant baseline prognostic factors (Halabi 2014, Guinney 2017, Sartor 2018) was performed as per the SAP and showed improvement in OS (HR=0.663; 95% CI: 0.464, 0.947) favoring treatment with niraparib + AAP treatment (Table TEFOS08_BRCA below). A forest plot of OS by pre-defined subgroups for the BRCA subgroup is presented in Figure 2. Generally consistent results in favor of niraparib + AAP were observed with only the HR point estimates greater than 1 for subjects with prior taxane-based chemotherapy, prior AAP use, presence of visceral metastases and higher PSA. Time to Symptomatic Progression (TSP) and Time to Initiation of Cytotoxic Chemotherapy (TCC) for the BRCA Subgroup The updated analysis of TSP at FA confirms a consistent and clinically meaningful improvement in TSP in subjects treated with niraparib + AAP compared to placebo + AAP in the BRCA subgroup (HR=0.562; 95% CI: 0.371, 0.849). Separation in the Kaplan Meier curves was seen early and widened over time, favoring treatment with niraparib + AAP (Figure 3a); median TSP was not reached for the niraparib + AAP group whereas the median TSP in the placebo + AAP group was 21.7 months. The updated analysis of TCC at FA continued to show delayed TCC in BRCA subjects receiving niraparib + AAP (HR=0.598; 95% CI: 0.387, 0.924). Similar to TSP, separation in the Kaplan Meier curves was seen early and widened over time, favoring the niraparib + AAP group (Figure 3b); median TCC was not reached in the niraparib + AAP group and was 28.2 months in the placebo + AAP group. Table 3: TSP and TCC at FA for the BRCA Subgroup Placebo+AAP Niraparib+AAP Event/N Median Median HR (95% CI)^* P-value^** TSP 96/225 21.7 months NE 0.562 (0.371, 0.849) 0.0056 TCC 86/2 *25 28.2 months NE 0.598 (0.387, 0.924) 0.0192 *^* HR estimates are from Stratified Cox Proportional Hazard model. P-values are based on stratified log-rank test. TCC in the All HRR population did not cross the prespecified significance boundary at FA. However, a clinically meaningful improvement was observed. Subsequent Therapies for Prostate Cancer in BRCA Subgroup More BRCA subjects in the placebo + AAP group received subsequent therapy for prostate cancer compared to the niraparib + AAP group at the FA. Chemotherapy was the most common subsequent therapy received in both treatment groups; subsequent PARP inhibitor use was more frequent in the placebo + AAP group (Table 4; Table TEFSUBTX02_BRCA below). Table 4: Summary of selected subsequent therapy for prostate cancer, Cohort 1 BRCA subgroup Placebo + AAP Niraparib + AAP N=112 N=113 Number of subjects with selected subsequent 75 (67.0%) 48 (42.5%) therapy for prostate cancer Chemotherapy 51 (45.5%) 35 (31.0%) PARP inhibitor 30 (26.8%) 4 (3.5%) 180 subjects (80%) in the BRCA subgroup had discontinued treatment by the time of FA CCO. Of these subjects, 146 discontinued treatment due to progressive disease: 60/113 (53.1%) in the niraparib + AAP group and 86/112 (76.8%) in the placebo + AAP group. In subjects who discontinued study treatment due to progressive disease, a higher proportion of placebo + AAP treated subjects received PARP inhibitors compared to subjects treated with niraparib + AAP (niraparib + AAP: 3/60 [5.0%]; placebo + AAP: 29/86 [33.7%]). The proportion of subjects who received subsequent chemotherapy following treatment discontinuation for progressive disease was similar in the 2 treatment groups (niraparib + AAP: 34/60 [56.7%]; placebo + AAP: 51/86 [59.3%]), indicating that treatment with niraparib + AAP did not preclude subjects with progressive disease from receiving subsequent chemotherapy. (Table TEFSUBTX02PD_BRCA below). Patient-Reported Outcomes for BRCA Subgroup Updated patient-reported outcome analyses in the BRCA subgroup demonstrated that the efficacy benefits of niraparib + AAP were achieved along with prolongation in time to pain progression. In the BRCA subgroup, the median time to clinically meaningful BPI-SF worst pain progression was not reached in subjects who received niraparib + AAP vs a median of 32.2 months in those who received placebo + AAP (HR=0.809; 95% CI: 0.524, 1.249; p=0.3378). Median time to BPI-SF pain interference progression was not reached in niraparib + AAP group and was 41.5 months in placebo + AAP group (HR=0.771; 95% CI: 0.481, 1.234; p=0.2778). Cohort 1, Final Safety Analysis (All HRR Population) All Cohort 1 subjects who received at least 1 dose of study treatment were included in the safety analyses. At FA CCO, subjects in Cohort 1 who were randomized to niraparib + AAP received a median of 20.2 months of treatment vs a median of 15.2 months for subjects randomized to placebo + AAP. The overall safety profile remained consistent with IA2 and the 4-month Safety Update (4MSU), with no new safety signals identified with additional treatment exposure. The overall summary of Treatment Emergent Adverse Events (TEAE) for Cohort 1 is presented in Table 6. The higher rates of Adverse Events (AE) observed in the niraparib + AAP group continue to be largely driven by the known hematologic AEs associated with niraparib. The most common TEAEs in the niraparib + AAP group remained unchanged since IA2, and the overall side-effect profile of the niraparib + AAP regimen remained manageable. There was a small numerical increase in Grade 3-4 TEAEs and Serious Adverse Events (SAE) reflecting the increased exposure to study treatment since IA2 and the 4MSU. Moreover, the safety profile observed in the BRCA subgroup treated with niraparib + AAP is consistent with the safety profile of the All HRR population in Cohort 1 (tables with updated adverse reaction rates and laboratory abnormalities observed in the BRCA subgroup are provided in Table TSFAE07_modified below). Table 6: Overall Safety Profile for Cohort 1 (All HRR) FA IA2 CCO=15May2023 CCO=17Jun2022 Placebo + AAP Niraparib + AAP Placebo + AAP Niraparib + AAP (N=211) (N=212) (N=211) (N=212) All TEAEs 205 (97.2%) 212 (100.0%) ^{203 (96.2%) 211 (99.5%)} Grade 3-4 treatment 108 (51.2%) 157 (74.1%) 104 (49.3%) 153 (72.2%) emergent adverse events (TEAEs) TEAEs leading to treatment 17 (8.1%) 39 (18.4%) 15 (7.1%) 32 (15.1%) discontinuation Serious AEs (SAE) 65 (30.8%) 100 (47.2%) 61 (28.9%) 93 (43.9%) Drug-related 8 (3.8%) 29 (13.7%) 8 (3.8%) 26 (12.3%) TEAEs leading to death 10 (4.7%) 22 (10.4%) 9 (4.3%) 20 (9.4%) Adverse events (all grades) 136 (64.5%) 179 (84.4%) 132 (62.6%) 178 (84.0%) of special interest Anemia 48 (22.7%) 111 (52.4%) 48 (22.7%) 106 (50.0%) Hypertension 49 (23.2%) 72 (34.0%) 47 (22.3%) 70 (33.0%) Thrombocytopenia 20 (9.5%) 51 (24.1%) 20 (9.5%) 49 (23.1%) Neutropenia 15 (7.1%) 34 (16.0%) 15 (7.1%) 32 (15.1%) Arrhythmia 16 (7.6%) _{28 (13.2%)} 16 (7.6%) 29 (13.7%) Cardiac failure 4 (1.9%) 6 (2.8%) 4 (1.9%) 5 (2.4%) Hepatotoxicity 27 (12.8%) 30 (14.2%) 27 (12.8%) 27 (12.7%) Cerebrovascular 5 (2.4%) 7 (3.3%) 4 (1.9%) 7 (3.3%) disorders Ischaemic heart disease 10 (4.7%) 11 (5.2%) 9 (4.3%) 9 (4.2%) Acute myeloid leukemia 1 (0.5%) 0 1 (0.5%) 0 K a ey: AAP = abiraterone acetate plus prednisone, AE = adverse event An AE is categorized as related if assessed by the investigator as related to niraparib, abiraterone acetate or p brednisone. cAEs leading to death are based on AE outcome of Fatal. An AE is counted as leading to discontinuation of study agent if it leads to withdrawal of niraparib, abiraterone acetate or prednisone. TEAEs Leading to Death There were 22 subjects (10.4%) in the niraparib + AAP group compared to 10 subjects (4.7%) in the placebo + AAP group in Cohort 1 with AEs leading to death at FA CCO (20 [9.4%] and 9 [4.3%] in the niraparib + AAP and placebo + AAP groups, respectively, at IA2). While the most common TEAE leading to death in both treatment groups was COVID-19, there have been no deaths due to COVID-19 since IA2. Adverse Events of Special Interest More subjects in the niraparib + AAP group experienced an adverse event of special interest (AESI) compared to the placebo + AAP group in Cohort 1 (Table 6). Similar to IA2 and the 4MSU, the higher frequency of AESIs in the niraparib + AAP group were driven largely by hematological toxicities, which were manageable with dose modifications and supportive care, and most subjects were able to continue treatment with niraparib + AAP. The overall incidence of other AESIs was similar to what was reported at IA2 and 4MSU, including cardiac disorders and hypertension. No cases of MDS or AML have been reported in the niraparib + AAP group (one subject with a TEAE of AML was observed in the placebo + AAP group at IA1). Dose Modifications More AEs leading to dose modifications were observed in the niraparib + AAP group compared to the placebo + AAP group in the Cohort 1 All HRR population (Table 7). The increase in the number of subjects with AEs leading to niraparib dose interruptions since IA2 reflects the increased exposure to study treatment between the IA2 and FA CCO; the most common AEs leading to niraparib dose interruptions in the niraparib + AAP group remain the same (anemia: 49 [23.1%], followed by thrombocytopenia: 24 [11.3%]. The number of subjects with AEs leading to dose reduction of niraparib or placebo remains the same since IA2, and again anemia and thrombocytopenia are the most common AEs leading to niraparib dose reductions in the niraparib + AAP group. Compared to IA2, 9 additional subjects at FA CCO had AEs leading to niraparib or placebo discontinuation (7 in the niraparib + AAP group, 2 in the placebo + AAP group); however, the majority of subjects in both groups continued study treatment until progressive disease or still remain on study treatment. Table 7: Dose modifications and treatment discontinuation of niraparib or placebo at FA and IA2 FA CCO IA2 CCO Placebo + AAP Niraparib + AAP Placebo + AAP Niraparib + AAP N=211 N=212 N=211 N=212 AEs leading to dose 60 (28.4%) 109 (51.4%) 58 (27.5%) 104 (49.1%) interruption of niraparib or placebo AEs leading to dose 8 (3.8%) 43 (20.3%) 8 (3.8%) 43 (20.3%) reduction of niraparib or placebo AEs leading to 14 (6.6%) 39 (18.4%) 12 (5.7%) 32 (15.1%) discontinuation of niraparib or placebo Cohort 3 Final Analysis Cohort 3 was enrolled after Cohorts 1 and 2 completed enrollment and consists of 95 subjects with HRR gene alterations who all received open-label FDC tablets (niraparib/AA) plus prednisone. Cohort 3 provided clinical experience with the FDC tablet formulation, and no formal hypotheses for efficacy were tested. At the time of FA CCO, 19 BRCA subjects (36.5%) remained on study treatment. The most common reason for treatment discontinuation was progressive disease (24 subjects [46.2%]); few subjects discontinued due to an AE (6 subjects [11.5%]). Overall, the safety profile seen in Cohort 3 subjects treated with niraparib/AA FDC plus prednisone is consistent with the safety profile of niraparib + AAP SAC in the Cohort 1 All HRR population and in the BRCA subgroup. With a median treatment duration of 19.5 months in Cohort 3, no new safety signals were identified, and similar patterns of AE reporting were seen in Cohort 3 subjects as in the niraparib + AAP group of Cohort 1. Conclusions Statistically significant and clinically meaningful improvement were observed for the primary endpoint of rPFS at the primary analysis (PA-IA1) in both the BRCA subgroup and All HRR population in Cohort 1. This final analysis demonstrates a strong trend toward improved OS with niraparib + AAP in the BRCA subgroup (HR=0.788; 95% CI: 0.544, 1.120; p=0.1828), with continued, clear separation of the Kaplan Meier curves, despite the higher proportion of subjects in the placebo + AAP group receiving subsequent therapy with approved life-prolonging agents, particularly taxane-based chemotherapies and PARP inhibitors. These results, further supported by the consistent and clinically meaningful improvement for both TSP and TCC, clearly demonstrate the benefit of niraparib +AAP as first-line therapy in mCRPC patients with BRCA gene alterations. Evaluation of prognostic risk factors between the two treatment groups demonstrates an imbalance favoring placebo + AAP (median risk score based on Halabi et al. model is 0.69 in the placebo + AAP group compared to 0.75 in the niraparib + AAP group), highlighting the importance of utilizing a multivariate model to adjust for these imbalances. Indeed, the pre- specified multivariate analysis adjusting for these imbalances shows a treatment benefit in OS in subjects treated with niraparib + AAP in the BRCA subgroup (HR = 0.663; 95% CI: 0.464, 0.947). A consistent and clinically meaningful improvement was observed for both TSP and TCC in Cohort 1 BRCA subgroup, with clear separation in the KM curves for both endpoints observed early and strengthening with longer follow-up. The benefits observed in these well-established, highly patient-relevant endpoints in mCRPC were reflected in observations in patient reported outcomes, with trends toward prolongation in time to clinically meaningful BPI-SF Worst Pain Intensity Progression and Pain Interference Progression among subjects with BRCA gene alterations treated with niraparib + AAP. The safety profile of niraparib + AAP at the FA was consistent with prior analyses, with no new safety signals observed with longer duration of exposure and additional follow up. The combination of niraparib + AAP was tolerable despite the high baseline disease burden in an elderly population, 26.5% of whom were over 75 years of age. Treatment with niraparib + AAP was manageable with dose interruptions, reductions, and supportive care in both the All HRR population and the BRCA subgroup in Cohort 1. The majority of subjects treated with niraparib + AAP were able to continue treatment until disease progression. The safety profile of the niraparib/AA FDC formulation + prednisone observed in Cohort 3 appears consistent with that observed in Cohort 1. In conclusion, results from the final analysis continue to demonstrate a positive benefit-risk in BRCA-mutated mCRPC subjects treated with niraparib + AAP. The efficacy analyses indicate a strong trend toward improvement in OS and clinically meaningful improvements in the key secondary endpoints of TSP and TCC while overall health-related quality of life was maintained in subjects treated with niraparib +AAP. The updated safety analyses confirm that niraparib + AAP is tolerable with manageable toxicities. Taken together, the MAGNITUDE study clearly demonstrates the robust benefit of niraparib + AAP for first-line treatment of mCRPC patients with BRCA alterations. Results Subject and Treatment Information ^ TSIDS02_BRCA: Study Disposition; Cohort 1 BRCA Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Total Analysis set: randomized 112 113 225 Terminated Study Participation 74 (66.1%) 62 (54.9%) 136 (60.4%) Reason for termination Death 69 (61.6%) 60 (53.1%) 129 (57.3%) ^ TSIDS04_BRCA: Treatment Disposition; Cohort 1 BRCA Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Total Analysis set: safety 112 113 225 Subjects ongoing 15 (13.4%) 30 (26.5%) 45 (20.0%) Discontinued study treatment 97 (86.6%) 83 (73.5%) 180 (80.0%) Reason for discontinuation Progressive disease 86 (76.8%) 60 (53.1%) 146 (64.9%) ^ TSIEX01_BRCA: Summary of Exposure to Study Agent; Cohort 1 BRCA Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Total Analysis set: safety 112 113 225 N 112 113 225 Mean (SD) 16.3 (11.24) 20.5 (12.47) 18.4 (12.03) Median 14.4 20.5 16.6 Range (0; 46) (0; 48) (0; 48) Duration o af study treatment (months) 0 - <3 months 7 (6.3%) 8 (7.1%) 15 (6.7%) 3 - <6 months 20 (17.9%) 10 (8.8%) 30 (13.3%) 6 - <9 months 8 (7.1%) 8 (7.1%) 16 (7.1%) 9 - <12 months 12 (10.7%) 10 (8.8%) 22 (9.8%) 12 - <15 months 11 (9.8%) 7 (6.2%) 18 (8.0%) 15 - <18 months 15 (13.4%) 7 (6.2%) 22 (9.8%) 18 - <21 months 9 (8.0%) 10 (8.8%) 19 (8.4%) 21 - <24 months 4 (3.6%) 9 (8.0%) 13 (5.8%) 24 - <27 months 0 5 (4.4%) 5 (2.2%) 27 - <30 months 9 (8.0%) 11 (9.7%) 20 (8.9%) 30 - <33 months 4 (3.6%) 8 (7.1%) 12 (5.3%) 33 - <36 months 5 (4.5%) 4 (3.5%) 9 (4.0%) 36 - <39 months 5 (4.5%) 7 (6.2%) 12 (5.3%) 39 - <42 months 1 (0.9%) 5 (4.4%) 6 (2.7%) 42 - <45 months 0 1 (0.9%) 1 (0.4%) 45 - <48 months 2 (1.8%) 3 (2.7%) 5 (2.2%) 48 - <51 months 0 0 0 Total number of cycles N 112 113 225 Mean (SD) 17.6 (11.84) 21.9 (13.30) 19.8 (12.76) Median 15.0 21.0 17.0 Range (1; 49) (1; 52) (1; 52) Total number of cycles ≥1 cycle 112 (100.0%) 113 (100.0%) 225 (100.0%) drug+1 divided by 30.4375. Efficacy ^ TEFOS01_BRCA: Summary of Overall Survival – Stratified Analysis; Cohort 1 BRCA Randomized Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: randomized 112 113 Event 70 (62.5%) 60 (53.1%) Censored 42 (37.5%) 53 (46.9%) Time to event (months) 25th percentile (95% CI) 17.03 (12.12, 19.48) 15.97 (12.09, 21.52) Median (95% CI) 28.55 (23.82, 32.95) 30.36 (27.60, NE) 75th percentile (95% CI) 42.05 (37.55, NE) NE (41.86, NE) Range (0.5, 45.1+) (1.9, 46.9+) 6-months event free rate (95% CI) 0.973 (0.919, 0.991) 0.947 (0.886, 0.976) 12-months event free rate (95% CI) 0.839 (0.757, 0.896) 0.841 (0.759, 0.897) 18-months event free rate (95% CI) 0.714 (0.621, 0.789) 0.735 (0.643, 0.806) 24-months event free rate (95% CI) 0.553 (0.456, 0.639) 0.628 (0.532, 0.710) 30-months event free rate (95% CI) 0.469 (0.372, 0.560) 0.509 (0.411, 0.599) 36-months event free rate (95% CI) 0.360 (0.260, 0.461) 0.438 (0.337, 0.535) 42-months event free rate (95% CI) 0.272 (0.159, 0.398) 0.376 (0.237, 0.515) p-value ^{a b} 0.1828 Hazard ratio (95% CI) 0.788 (0.554,1.120) a bnd prior AAP use (yes versus no). Hazard ratio is from stratified proportional hazards model. Hazard ratio <1 favors niraparib + AAP treatment. Note: + = censored observation, NE = not estimable ^ TEFOS08_BRCA: Summary of Overall Survival (Multivariate Analysis) Proportional Hazards Model; Cohort 1 BRCA Randomized Analysis Set (Study 64091742PCR3001) Model Fit Hazard Ratio Coeff. (SE) p-value Estimate 95% C.I. . The logarithmic value of PSA and Lactate dehydrogenase is used.

TEFSPR01_BRCA: Summary of Time to Symptomatic Progression – Stratified Analysis; Cohort 1 BRCA Randomized Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: randomized 112 113 Event 58 (51.8%) 38 (33.6%) Censored 54 (48.2%) 75 (66.4%) Time to event (months) 25th percentile (95% CI) 11.86 (6.44, 15.90) 17.94 (12.68, 24.71) Median (95% CI) 21.65 (17.61, 35.81) NE (36.24, NE) 75th percentile (95% CI) NE (36.63, NE) NE (NE, NE) Range (0.3, 45.1+) (0.2, 46.9+) 6-months event free rate (95% CI) 0.837 (0.754, 0.894) 0.928 (0.862, 0.963) 12-months event free rate (95% CI) 0.741 (0.647, 0.813) 0.852 (0.769, 0.906) 18-months event free rate (95% CI) 0.585 (0.483, 0.674) 0.746 (0.649, 0.820) 24-months event free rate (95% CI) 0.484 (0.381, 0.579) 0.689 (0.586, 0.771) 30-months event free rate (95% CI) 0.439 (0.335, 0.538) 0.632 (0.522, 0.723) 36-months event free rate (95% CI) 0.386 (0.272, 0.498) 0.632 (0.522, 0.723) 42-months event free rate (95% CI) 0.351 (0.231, 0.473) 0.524 (0.377, 0.651) p-value ^{a b} 0.0056 Hazard ratio (95% CI) 0.562 (0.371,0.849) a bnd prior AAP use (yes versus no). Hazard ratio is from stratified proportional hazards model. Hazard ratio <1 favors niraparib + AAP treatment. Note: + = censored observation, NE = not estimable TEFCYT01_BRCA: Summary of Time to Initiation of Cytotoxic Chemotherapy – Stratified Analysis; Cohort 1 BRCA Randomized Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: randomized 112 113 Time to event (months) 25th percentile (95% CI) 13.14 (8.57, 16.16) 21.49 (14.29, 26.48) Median (95% CI) 28.16 (20.73, NE) NE (31.44, NE) 75th percentile (95% CI) NE (NE, NE) NE (NE, NE) Range (0.5+, 45.1+) (1.9+, 46.9+) 6-months event free rate (95% CI) 0.891 (0.817, 0.937) 0.964 (0.906, 0.986) 12-months event free rate (95% CI) 0.769 (0.677, 0.838) 0.867 (0.786, 0.919) 18-months event free rate (95% CI) 0.634 (0.533, 0.719) 0.783 (0.689, 0.852) 24-months event free rate (95% CI) 0.534 (0.428, 0.629) 0.715 (0.614, 0.794) 30-months event free rate (95% CI) 0.489 (0.381, 0.589) 0.652 (0.545, 0.740) 36-months event free rate (95% CI) 0.422 (0.296, 0.544) 0.611 (0.494, 0.708) 42-months event free rate (95% CI) 0.422 (0.296, 0.544) 0.611 (0.494, 0.708) p-value ^{a b} 0.0192 Hazard ratio (95% CI) 0.598 (0.387,0.924) a bnd prior AAP use (yes versus no). Hazard ratio is from stratified proportional hazards model. Hazard ratio <1 favors niraparib + AAP treatment. Note: + = censored observation, NE = not estimable TEFSUBTX02_BRCA: Summary of Selected Subsequent Therapy for Prostate Cancer; Cohort 1 BRCA Randomized Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: randomized 112 113 Number of subjects with selected subsequent therapy for prostate cancer 75 (67.0%) 48 (42.5%)

TEFSUBTX02PD_BRCA: Summary of Selected Subsequent Therapy for Prostate Cancer for Subjects Who Discontinued Treatment Due to Progressive Disease; Cohort 1 BRCA Randomized Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: randomized subjects discontinued treatment due to progressive disease 86 60 Number of subjects with selected subsequent therapy for prostate cancer 74 (86.0%) 42 (70.0%) Chemotherapy 51 (59.3%) 34 (56.7%) Docetaxel 40 (46.5%) 23 (38.3%)

Safety TSFAE01_HRR: Overall Summary of Treatment-emergent Adverse Events; Cohort 1 All HRR Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: safety 211 212 Subjects with 1 or more: AEs 205 (97.2%) 212 (100.0%) cAEs leading to death are based on AE outcome of Fatal. An AE is counted as leading to discontinuation of study agent if it leads to withdrawal of niraparib, abiraterone acetate or prednisone.

^, _y ^r _o ^g _e ^t _a ^s _e ^r _e ^{t I} _l ^{b I o e} _v ^t _t ^S _c ^e _j ^r _o ⁷ ₃ ⁶ ₁ ⁶ _{1 1} ⁵ ₁ ⁵ _{1 22 1 61 1 1 21 1 22 44 7 5} ^b _u ^h _o ^{S C f} _{o; )} % _{) 6} %_{) .} ⁶% _{) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) .} ⁶ %% % %_. %_. %_. %_. %% % % % %_. %_. % %% %_. %_{. r} ^e _{d 1} ^. ₆ 1 ( ⁶ (⁶ ( _{00 .} ³³ _{( .} ³ _. ⁵ ₀ ² 7³ _{( 7} ⁰ _{( 1} ⁶ (²⁶ ( ⁵⁸ (²⁶ (_. ⁹⁰ _{( .} ⁵ _0. ⁵ _00. ⁵ _0. ^{9 2} 2⁰ _{( 1} ⁰ _{( 1} ⁰ _{( 1} ⁰ _{( 2} ⁶ (²⁶ ( _0. ⁵⁰ _{( .} ⁸ _. ^{8 7} 1 ² ₍ ² ₍ ⁴ ( ⁷⁴ (^e _b ^a _r ^{5 4} ₁ ⁴ ₁ ³ ₁ ³ ₁ ⁸ ₁ ³ ₁ ³ ₁ ³ _{1 66} ⁰ ₁ ⁰ ₁ ^m _u ^G ₃ yt _{) ) ) ) )} N_i ^c _l x _{t o} ^{a %} ₅ ^%% ₎ ^%% _{) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) i} ^o _{1 T} ¹ ₂ ^. _{4 77} % ₂₂ % % %% ^% ₂%%%%% %%% ^% ₄ ^% ₄ % %% ^% ₈ ^% ₀ 6₍ ^. ₂ ^. _20. ^{5 .} ₃ ^. _{3 .} ⁵ _. ⁵ _. ⁵ 6 ₍ ² ₍ ² ₍ ⁰ _{1 (} ² ₍ ² ₍ ⁰ _{1 (} ⁰ ₁ ⁹ (_. ⁵⁹ ( ^. _4. ⁰⁹ _. ⁴ _. ⁵ _. ⁵ _. ⁹ _00. ⁴ _. ⁵ _. ^{4 .} ₀ ^. _{0 0.} ⁵ _. ¹⁷ _. ^{17 .} ₂ ^. ₀ 0⁰ ₍ ¹ ( 9₍ ¹ ₃₍ ⁰ _{1 (} ⁰ _{1 (} ⁰ _{2 (} ¹ ₃₍ ⁰ _{1 (} ¹ _{3 (} ¹ ₍ ¹ ₍ ⁰ ₁ ( ( 5⁵ ₍ ¹ ₍ ^{1 T 3 8} ₄ ⁸ ₄ ⁹ ₄ ⁹ _{4 22} ⁰ ₃₁ ² ₂ ² _{2 1 1} ⁷ ₂ ¹ _{2 :} ^d _{1 n} R ^{a c}i Rm _{e l} rt o_{s y r} ^{e r} _o ^ci_t ^d _e ^s _a ^H _r ^ot _{s a a} m_{lr g ni i} ^{a e} _{_} ^r _e ³T _t ^y _f ^{e m} _{r t} ^{e g n} i _e ^t _a ^y _{c r} ^{e oc} _{e 0d} ^a _r ^y E^e _s ^{o e} _{s r} ^e _a ^{i i} _{n r} :_t ^{1 l} _a ^c _{t r} ^{m c} _a ^dt _{i n} ^e _p ^e _d ^a r _{n i} ^u _{s l} ^y _t ^e _d ^u _s ^e _pt ^{o e} _o ^e _h ⁿ _l ^il _{e n} ^{o /} _{i n} ^pi_rw ^os _ugi ^{n d} _aa ^s _{u l} ^om_f ^{f ex} _{a i} ^am_i m^{u m} _{e sr} ^{a s} _{s f d} ^a _s ^{e e} _a ^s _n e A^r _s ^ht_i ⁱ _c e_p ^s _e ^r _{t e} ^e _{d i} ^{a m} _i ^ac _o ^t _n ^o i^os _nt ^s _e ^r _p ^a _u q^el_l ^s _e ^r _{d p} ^e _{s t} ^oy _c y^o _{b i} ^{oe t} _p ^s _{l nar} ^a _gf ^f _l e_l ^l _e ^r w_ae ^e _d ^{l ve} _oa ⁱ _d ^r _ot ^h _i ^ae _a ^l _{t a} ^ao _p ^e _{s n} g_{a a} ^{i i} _n ^e _p ^y _i ^t _i ^c _t ^e _r ^at _{d o} ^e _s ^F _e ^si_s ^w _t ^{s s} _f ^t _nr ^e _S ^f _{e l} ^{y c} _e ^{o i} _l ^r _e ^{f j s} _i ^a _e ^r _i ^am _e m^a _n ^m _ea a_nm ^{s e} _n ^e a _t ^er _eder ^{o r} _e ^p _y ^o _o ^{d l} _{a i} ^{t n} _nd ^{a o} _c ^o _{e c o} ^{r l} _{c i} ^{o n} _bm m_r ^o _t ^{e h e} _r ^m _e ^e _{h d} ^d _e ^pni i _{l r} ^{l e} _er ^{a wu} _e ^s _t ^m _eod ^{h l} _i ^nd _e ⁱ _p ^r _{a u} ^l m^{c y}i_{r r} ^{o m} _e d_y ^l _a ^{k k} _od ^a _{e o} ^p _y ^o _o ^r _c ^m _{o n} e ^{l e} _d ^p _{y p} ^or_t ^x _{o r} ^o _t ^u _e ^t _t ^a o^{r t} _ai ^na _e ^r _{c a} ^p _s ^m _{a i} ⁿ T^r _P ^a _{n bE} ^c _P A A H H _{B B r} ^o _T O _{P S P} ^o _J O _{F L} ^e _P H H _B H N A A ^u _S A _e p _S ^e _n ^p A _y ⁱ H ^h _{T u} ^l _F ^p _y H ^u _e N ^p _e H ^, _y ^r _o ^C _t ^s _e ^r _e ^I _l ^{b I o} _v ^{E At S w e r} _{o 4 43 1 1 j} ^b _u ^h _o ^{S C f} _{o; )} e_{d 1} %_{) ) ) ) ) ) ) ) ) .} ⁸% 3_{( .} ⁵ % 0_{( .} ⁵ %%% % % % % 0_{( 00 0000 .} ⁸³ _{( .} ⁵⁰ _{( .} ⁴² _{( 0.} ⁵⁰ _{00 000.} ⁵⁰ _{0 00000 .} ⁵⁰ _{00 00.} ⁵⁰ _{0 0 r} ^e _{81 1 81 5 ( 1 ( 1 ( 1 ( 1 b} ^a _r ^m _u ^Gyt N_{i ) i} ^c _l x _{t o} ^{a %} ₄₎ o _T ^. ₀% _{) (} ¹ _. ⁹ %_{) ) (} ⁰ _. ⁵%_. %_{) )} 5_{0 0000 .} ⁶%_{) .} ⁹%_{) .} ⁴%_{) .} ⁵% _{) .} ⁵ ₀% _{) .} ⁵ ₀₀₀% _{) .} ⁵ _{0 00}%_{) .} ⁵%_{) .} % _{) ) ) ) )} 5%_. ⁵ _. ⁷ %_. ⁹%_. ⁴ ₀%_. ⁴%_. %_{. 2 (} ⁰ _{1 (} ⁰ ₁ ⁷ (₍ ¹ ₄₍ ² ₅₍ ⁰ _{1 (} ⁰ _{1 (} ⁰ _{1 (} ⁰ _{1 (} ⁰ _{1 (} ⁰ _{1 (} ⁰ ₁ ⁴ ( ₍ ^{0 5} ₀ ⁵ 2₍ ¹ _{3 (} ¹ ₍ ⁰ ₍ ^{0 T 2 6} ₁ ⁰ _{1 31 1 :} ^d _{2 n} R ^a _{n i} Rm ^e _i ^a _e ^H _s ^{a e} m _{s r} ^{a e} _{s d i} ^o _{t r} ^d _{e n} ^s _{a s n a} ^e _{s l} ^{a a} _c ^s _{al i} ^ot _c ^es_{i y _} ^r _e ³T _r ^a _f ^{e e} _ai ⁿ _f ^es _{n r} ^a _{i 0d} ^s _{n r r} ^eyt_{i f} ^{e s} _{i y} ^l _ot ^{a e} _{r r r} ^e _i ^ot _{a r a} ^da _{l c} ^au _{l ca} ^{a i} _d u_c ^s _e ^r _a ^t _s ^a _e ^li r_{c r} ^y _h ^e _{s t} ^{h s} _ei ^b r ^f _r ^c _a ^{t i} _di ^a t _r ^{d r} _a a ^f _ny ^{d i r} _{a r} ^{y e} _i ^s _r a_d ^b _ui ^{r a} _r ^y _t ^{h t r} _o ^e _r ^{t a} _{p l t} ^l _yd ^ul_{i f} ^a _i ^{c s x} _{n r} ^al _a ^t _y ^u _c ^a _{d l s} ^r _o ^l _i ^{r i} _d ^s _n ^y _h ⁱr_t ⁱ _d ^r _a ⁱr_t ^l _o ^t _s ^c _y h_cr ^er _a ⁿ i t^ea _erl ^al _o ^t _{s rl} ^a _t ^et _a ⁱ _drl ^a _r ^a _ec o_ynli ^an _o ^r _e ^t m ^a _c ^{e a} _ni ^co _y E^e _r A^r _e ^e _n ^{t i} _o ^e _{s ni} ^na _e ^{i r} _b-_{a c} ^r _e ^m _a ^e _s ^a _{ot ei} ^ct _o ^e _t ^at _or ^{m c} _i ^ci _i ^t _i ^{s d} _i ^a _b ⁱ f ^r _a ^{c p}m _y ^oi_tt ^ac _a ^{t n} _e v^c _ye pⁿ _e ^y _s ^a t _cr ^{a dn} _e ^u _c ^y _s ^u _cu ^l f ^r _a ^cu _c ^h _i ^moi_{t r} ^cd _{r o} c_r ^o _r ^{y a} _par ^{y a} _i ^os _umm_i ^{o mt} _u ^r _c ^t _a ^t _a ^r _ai ^no _n ^t _a ^t _ar ^e _v ^m _h ^l _a ⁱr^h _cil ^p _s u_a ^r _p ^h _co ^c _n ^v _a ^r _p ^ar_t ^l _a ⁱ _i ^at r_r ^d _r ^d _d ⁱr_t ^ar_t ⁱr_t ^l _a ⁱ _y ⁱr r^d _at ^c m_t ^e _f ^aa _c o_yt ^ed _{nn r} ^o _i ^{n g} _{n r} ^ol _c ^e _ar ^{d F} _S ^f _{e l} ^a A^m _{a i} ⁿ _y H_a G^l _{g i} ^np _e H^p _e H^p _s A^m _a ^b _a ^p _e H^p _e Hⁱ _L ^t _{yt n r} ^h A^a _T ^a _P ⁱ _S ^u _{S t} ^ay _S ^u _S ^x _et A^a _C ^a _e H^u _S ⁿ _e V^x _e ⁿ _e V_t A^r _B ⁿ _e V ^e _a ^u _c h A _i ⁿ M^u _c A^y _s ^o _Cn A^o _C ^c _o ^h _{c I} ^{s a} _c T^r _{P r} A _{c I} ^s g ^, _y ^r _o ^g _e ^t _a ^C _t ^s _e ^r _e ^t _n ^I _li ^ac _e ^p _Sy ^b _t ^s _e ^r _e ^{t I} _f ^o _s ^t _n ^Ee _s ^r _{e d} ^{A S} t_i ^w _s ^Ac _a ^{i l} _P ^o _{) T2}% _{) .} ⁴ _000000000 % _{) .} ⁵ % _{) .} ⁹ % _{) .} ⁵ _{0 0 0} % _{) .} %_{) ) )} ^e _{h .} %_. %_. %_. ^t _{f t} ^a _t ^{o t} _c ¹ _t ¹ ₍ ⁰ ₍ ⁰ ₍ ⁰ _{( 00} ⁵⁰ ₍ ⁹¹ ₍ ⁹¹ _{( 0 0 0 0 0} ⁵⁰ ₍ ⁵⁰ _t ^o _{s e} ^e _{3 1 2 1 1 44 1 ( 1} ⁿ _e ^s _{e t} ^h _j ^r _o ^v _e ^b _e ^l _di ⁿ _u ^h _{o r} ^{s r} _ad ^{S C f} _{o; )} e_{d 1 0000000000 0 0} %_{) .} ⁹% ₎ 0_. ⁹⁰ _{0 000}% ₎ ^e _v ^g _e ^r _t ^e , ⁿ _{u .} ⁵ %₎ 0 _. ⁹%₎ 0_. ⁵% ^d _{a .} ^{t 5} _n ^o _{c 0 0 0 0 00 = E} ^e _vy ^{. l} _{0 n} ^. _{4 r ( 2( 2 ( 1 ( 2} ⁰ _{( 1} ⁰ ₍ ^{en o 2 e} _b ^a _{r 1} ^A, _eei ^v _s ⁱ _t ⁿ _o ⁱ _s ^m _u ^{G n y} _o t _i ^{s gc} _e n^y _n ^j _b ^r _e V N_ii ^c _{l ) t} ^a% _{) .} %_{) .} % _{) .} % _{) .} % _{) .} %_{) ) ) ) ) ) ) ) ) ) ) d .} %_. %_. %_. %_. %_. %_. %_. %_. %_. %_. % _r ^{e a} _{r f} ^{u o} _seA t R x_o ^{o4 T} _T( ² _0000000 ⁵ 5 ₍ ⁰⁵ 1 ₍ ^{0 5} 1 ₍ ^{0 9} 1 ₍ ^{0 9} 2 ₍ ^{1 4} 4₍ ¹ _{0 000} ⁹ 3 ₍ ^{0 8} 2 ₍ ²⁴ 6₍ ²⁵ 5₍ ^{0 5} 1 ₍ ^{0 5} 1 ₍ ^{0 5} 1 ₍ ^{0 5} 1 ₍ ^{0 5} 1 ₍ ⁰ _. ⁵ 1 ₍ ^{0 p} _{s 1 l} ^ue _c ^h _,t D p_t ⁿ _o ^d _{e y} ⁿ _e v_eM_{g :} ^d _n ^{e a} _{s n} o _s i ⁱ _{s i} ^c _{y t} ^al t^{h e} _{n c} ^o _e a^d _er ^{s ni e} _{s v} ^u RRm ^r _e ^H _{_} ^r _{e r} ^d _s o_{s l} ^u _a ³T _i ^c _c ^m _{r o} ^{o t} _l d _a ^ec _a ⁿ _{o s} ^{e y} _{h y} m^r _{h g} ^a _p ^e _n ^t _n u^d _a ^d _e c _i ^ndd _e ^o _{y r} ^o _t ^e _o ^c _c ^{d i}f _{o i} ^c _0d ^r _a ^o _r ^y _i ^sm^{o e}i_{r k r} ^o _i ^d _e g_a ^t _{a r} ^er _a n_{o r} ^e _e ^e _{d e} ^l _a ^e _or ^e _u ^l _c ^t _a ^l _{e s i} ^d _i ^d m^/ _s ^{i a}r_{i r} ^{e ac} _er ^{e a} _s E^e _r ^l _{u i} ^{s c} _s ^ai_r ^s _e ^{e r} _r ^t _a aⁱ _g ^s _e ^r _{a a} ^het l _r ^t s a ^{a o l} _{n ai} ^ch _cr ^{h p} _o r _{r or} ^l _a ^eul u_i m ^ul_i l_i ^a _f ^l _ua ^a _{f i} ^v _t ⁿ _oy ^ul_i ⁿ m^r _a ^a _f ⁱ - _i ^{r s} _i ^{s i} _s s _{a l} ^o o _r ^oi _n ^e _yi ^a m _{s l} ^o i^ee _yi ^a _s m _l ^{y b} _as ^p _s ^{t o} _yt ^h ₌ ^t _cj ^a _{r n} ^e _v A^{r F} _e ^a _vt ^h _{a S} ^f _e ^o _r ^r _ai ^p _i ^as _a ^d _t ⁱ _l ^{e b} _{r e} ^s _y ^o _i ^p _i ^pr _d ^r _u d_b ^r _bm r^ee _ar ^a _l ^ah _p a_b ^m _e ^u _c ^e _c ^a f _c c_i ^{a p}m_{c r} ^d _t ^ee _di ^as _e ^l _{u r} ^{n dg} _n ^p _{r oci} ^{a s} _{o r} ^{r d r} _oos ^o _p ^e _p ^me _a ^{c pe} _r ^o _e ^o _{e t} ^ek _{u n} ^{me a} _{a y nt} ^ek _u ^m _o ^a _{p P} ^e A^b _{u f} ^{o ee} _s D^m _e ^h H_p A^a _C ^m _e ^a H_u Q^u _S ^e _C ^h _{c I} ^{s u} _S ^a _h ^s _a Vⁿ _{e a} ⁱ _d ^a _C ^u _c A^e _o ^a _C ^o _c ^o _{l C} ^mu _P ^a _C ^p _{oot t} ^ut _s ^t _s ^u _{c l} ^e _i ^gu _{c l} ^{e d} _b ^o _y ^A _: ^S: _t ^yi _c ^r _e T^r _P ^r _e ^eec _a O O _l A ^l A M _e ⁱ C ^r _a C ^t _s O^s _{o f} ^r m _a A M ^a _h R ^y _e ^t K_o N_{x t} ^{v o} _d A TSFAE05_HRR: Number of Subjects with Treatment-emergent Serious Adverse Events by System Organ Class and Preferred Term; Cohort 1 All HRR Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: safety 211 212 Subjects with 1 or more SAEs 65 (30.8%) 100 (47.2%) System organ class Preferred term Infections and infestations 20 (9.5%) 40 (18.9%) COVID-19 3 (1.4%) 11 (5.2%) Pneumonia 5 (2.4%) 9 (4.2%) COVID-19 pneumonia 2 (0.9%) 8 (3.8%) Cellulitis 0 2 (0.9%) Sepsis 1 (0.5%) 2 (0.9%) Urinary tract infection 2 (0.9%) 2 (0.9%) Urosepsis 1 (0.5%) 2 (0.9%) Abscess oral 0 1 (0.5%) Diverticulitis 0 1 (0.5%) Infection 1 (0.5%) 1 (0.5%) Lower respiratory tract infection 0 1 (0.5%) Pyelonephritis 0 1 (0.5%) Septic shock 1 (0.5%) 1 (0.5%) Abdominal sepsis 1 (0.5%) 0 Bacteraemia 1 (0.5%) 0 Erysipelas 1 (0.5%) 0 Fournier's gangrene 1 (0.5%) 0 Medical device site joint infection 1 (0.5%) 0 Oesophageal candidiasis 1 (0.5%) 0 Respiratory tract infection 2 (0.9%) 0 Suspected COVID-19 2 (0.9%) 0 Blood and lymphatic system disorders 6 (2.8%) 20 (9.4%) Anaemia 3 (1.4%) 14 (6.6%) Thrombocytopenia 0 5 (2.4%) Neutropenia 1 (0.5%) 3 (1.4%) Lymphoid tissue hyperplasia 1 (0.5%) 0 Lymphopenia 1 (0.5%) 0 Cardiac disorders 10 (4.7%) 15 (7.1%) Acute myocardial infarction 2 (0.9%) 4 (1.9%) Myocardial infarction 3 (1.4%) 3 (1.4%) Acute coronary syndrome 0 2 (0.9%) Atrial fibrillation 1 (0.5%) 2 (0.9%) Arrhythmia 0 1 (0.5%) Cardiac arrest 0 1 (0.5%) Cardiac failure 1 (0.5%) 1 (0.5%) Cor pulmonale 0 1 (0.5%) Defect conduction intraventricular 0 1 (0.5%) Tachycardia 0 1 (0.5%) Ventricular fibrillation 0 1 (0.5%) Aortic valve stenosis 1 (0.5%) 0 Coronary artery disease 2 (0.9%) 0 Ischaemic cardiomyopathy 1 (0.5%) 0 Palpitations 1 (0.5%) 0 General disorders and administration site conditions 6 (2.8%) 11 (5.2%) Fatigue 2 (0.9%) 2 (0.9%) Pyrexia 1 (0.5%) 2 (0.9%) Adverse drug reaction 0 1 (0.5%) Asthenia 0 1 (0.5%) Death 0 1 (0.5%) General physical health deterioration 1 (0.5%) 1 (0.5%) Hernia 0 1 (0.5%) TSFAE05_HRR: Number of Subjects with Treatment-emergent Serious Adverse Events by System Organ Class and Preferred Term; Cohort 1 All HRR Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Pain 0 1 (0.5%) Sudden death 0 1 (0.5%) Chest pain 1 (0.5%) 0 Non-cardiac chest pain 1 (0.5%) 0 Renal and urinary disorders 14 (6.6%) 11 (5.2%) Haematuria 3 (1.4%) 4 (1.9%) Urinary retention 2 (0.9%) 4 (1.9%) Calculus bladder 0 2 (0.9%) Acute kidney injury 2 (0.9%) 1 (0.5%) Bladder mass 0 1 (0.5%) Urethral stenosis 0 1 (0.5%) Urinary incontinence 0 1 (0.5%) Bladder perforation 1 (0.5%) 0 Hydronephrosis 2 (0.9%) 0 Renal failure 2 (0.9%) 0 Renal impairment 1 (0.5%) 0 Urinary tract obstruction 2 (0.9%) 0 Gastrointestinal disorders 5 (2.4%) 9 (4.2%) Diarrhoea 0 2 (0.9%) Abdominal pain 1 (0.5%) 1 (0.5%) Abdominal pain upper 0 1 (0.5%) Anal haemorrhage 0 1 (0.5%) Constipation 0 1 (0.5%) Gastric ulcer 0 1 (0.5%) Haematochezia 0 1 (0.5%) Proctitis 0 1 (0.5%) Small intestinal obstruction 0 1 (0.5%) Upper gastrointestinal haemorrhage 0 1 (0.5%) Vomiting 0 1 (0.5%) Dysphagia 1 (0.5%) 0 Inguinal hernia 2 (0.9%) 0 Large intestinal obstruction 1 (0.5%) 0 Metabolism and nutrition disorders 5 (2.4%) 9 (4.2%) Hypokalaemia 1 (0.5%) 4 (1.9%) Dehydration 0 2 (0.9%) Hyperglycaemia 0 2 (0.9%) Decreased appetite 0 1 (0.5%) Diabetes mellitus inadequate control 0 1 (0.5%) Hypocalcaemia 0 1 (0.5%) Hypophosphataemia 0 1 (0.5%) Hypoglycaemia 1 (0.5%) 0 Hyponatraemia 2 (0.9%) 0 Type 2 diabetes mellitus 1 (0.5%) 0 Injury, poisoning and procedural complications 9 (4.3%) 8 (3.8%) Femur fracture 0 2 (0.9%) Femoral neck fracture 1 (0.5%) 1 (0.5%) Limb injury 0 1 (0.5%) Skeletal injury 0 1 (0.5%) Spinal compression fracture 0 1 (0.5%) Subdural haematoma 0 1 (0.5%) Vaccination complication 0 1 (0.5%) Fall 1 (0.5%) 0 Hip fracture 1 (0.5%) 0 Lower limb fracture 1 (0.5%) 0 Muscle injury 1 (0.5%) 0 Patella fracture 1 (0.5%) 0 Spinal fracture 1 (0.5%) 0 Upper limb fracture 1 (0.5%) 0 Wound dehiscence 1 (0.5%) 0 TSFAE05_HRR: Number of Subjects with Treatment-emergent Serious Adverse Events by System Organ Class and Preferred Term; Cohort 1 All HRR Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Respiratory, thoracic and mediastinal disorders 4 (1.9%) 8 (3.8%) TSFAE05_HRR: Number of Subjects with Treatment-emergent Serious Adverse Events by System Organ Class and Preferred Term; Cohort 1 All HRR Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP event. Adverse events are coded using MedDRA Version 24.0

TSFAE18_HRR: Number of Subjects with Treatment Emergent Adverse Events Leading to Death by System Organ Class and Preferred Term; Cohort 1 All HRR Safety Analysis Set (Study 64091742PCR3001) Placebo + AAP Niraparib + AAP Analysis set: safety 211 212 Subjects with 1 or more AEs Leading to Death 10 (4.7%) 22 (10.4%) System organ class Preferred term Infections and infestations 3 (1.4%) 13 (6.1%) COVID-19 0 6 (2.8%) COVID-19 pneumonia 0 4 (1.9%) Pneumonia 0 1 (0.5%) Sepsis 0 1 (0.5%) Septic shock 1 (0.5%) 1 (0.5%) Suspected COVID-19 2 (0.9%) 0 General disorders and administration site conditions 0 3 (1.4%) Adverse drug reaction 0 1 (0.5%) Death 0 1 (0.5%) Sudden death 0 1 (0.5%) Cardiac disorders 4 (1.9%) 2 (0.9%) Acute myocardial infarction 2 (0.9%) 1 (0.5%) Cor pulmonale 0 1 (0.5%) Myocardial infarction 2 (0.9%) 0 Hepatobiliary disorders 0 1 (0.5%) Hepatic failure 0 1 (0.5%) Psychiatric disorders 0 1 (0.5%) Completed suicide 0 1 (0.5%) Respiratory, thoracic and mediastinal disorders 1 (0.5%) 1 (0.5%) Dyspnoea 0 1 (0.5%) Pulmonary embolism 1 (0.5%) 0 Vascular disorders 1 (0.5%) 1 (0.5%) Embolism 0 1 (0.5%) Circulatory collapse 1 (0.5%) 0 Nervous system disorders 1 (0.5%) 0 Cerebral arteriosclerosis 1 (0.5%) 0 event. Adverse events are coded using MedDRA Version 24.0

TSFAE07_modified: Adverse Reactions in MAGNITUDE (BRCA population) System/Organ Class TRADENAME Placebo N=113 N=112 All All Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 Adverse Reaction % % % % % % Infections and infestations Urinary tract infection 12.4 2.7 0 8.9 0.9 0 Nasopharyngitis 2.7 0 0 3.6 0 0 Bronchitis 2.7 0 0 0 0 0 Conjunctivitis 1.8 0 0 0 0 0 Sepsis 0.9 0 0.9 0.9 0 0.9 Blood and lymphatic system disorders Anemia 48.7 26.5 2.7 25.9 8.9 0 Thrombocytopenia 23.9 4.4 5.3 8.9 2.7 0 Neutropenia 15.9 6.2 0.9 7.1 1.8 0.9 Lymphopenia 12.4 4.4 0.9 2.7 1.8 0 Leukopenia 9.7 1.8 0 3.6 0.9 0 Metabolism and nutrition disorders Decreased appetite 15.0 1.8 0 9.8 0 0 Hypokalemia 12.4 4.4 0.9 9.8 5.4 0 Hypertriglyceridemia 2.7 0 0 0.9 0 0 Psychiatric disorders Insomnia 11.5 0 0 5.4 0 0 Depression 3.5 0 0 1.8 0 0 Anxiety 1.8 0 0 3.6 0 0 Confusional state 0.9 0 0 0.9 0 0 Nervous system disorders Headache 12.4 0.9 0 9.8 0 0 Dizziness 10.6 0 0 8.9 0 0 Cardiac disorders Tachycardia 1.8 0 0 0.9 0 0 Palpitations 5.3 0 0 0 0 0 Atrial fibrillation 4.4 1.8 0 1.8 0 0 Cardiac failure¹ 1.8 0.9 0.9 0 0 0 Myocardial infarction 0.9 0 0.9 0 0 0 Vascular disorders Hypertension 34.5 15.0 0 25.9 16.1 0 Respiratory, thoracic and mediastinal disorders Dyspnea 13.3 0.9 0 7.1 1.8 0 Cough 12.4 0 0 5.4 0 0 Pulmonary embolism 2.7 1.8 0 0.9 0.9 0 Pneumonitis 1.8 0 0 0 0 0 Gastrointestinal disorders Constipation 35.4 0.9 0 20.5 0 0 Nausea 32.7 0.9 0 20.5 0 0 Vomiting 15.9 0.9 0 8.0 0.9 0 Abdominal pain² 12.4 1.8 0 13.4 0.9 0 Dyspepsia 5.3 0 0 4.5 0 0 Dry mouth 4.4 0 0 1.8 0 0 Abdominal distention 3.5 0 0 0.9 0 0 Stomatitis 2.7 0 0 1.8 0 0 Hepatobiliary disorders Hepatic failure³ 3.5 0.9 0 0 0 0 Skin and subcutaneous tissue disorders Rash⁴ 5.3 0 0 5.4 0 0 Photosensitivity 0.9 0 0 0 0 0 Musculoskeletal and connective tissue disorders Back pain 19.5 2.7 0 24.1 1.8 0 Arthralgia 17.7 0 0 9.8 2.7 0 Renal and urinary disorders Hematuria 8.8 2.7 0 8.0 1.8 0 General disorders and administration site conditions Fatigue 27.4 4.4 0 21.4 3.6 0 Asthenia 20.4 1.8 0 10.7 0 0 Edema peripheral 13.3 0 0 8.0 0 0 Investigations Weight decreased 12.4 0.9 0 4.5 0.9 0 Injury, poisoning and procedural complications Fractures⁵ 8.8 2.7 0 9.8 3.6 0 ^{1 2 Includes cardiac failure and cardiac failure congestive 3 Includes abdominal pain upper 4} Includes hepatic cytolysis, hepatotoxicity ⁵ Includes rash, erythema, dermatitis, rash maculo-papular, rash pruritic Includes osteoporosis and all fractures with the exception of pathological fractures TSFAE07_modified: Laboratory Abnormalities Occurring in MAGNITUDE (BRCA population) TRADENAME Placebo N=113 N=112 All All Laboratory Abnormality Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 % % % % % % Chemistry blood alkaline phosphatase increased 12.4 5.3 0.9 9.8 3.6 0 blood creatinine increased 9.7 1.8 0 4.5 0 0.9 AST increased 6.2 1.8 0 10.7 1.8 0 ALT increased 6.2 0 0 9.8 3.6 0 gamma-glutamyl transferase 1.8 0 0 0.9 0 0 increased Example 2 – Approved Drug Product Label by European Medicines Agency (EMA) Approval date: 19 April 2023 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Akeega 50 mg/500 mg film-coated tablets Akeega 100 mg/500 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Akeega 50 mg/500 mg film-coated tablets Each film-coated tablet contains niraparib tosylate monohydrate equivalent to 50 mg of niraparib and 500 mg of abiraterone acetate equivalent to 446 mg of abiraterone. Akeega 100 mg/500 mg film-coated tablets Each film-coated tablet contains niraparib tosylate monohydrate equivalent to 100 mg of niraparib and 500 mg of abiraterone acetate equivalent to 446 mg of abiraterone. Excipients with known effect Each film-coated tablet contains 241 mg of lactose (see section 4.4) For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Akeega 50 mg/500 mg film-coated tablets Yellowish orange to yellowish brown, oval, film-coated tablets (22 mm x 11 mm), debossed with “N 50 A” on one side, and plain on the other side. Akeega 100 mg/500 mg film-coated tablets Orange, oval, film-coated tablets (22 mm x 11 mm), debossed with “N 100 A” on one side, and plain on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Akeega is indicated with prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated. 4.2 Posology and method of administration Treatment with niraparib and abiraterone acetate plus prednisone or prednisolone should be initiated and supervised by specialist physicians experienced in the medical treatment of prostate cancer. Before initiation of Akeega therapy, positive BRCA status must be established using a validated test method (see section 5.1). Posology The recommended starting dose of Akeega is 200 mg/1000 mg (two 100 mg niraparib/500 mg abiraterone acetate tablets), as a single daily dose at approximately the same time every day (see “Method of administration” below). The 50 mg/500 mg tablet is available for dose reduction. Medical castration with a gonadotropin-releasing hormone (GnRH) analogue should be continued during treatment in patients not surgically castrated. Dosage of prednisone or prednisolone Akeega is used with 10 mg prednisone or prednisolone daily. Duration of treatment Patients should be treated until disease progression or unacceptable toxicity. Missed dose If a dose of either Akeega, prednisone or prednisolone is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra tablets must not be taken to make up for the missed dose. Dose adjustments for adverse reactions Non-haematological adverse reactions For patients who develop Grade ≥ 3 non-haematological adverse reactions, treatment should be interrupted and appropriate medical management should be instituted (see section 4.4). Treatment with Akeega should not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or baseline. Haematological adverse reactions For patients who develop a ≥ Grade 3 or intolerable haematological toxicity, dosing with Akeega should be interrupted rather than discontinued and supportive management considered. Akeega should be permanently discontinued if haematological toxicity has not returned to acceptable levels within 28 days of the dose interruption period. The dose adjustment recommendations for thrombocytopenia and neutropenia are listed in Table 1. Table 1: Dose adjustment recommendations for thrombocytopenia and neutropenia Grade 1 No change, consider weekly monitoring Grade 2 At least weekly mon 1itoring and consider withholding Akeega until recovery to Grade 1 or baseline. Resume Akeega with recommendation of weekly monitoring for 28 days after restarting dose. Grade ≥ 3 Withhold Akeega and monitor at least weekly until platelets and neutrophils recover to Grade 1 or baseline.¹ Then resume Akeega or, if warranted, use two lower strength tablets (50 mg/500 mg). Weekly monitoring of blood counts is recommended for 28 days after restarting dose or starting the lower strength dose (two 50 mg/500 mg tablets). When starting the lower strength dose, please refer to “Recommended monitoring” below for further information regarding liver function. Second Withhold Akeega and monitor at least weekly until platelets and/or neutrophils occurrence recover to Grade 1. Further treatment should restart with two lower strength ≥ grade 3 tablets (50 mg/500 mg). Weekly monitoring is recommended for 28 days after resuming treatment with lower strength Akeega. When starting the lower strength dose (two 50 mg/500 mg tablets), please refer to “Recommended monitoring” below for further information regarding liver function. If patient was already on lower strength Akeega tablet (50 mg/500 mg), consider treatment discontinuation. Third occurrence Permanently discontinue treatment. ≥ 1 grade 3 During Akeega treatment interruption, abiraterone acetate and prednisone or prednisolone may be considered by the physician and given to maintain daily dose of abiraterone acetate (see abiraterone acetate prescribing information). Further dosing with Akeega may be resumed only when toxicity due to thrombocytopenia and neutropenia is improved to Grade 1 or resolved to baseline. Treatment may resume at a lower strength of Akeega 50 mg/500 mg (2 tablets). For the most common adverse reactions, see section 4.8. For Grade ≥3 anaemia, Akeega should be interrupted and supportive management provided until recovered to Grade ≤2. Dose reduction (two 50 mg/500 mg tablets) should be considered if anaemia persists based on clinical judgment. The dose adjustment recommendations for anaemia are listed in Table 2. Table 2: Dose adjustment recommendations for anaemia Grade 1 No change, consider weekly monitoring. Grade 2 At least weekly monitoring for 28 days, if baseline anaemia was Grade ≤ 1. Grade ≥ 3 Withhold Akeega¹ and provide supportive management with monitoring at least weekly until recovered to Grade ≤ 2. Dose reduction [two lower strength tablets (50 mg/500 mg)] should be considered if anaemia persists based on clinical judgment. When starting the lower strength dose, please refer to “Recommended monitoring” below for further information regarding liver function. Table 2: Dose adjustment recommendations for anaemia Second Withhold Akeega, provide supportive management and monitor at least weekly occurrence until recovered to Grade ≤ 2. Further treatment should restart with two lower ≥ Grade 3 strength tablets (50 mg/500 mg). Weekly monitoring is recommended for 28 days after resuming treatment with lower strength Akeega. When starting the lower strength dose, please refer to “Recommended monitoring” below for further information regarding liver function. If patient was already on lower strength Akeega tablet (50 mg/500 mg), consider treatment discontinuation. Third occurrence Consider discontinuing treatment with Akeega based on clinical judgment. ≥ 1 Grade 3 During Akeega treatment interruption, abiraterone acetate and prednisone or prednisolone may be considered by the physician and given to maintain daily dose of abiraterone acetate (see abiraterone acetate prescribing information). Hepatotoxicity For patients who develop ≥ Grade 3 hepatotoxicity (alanine aminotransferase [ALT] increases or aspartate aminotransferase [AST] increases above five times the upper limit of normal [ULN]), treatment with Akeega should be interrupted and liver function closely monitored (see section 4.4). Re-treatment may take place only after return of liver function tests to the patient’s baseline and at a reduced dose level of one regular strength Akeega tablet (equivalent to 100 mg niraparib/500 mg abiraterone acetate). For patients being re-treated, serum transaminases should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 100 mg/500 mg daily (1 tablet), treatment with Akeega should be discontinued. If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) while on Akeega, treatment should be permanently discontinued. Permanently discontinue Akeega for patients who develop a concurrent elevation of ALT greater than 3 ^ ULN, and total bilirubin greater than 2 ^ ULN, in the absence of biliary obstruction or other causes responsible for the concurrent elevation (see section 4.4). Recommended monitoring Complete blood counts should be obtained prior to starting treatment, weekly for the first month, every two weeks for the next two months, followed by monthly monitoring for the first year and then every other month for the remainder of treatment to monitor for clinically significant changes in any haematologic parameter (see section 4.4). Serum aminotransferases and total bilirubin should be measured prior to starting treatment, every two weeks for the first three months of treatment and monthly thereafter for the first year and then every other month for the duration of treatment. When starting the lower strength dose (two tablets) after dose interruption, liver function should be monitored every two weeks for six weeks due to risk of increased abiraterone exposure (see section 5.2), before resuming regular monitoring. Serum potassium should be monitored monthly for the first year and then every other month for the duration of treatment (see section 4.4). Blood pressure monitoring should occur weekly for the first two months, monthly for the first year and then every other month for the duration of treatment. In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated with Akeega, consider maintaining the patient’s potassium level at ≥ 4.0 mM. Special populations Elderly No dose adjustment is necessary for elderly patients (see section 5.2). Hepatic impairment No dose adjustment is necessary for patients with pre-existing mild hepatic impairment (Child-Pugh Class A). There are no data on the clinical safety and efficacy of multiple doses of Akeega when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No dose adjustment can be predicted. The use of Akeega should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see sections 4.4 and 5.2). Akeega is contraindicated in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2). Renal impairment No dose adjustment is necessary for patients with mild to moderate renal impairment, although close monitoring of safety events should be conducted with moderate renal impairment due to the potential for increased niraparib exposure. There are no data on the use of Akeega in patients with severe renal impairment or end stage renal disease undergoing haemodialysis, Akeega may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events (see sections 4.4 and 5.2). Paediatric population There is no relevant use of Akeega in the paediatric population. Method of administration Akeega is for oral use. The tablets must be taken as a single dose, once daily. Akeega should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal (see section 5.2). For optimal absorption, Akeega tablets must be swallowed whole with water, they must not be broken, crushed, or chewed. Precaution to be taken before manipulating or administering the product Women who are or may become pregnant should wear gloves when handling the tablets (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Women who are or may become pregnant (see section 4.6). Severe hepatic impairment [Child-Pugh Class C (see sections 4.2, 4.4 and 5.2)]. Akeega plus prednisone or prednisolone is contraindicated in combination with Ra-223 treatment. 4.4 Special warnings and precautions for use Haematological adverse reactions Haematological adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in patients treated with Akeega (see section 4.2). Testing complete blood counts weekly for the first month, every two weeks for the next two months, followed by monthly monitoring for the first year and then every other month for the remainder of treatment is recommended to monitor for clinically significant changes in any haematological parameter while on treatment (see section 4.2). Based on individual laboratory values, weekly monitoring for the second month may be warranted. If a patient develops severe persistent haematological toxicity including pancytopenia that does not resolve within 28 days following interruption, Akeega should be discontinued. Due to the risk of thrombocytopenia, other medicinal products known to reduce platelet counts should be used with caution in patients taking Akeega (see section 4.8). When starting the lower strength dose (two tablets) after dose interruption due to haematological adverse reactions, liver function should be monitored every two weeks for six weeks due to risk of increased abiraterone exposure (see section 5.2), before resuming regular monitoring (see section 4.2). Hypertension Akeega may cause hypertension and pre-existing hypertension should be adequately controlled before starting Akeega treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and every other month thereafter during treatment with Akeega. Hypokalaemia, fluid retention, & cardiovascular adverse reactions due to mineralocorticoid excess Akeega may cause hypokalaemia and fluid retention (see section 4.8) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment). QT prolongation has been observed in patients experiencing hypokalaemia in association with Akeega treatment. Hypokalaemia and fluid retention should be corrected and controlled. Before treating patients with a significant risk for congestive heart failure (e.g., a history of cardiac failure, or cardiac events such as ischaemic heart disease), cardiac failure should be treated and cardiac function optimised. Fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every two weeks for three months, then monthly thereafter and abnormalities corrected. Akeega should be used with caution in patients with a history of cardiovascular disease. Management of cardiac risk factors (including hypertension, dyslipidaemia, and diabetes) should be optimised in patients receiving Akeega and these patients should be monitored for signs and symptoms of cardiac disease. Abiraterone acetate, a component of Akeega, increases mineralocorticoid levels and carries a risk for cardiovascular events. Mineralocorticoid excess may cause hypertension, hypokalaemia, and fluid retention. Previous androgen deprivation therapy (ADT) exposure as well as advanced age are additional risks for cardiovascular morbidity and mortality. The MAGNITUDE study excluded patients with clinically significant heart disease as evidenced by myocardial infarction, arterial and venous thrombotic events in the past six months, severe or unstable angina, or NYHA Class II to IV heart failure or cardiac ejection fraction measurement of < 50%. Patients with a history of cardiac failure should be clinically optimised and appropriate management of symptoms instituted. If there is a clinically significant decrease in cardiac function, discontinuation of Akeega should be considered. Infections In MAGNITUDE, severe infections including COVID-19 infections with fatal outcome occurred more frequently in patients treated with Akeega. Patients should be monitored for signs and symptoms of infection. Severe infections may occur in absence of neutropenia and/or leukopenia. Pulmonary embolism (PE) In MAGNITUDE, cases of PE were reported in patients treated with Akeega with a higher frequency compared to control. Patients with a prior history of PE or venous thrombosis may be more at risk of a further occurrence. Patients should be monitored for clinical signs and symptoms of PE. If clinical features of PE occur, patients should be evaluated promptly, followed by appropriate treatment. Posterior reversible encephalopathy syndrome (PRES) PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). There have been reports of PRES in patients receiving 300 mg niraparib (a component of Akeega) as a monotherapy in the ovarian cancer population. In the MAGNITUDE study, among prostate cancer patients treated with 200 mg of niraparib, there were no PRES cases reported. In case of PRES, treatment with Akeega should be permanently discontinued and appropriate medical management should be instituted. Hepatotoxicity and hepatic impairment Hepatotoxicity had been recognised as an important identified risk for abiraterone acetate, a component of Akeega. The mechanism for hepatotoxicity of abiraterone acetate is not fully understood. Patients with moderate and severe hepatic impairment (NCI classification) and patients with Child-Turcotte-Pugh Class B and C were excluded from Akeega combination studies. In the MAGNITUDE study and all combination clinical studies, the risk for hepatotoxicity was mitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver function tests (Serum total bilirubin > 1.5 ^ ULN or direct bilirubin > 1 ^ ULN and AST or ALT > 3 ^ ULN). Marked increases in liver enzymes leading to treatment interruption or discontinuation occurred in clinical studies, although these were uncommon (see section 4.8). Serum aminotransferase and total bilirubin levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. When starting the lower strength dose (two tablets) after dose interruption, liver function should be monitored every two weeks for six weeks due to risk of increased abiraterone exposure (see section 5.2), before resuming regular monitoring. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. Development of elevated aminotransferases in patients treated with Akeega should be promptly managed with treatment interruption. If at any time the ALT or AST rises above 5 times the ULN, treatment with Akeega should be interrupted and liver function closely monitored. Re-treatment may take place only after return of liver function tests to the patient’s baseline and at a reduced dose level (see section 4.2). Treatment should be permanently discontinued in patients with elevations of ALT or AST > 20 ^ ULN. Treatment should be permanently discontinued in patients who develop a concurrent elevation of ALT > 3 ^ ULN and a total bilirubin > 2 ^ ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation. If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, treatment with Akeega should be permanently discontinued. Patients with active or symptomatic viral hepatitis were excluded from clinical studies; thus, there are no data to support the use of Akeega in this population. Moderate hepatic impairment (Child-Pugh Class B or any AST and TB > 1.5 x - 3 x ULN) has been shown to increase the systemic exposure to abiraterone and niraparib (see section 5.2). There are no data on the clinical safety and efficacy of multiple doses of Akeega when administered to patients with moderate or severe hepatic impairment. The use of Akeega should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). Akeega should not be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2). Hypoglycaemia Cases of hypoglycaemia have been reported when abiraterone acetate (a component of Akeega) plus prednisone or prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (metabolised by CYP2C8) (see section 4.5). Blood sugar should, therefore, be monitored in patients with diabetes. Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) MDS/AML, including cases with fatal outcome, have been reported in ovarian cancer studies among patients who received 300 mg of niraparib (a component of Akeega). No cases of MDS/AML have been observed in patients treated with 200 mg of niraparib and 1000 mg of abiraterone acetate plus prednisone or prednisolone. For suspected MDS/AML or prolonged haematological toxicities that has not resolved with treatment interruption or dose reduction, the patient should be referred to a haematologist for further evaluation. If MDS and/or AML is confirmed, treatment with Akeega should be permanently discontinued, and the patient should be treated appropriately. Corticosteroid withdrawal and coverage of stress situations Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If Akeega is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information above). In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of corticosteroids may be indicated before, during and after the stressful situation. Bone density Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of abiraterone acetate (a component of Akeega) in combination with a glucocorticoid could increase this effect. Increased fractures and mortality in combination with Radium (Ra) 223 Dichloride Treatment with Akeega plus prednisone or prednisolone in combination with Ra-223 treatment is contraindicated (see section 4.3) due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical studies with abiraterone acetate, a component of Akeega. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of Akeega in combination with prednisone or prednisolone. Hyperglycaemia The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured frequently in patients with diabetes. Skeletal muscle effects Cases of myopathy and rhabdomyolysis have not been seen in patients treated with Akeega. In abiraterone acetate (a component of Akeega) monotherapy studies, most cases developed within the first six months of treatment and recovered after abiraterone acetate withdrawal. Caution is recommended in patients concomitantly treated with medicinal products known to be associated with myopathy/rhabdomyolysis. Interactions with other medicinal products Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure of abiraterone (see section 4.5). Lactose and sodium This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Pharmacokinetic interactions No clinical study evaluating drug interactions has been performed using Akeega. Interactions that have been identified in studies with individual components of Akeega (niraparib or abiraterone acetate) determine the interactions that may occur with Akeega. Effects of other medicinal products on niraparib or abiraterone acetate CYP3A4 inducers and inhibitors Abiraterone is a CYP3A4 substrate. In a clinical study in healthy subjects pretreated with the strong CYP3A4 inducer rifampicin, 600 mg daily for six days, followed by a single dose of abiraterone acetate 1000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John’s wort [Hypericum perforatum]) during treatment with Akeega should be avoided unless there is no therapeutic alternative (see section 4.4). In a separate clinical study in healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effects of niraparib or abiraterone acetate on other medicinal products CYP2D6 substrates Abiraterone is an inhibitor of CYP2D6. In a clinical study to determine the effects of abiraterone acetate plus prednisone (AAP) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9-fold. The AUC₂₄ for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol. CYP2C8 substrates Abiraterone is an inhibitor of CYP2C8. In a clinical study in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1000 mg abiraterone acetate. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with Akeega because of the abiraterone acetate component. Examples of medicinal products metabolised by CYP2C8 include pioglitazone and repaglinide (see section 4.4). Pharmacodynamic interactions Akeega with vaccines or immunosuppressant agents has not been studied. The data on niraparib, in combination with cytotoxic medicinal products, are limited. Caution should be taken if Akeega is used in combination with live or live-attenuated vaccines, immunosuppressant agents or with other cytotoxic medicinal products. Use with products known to prolong QT interval Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering Akeega with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes, such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. Use with spironolactone Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with Akeega is not recommended (see section 5.1). 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception in males and females It is not known whether components of Akeega or their metabolites are present in semen. During treatment and for four months after the last dose of Akeega: ^ A condom is required if the patient is engaged in sexual activity with a pregnant woman. ^ If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies in animals have shown reproductive toxicity (see section 5.3). Pregnancy Akeega is not for use in women (see section 4.3). There are no data from the use of Akeega in pregnant women. Akeega has the potential to cause foetal harm based on the mechanism of action of both components and findings from animal studies with abiraterone acetate. Animal developmental and reproductive toxicology studies were not conducted with niraparib (see section 5.3). Breast-feeding Akeega is not for use in women. Fertility There are no clinical data on fertility with Akeega. In animal studies, male fertility was reduced with niraparib or abiraterone acetate but these effects were reversible following treatment cessation (see section 5.3). 4.7 Effects on ability to drive and use machines Akeega has moderate influence on the ability to drive or use machines. Patients who take Akeega may experience asthenia, fatigue, dizziness or difficulties concentrating. Patients should use caution when driving or using machines. 4.8 Undesirable effects Summary of the safety profile The overall safety profile of Akeega is based on data from a Phase 3, randomised, double-blind, placebo-controlled study, MAGNITUDE cohort 1 (N=212). The most common adverse reactions of all grades occurring in >10% in the niraparib plus AAP arm were anaemia (50.0%), hypertension (33.0%), constipation (33.0%), fatigue (29.7%), nausea (24.5%), thrombocytopenia (23.1%), dyspnoea (17.9%), back pain (17.0%), decreased appetite (15.6%), neutropenia (15.1%), arthralgia (15.1%), vomiting (14.6%), hypokalaemia (13.7%), dizziness (12.7%), insomnia (11.3%), hyperglycaemia (11.8%) and urinary tract infection (10.4%). The most frequently observed Grade 3-4 adverse reactions were anaemia (30.2%), hypertension (15.6%), thrombocytopenia (7.5%), neutropenia (6.6%) and blood alkaline phosphatase increased (5.7%). Tabulated list of adverse reactions Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 3: Adverse reactions identified in clinical studies System Organ Class Frequency Adverse reaction Infections and infestations very common urinary tract infection common pneumoniae, bronchitis, nasopharyngitis uncommon urosepsis, conjunctivitis Blood and lymphatic system very common anaemia, thrombocytopenia, neutropenia, disorders leukopenia common lymphopenia not known pancytopenia⁷ Immune system disorders not known hypersensitivity (including anaphylaxis)⁷ Metabolism and nutrition very common decreased appetite, hypokalaemia disorders common hypertriglyceridaemia Psychiatric disorders very common insomnia common depression, anxiety uncommon confusional state, cognitive impairment⁸ Nervous system disorders very common dizziness common headache uncommon dysgeusia not known posterio 7r reversible encephalopathy syndrome (PRES) Cardiac disorders common tachyca 1rdia, palpitations, atrial fibrillation, cardiac failure, myocar 2dial infarction uncommon angina pectoris , QT prolongation Vascular disorders very common hypertension not known hypertensive crisis⁷ Endocrine disorders not known adrenal insufficiency⁹ Respiratory, thoracic and very common dyspnoea mediastinal disorders common cough, pulmonary embolism, pneumonitis uncommon epistaxis Table 3: Adverse reactions identified in clinical studies System Organ Class Frequency Adverse reaction not known allergic alveolitis⁹ Gastrointestinal disorders very common constipation, na 3usea, vomiting common abdominal pain , dyspepsia, diarrhoea, abdominal distention, stomatitis, dry mouth uncommon mucosal inflammation Hepatobiliary disorders common hepatitis⁴ uncommon acute 5 hepatic failure Skin and subcutaneous tissue common rash disorders uncommon photosensitivity Musculoskeletal and connective very common back pain, arthralgia tissue disorders common myalgia not known myopathy⁹, rhabdomyolysis⁹ Renal and urinary disorders common haematuria General disorders and very common fatigue, asthenia administration site conditions common oedema peripheral Investigations very common blood alkaline phosphatase increased, weight decreased common blood creatinine increased, AST increased, ALT increased uncommon gamma-g 6lutamyl transferase increased Injury, poisoning and procedural very common fractures c 1omplications 2 Includes cardiac failure congestive, cor pulmonale, left ventricular dysfunction 3 Includes coronary artery disease, acute coronary syndrome 4 Includes abdominal pain upper 5 Includes hepatitis acute, fulminant, hepatic cytolysis, hepatotoxicity 6 Includes rash, erythema, dermatitis, rash maculo-papular, rash pruritic 7 Includes osteoporosis and osteoporosis-related fractures 8 Not observed with Akeega. Reported in post-marketing experience with niraparib monotherapy 9 Not observed with Akeega. Reported with niraparib monotherapy Not observed with Akeega. Reported in post-marketing experience with abiraterone monotherapy Description of selected adverse reactions Haematological toxicities Haematological toxicities (anaemia, thrombocytopenia and neutropenia) including laboratory findings are the most frequent adverse reactions attributable to niraparib (a component of Akeega). These toxicities generally occurred within the first two months of treatment with the incidence decreasing over time. In the MAGNITUDE study and other Akeega studies, the following haematological parameters were inclusion criteria: absolute neutrophil count (ANC) ≥ 1500 cells/μL; platelets ≥ 100000 cells/μL and haemoglobin ≥ 9 g/dL. Haematological adverse reactions were managed with laboratory monitoring and dose modifications (see sections 4.2 and 4.4). Anaemia Anaemia was the most frequent adverse reaction (50.0%) and most commonly observed Grade 3-4 event (30.2%) in the MAGNITUDE study. Anaemia occurred early during the course of therapy (median time to onset of 59 days). In the MAGNITUDE study, dose interruptions occurred in 22.6% and dose reductions in 13.7% of patients. Twenty-seven percent of patients received at least one anaemia-related transfusion. Anaemia caused discontinuation in a relatively small number of patients (2.4%). Thrombocytopenia In the MAGNITUDE study, 23.1% of treated patients reported thrombocytopenia while 7.5% of patients experienced Grade 3-4 thrombocytopenia. Median time from first dose to first onset was 56 days. In the MAGNITUDE study, thrombocytopenia was managed with dose modification (interruption 10.8% and reduction in 2.8%) and platelet transfusion (2.4%) where appropriate (see section 4.2). Discontinuation occurred in 0.5% of patients. In the MAGNITUDE study, 1.4% of patients experienced a nonlife-threatening bleeding event. Neutropenia In the MAGNITUDE study, 15.1% of patients experienced neutropenia with Grade 3-4 neutropenia reported in 6.6% of patients. Median time from first dose to first report of neutropenia was 54 days. Neutropenia led to treatment interruption in 6.6% of patients and dose reduction in 1.4%. There were no treatment discontinuations due to neutropenia. In the MAGNITUDE study, 0.9% of patients had a concurrent infection. Hypertension Hypertension is an adverse reaction for both components of Akeega and patients with uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg) were excluded in all combination studies. Hypertension was reported in 33% of patients of whom 15.6% had Grade ≥ 3. The median time to onset of hypertension was 60.5 days. Hypertension was managed with adjunctive medicinal products. Patients should have blood pressure controlled before initiating Akeega and blood pressure should be monitored on treatment (see section 4.4). Cardiac events In the MAGNITUDE study, the incidence of TEAEs of cardiac disorder (all grades) was similar in both arms, except for the arrhythmia category, where AEs were observed in 13.7% of patients in the niraparib plus AAP arm and 7.6% of patients in the placebo plus AAP arm (see section 4.4). Higher frequency of arrhythmias was largely due to low grade events of palpitations, tachycardias and atrial arrhythmias. The median time to onset of the events of arrhythmias was 105 days in the niraparib plus AAP arm and 262 days in the placebo plus AAP arm. Events of arrhythmia were resolved in 62% of patients in the niraparib plus AAP arm and 63% of subjects in the placebo plus AAP arm. The incidence of cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive was 2.4% in the niraparib plus AAP arm vs 1.9% in placebo plus AAP arm. The median time to onset of the AESI of cardiac failure was 206 days in the niraparib plus AAP arm and 83 days in the placebo plus AAP arm. Events of cardiac failure were resolved in 20% of patients the niraparib plus AAP arm and 25% of patients in the placebo plus AAP arm. The grouped term of ischemic heart disease (included preferred terms of angina pectoris, acute myocardial infarction, acute coronary syndrome, unstable angina, and arteriosclerosis coronary artery) occurred in 4.2% of the niraparib plus AAP arm vs 4.3% in the placebo plus AAP arm. The median time to onset of the AESI of ischemic heart disease was 538 days in the niraparib plus AAP arm and 257 days in the placebo plus AAP arm. Events of ischemic heart disease were resolved in 78% of patients in both arms. Hepatotoxicity The overall incidence of hepatotoxicity in the MAGNITUDE study was similar for the niraparib plus AAP (12.7%) and placebo plus AAP (12.8%) arms (see sections 4.2 and 4.4). The majority of these events were low grade aminotransferase elevations. Grade 3 events occurred in 1.4% of patients and a Grade 4 event occurred in only one patient (0.5%). The incidence of SAEs was also 0.9%. The median time to onset of hepatotoxicity in the MAGNITUDE study was 34 days. Hepatotoxicity was managed with dose interruptions in 0.9% and dose reduction in 0.5% of patients. In the MAGNITUDE study, 0.5% of patients discontinued treatment due to hepatotoxicity. Paediatric population No studies have been conducted in paediatric patients with Akeega. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose There is no specific treatment in the event of Akeega overdose. In the event of an overdose, physicians should follow general supportive measures and should treat patients symptomatically, including monitoring for arrhythmias, hypokalaemia and signs and symptoms of fluid retention. Liver function also should be assessed. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XK Mechanism of action Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and abiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic dependencies in patients with mCRPC and HRR gene mutations. Niraparib Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis and cell death. Abiraterone acetate Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in, and is required for, androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see section 4.4). Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with luteinising hormone releasing hormone (LHRH) analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy). Pharmacodynamic effects Abiraterone acetate Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. Clinical efficacy and safety First-line treatment of mCRPC patients with BRCA 1/2 mutations The efficacy of Akeega was established in a randomised placebo-controlled multicentre Phase 3 clinical study of patients with mCRPC, MAGNITUDE (Study 64091742PCR3001). MAGNITUDE was a Phase 3, randomised, double-blind, placebo-controlled, multicentre study that evaluated treatment with the combination of niraparib (200 mg) and abiraterone acetate (1000 mg) plus prednisone (10 mg) daily versus AAP standard of care. Efficacy data are based on Cohort 1 that consisted of 423 patients with mCRPC and select HRR gene mutations, who were randomised (1:1) to receive either niraparib plus AAP (N=212) or placebo plus AAP (N=211) orally daily. Treatment was continued until disease progression, unacceptable toxicity, or death. Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior AAP (up to 4 months) and ongoing ADT, were eligible. Plasma, blood, and/or tumour tissue samples for all patients were tested by validated next generation sequencing tests to determine germline and/or somatic HRR gene mutation status. There were 225 subjects with a BRCA1/2 mutation enrolled in the study (113 received Akeega). There were an additional 198 patients with a non-BRCA1/2 mutation (ATM, CHEK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) enrolled in the study (99 received Akeega). The primary endpoint was radiographic progression free survival (rPFS) as determined by blinded independent central radiology (BICR) review based on Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 (soft and tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Time to symptomatic progression (TSP), time to cytotoxic chemotherapy (TCC), and overall survival (OS) were included as secondary efficacy endpoints. In the All HRR Population, the primary efficacy results with a median follow-up of 18.6 months showed statistically significant improvement in BICR-assessed rPFS with a HR =0.729 (95% CI: 0.556, 0.956; p=0.0217). Table 4 summarises the demographics and baseline characteristics of BRCA patients enrolled in Cohort 1 of the MAGNITUDE study. The median PSA at diagnosis was 41.07 ug/L (range 01-12080). All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. All patients who had not received prior orchiectomy continued background androgen deprivation therapy with a GnRH analogue.

Table 4: Summary of demographics and baseline characteristics in the MAGNITUDE study Cohort 1 (BRCA) Total N=225 n (%) Age (years) < 65 76 (33.8) ≥ 65-74 96 (42.7) ≥ 75 53 (23.6) Median 68.0 Range 43-100 Race Caucasian 162 (72.0) Asian 38 (16.9) Black 3 (1.3) Unknown 22 (9.8) Stratification factors Past taxane-based chemotherapy exposure 55 (24.4) Past AR-targeted therapy exposure 11 (4.9) Prior AAP use 59 (26.2) Baseline disease characteristics Gleason score ≥ 8 155 (69.2) Bone involvement 192 (85.3) Visceral disease (liver, lung, adrenal gland, other) 48 (21.3) Metastasis stage at initial diagnosis (M1) 120 (53.3) Median time from initial diagnosis to randomization (years) 2.26 Median time from mCRPC to first dose (years) 0.27 BPI-SF pain score at baseline (last score before first dose) 0 114 (50.7) 1 to 3 91 (40.4) > 3 20 (8.9) A statistically significant improvement in BICR-assessed rPFS was observed in the primary analysis for BRCA subjects treated with niraparib plus AAP, compared with BRCA subjects treated with placebo plus AAP. Key efficacy results in the BRCA population are presented in Table 5. The Kaplan- Meier curves for BICR assessed rPFS in the BRCA population are shown in Figure 4. Table 5: Efficacy results from the BRCA population of the MAGNITUDE study Akeega Placebo Endpoints 1 (N=113) (N=112) Radiographic Progression-free Survival Event of disease progression or death (%) 45 (39.8%) 64 (57.1%) Median, months (95% CI) 16.6 (13.9, NE) 10.9 (8.3, 13.8) Hazard Ratio (95% CI) 0.533 (0.361, 0.789) p-value 2 0.0014 Overall Survival 1 Hazard Ratio (95% CI) 0.881 (0.582, 1.335) Primary analysis/Interim analysis (data cut-off: 08OCT2021), with 18.6 months median follow-up 2 Interim analysis 2 (data cut-off: 17JUN2022), with 26.8 months median follow-up NE = Not estimable Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Akeega in all subsets of the paediatric population in prostate malignant neoplasms. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Co-administration of niraparib and abiraterone has no impact on the exposures of the individual moeities. The AUC and Cmax are comparable for niraparib and abiraterone when administered as Akeega regular strength (100 mg/500 mg) film-coated tablet or as combination of individual components when compared to respective monotherapy exposures. Absorption Akeega In mCRPC patients, under fasted and modified fasted conditions, upon administration of multiple doses of Akeega tablets, the maximum plasma concentration was achieved within a median of 3 hours for niraparib, and a median of 1.5 hours for abiraterone. In a relative bioavailability study, the maximum (Cmax) and total (AUC0-72h) exposure of abiraterone in mCRPC patients (n=67) treated with Akeega lower strength film-coated tablets (2 x 50 mg/500 mg) was 33% and 22% higher, respectively, when compared to exposures in patients (n=67) taking individual single agents (100 mg niraparib capsule and 4 x 250 mg abiraterone acetate tablets) (see section 4.2). The inter-subject variability (%CV) in exposures were 80.4% and 72.9%, respectively. Niraparib exposure was comparable between Akeega lower strength film-coated tablets and single agents. Niraparib The absolute bioavailability of niraparib is approximately 73%. Niraparib is a substrate of P- glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with medicinal products that inhibit these transporters is unlikely. Abiraterone acetate Abiraterone acetate is rapidly converted in vivo to abiraterone (see section 5.1). Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in highly variable exposures. Therefore, abiraterone acetate must not be taken with food. Distribution Based on population pharmacokinetic analysis, the apparent volume of distribution of niraparib and abiraterone were 1,117 L and 25,774 L, respectively, indicative of extensive extravascular distribution. Niraparib Niraparib was moderately protein-bound in human plasma (83.0%), mainly with serum albumin. Abiraterone acetate The plasma protein binding of ¹⁴C-abiraterone in human plasma is 99.8%. Biotransformation Niraparib Niraparib is metabolised primarily by carboxylesterases (CEs) to form a major inactive metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major circulating metabolites. The potential to inhibit CYP3A4 at the intestinal level has not been established at relevant niraparib concentrations. Niraparib weakly induces CYP1A2 at high concentrations in vitro. Abiraterone acetate Following oral administration of ¹⁴C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed by CEs to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. Abiraterone is a substrate of CYP3A4 and sulfotransferase 2A1 (SULT2A1). The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, two main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity. Abiraterone is an inhibitor of the hepatic drug metabolising enzymes CYP2D6 and CYP2C8 (see section 4.5). Elimination Akeega The mean t½ of niraparib and abiraterone when given in combination were approximately 62 hours and 20 hours, respectively, and apparent CL/F of niraparib and abiraterone were 16.7 L/h and 1673 L/h, respectively based on the population pharmacokinetic analysis in subjects with mCRPC. Niraparib Niraparib is eliminated primarily through th 1⁴e hepatobiliary and renal routes. Following an oral administration of a single 300 mg dose of [ C]-niraparib, on average 86.2% (range 71% to 91%) of the dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accounted for 47.5% (range 33.4% to 60.2%) and in the faeces for 38.8% (range 28.3% to 47.0%) of the dose. In pooled samples collected over six days, 40.0% of the dose was recovered in the urine primarily as metabolites and 31.6% of the dose was recovered in the faeces primarily as unchanged niraparib. The metabolite M1 is a substrate of Multidrug And Toxin Extrusion (MATE) 1 and 2. Abiraterone acetate Following oral administration of ¹⁴C-abiraterone acetate 1000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively). Effects of niraparib or abiraterone on transporters Niraparib inhibits P-gp weakly with an IC50=161 μM. Niraparib is an inhibitor of BCRP, Organic Cation Transporter 1 (OCT1), MATE-1 and 2 with IC50 values of 5.8 μM, 34.4 μM, 0.18 μM and ≤ 0.14 μM, respectively. The major metabolites of abiraterone, abiraterone sulphate and N-oxide abiraterone sulphate, were shown to inhibit the hepatic uptake transporter Organic Anion Transport Polypeptide 1B1 (OATP1B1) and as a consequence, the plasma exposures of medicinal products eliminated by OATP1B1 may increase. There are no clinical data available to confirm transporter OATP1B1 based interaction. Special populations Hepatic impairment Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib/AA in combination, mild hepatic impairment (NCI- ODWG criteria, n=231) did not affect the exposure of niraparib. In a clinical study of cancer patients using NCI-ODWG criteria to classify the degree of hepatic impairment, niraparib AUCinf in patients with moderate hepatic impairment (n=8) was 1.56 (90% CI: 1.06 to 2.30) times the niraparib AUCinf in patients with normal hepatic function (n=9) following administration of a single 300 mg dose. The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased by approximately 1.11-fold and 3.6-fold in subjects with mild and moderate pre-existing hepatic impairment, respectively. In another study, the pharmacokinetics of abiraterone were examined in subjects with pre-existing severe (n = 8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The AUC of abiraterone increased by approximately 7-fold and the fraction of free drug increased by 1.8-fold in subjects with severe hepatic impairment compared to subjects with normal hepatic function. There is no clinical experience using Akeega in patients with moderate and severe hepatic impairment (see section 4.2). Renal impairment Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib/AA in combination, patients with mild (creatinine clearance 60-90 mL/min, n=337) and moderate (creatinine clearance 30-60 mL/min, n=114) renal impairment had mildly reduced niraparib clearance compared to individuals with normal renal function (up to 13% higher exposure in mild and 13-40% higher exposure in moderate renal impairment). The pharmacokinetics of abiraterone was compared in patients with end-stage renal disease on a stable haemodialysis schedule (n=8) versus matched control subjects with normal renal function (n=8). Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis. There is no clinical experience using Akeega in patients with severe renal impairment (see section 4.2). Weight, age and race Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib or abiraterone acetate alone or in combination: ^ Body weight did not have a clinically meaningful influence on the exposure of niraparib (body weight range: 43.3-165 kg) and abiraterone (body weight range: 56.0-135 kg). ^ Age had no significant impact on the pharmacokinetics of niraparib (age range 45-90 years) and abiraterone (age range 19-85 years). ^ There is insufficient data to conclude on the impact of race on the pharmacokinetics of niraparib and abiraterone. Paediatric population No studies have been conducted to investigate the pharmacokinetics of Akeega in paediatric patients. 5.3 Preclinical safety data Akeega Non-clinical studies with Akeega have not been performed. The nonclinical toxicology data are based on findings in studies with niraparib and abiraterone acetate individually. Niraparib In vitro, niraparib inhibited the dopamine transporter at concentration levels below human exposure levels. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites in cortex. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinical relevance of these findings is not known. No effect on behavioural and/or neurological parameters have been observed in repeat-dose toxicity studies in rats and dogs at estimated CNS exposure levels similar to or below expected therapeutic exposure levels. Decreased spermatogenesis was observed in both rats and dogs at exposure levels below therapeutic exposure levels and were largely reversible within four weeks of cessation of dosing. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test but was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Reproductive and developmental toxicity studies have not been conducted with niraparib. Carcinogenicity studies have not been conducted with niraparib. Abiraterone acetate In animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period. In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was completely reversible in four to 16 weeks after abiraterone acetate was stopped. In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reduced foetal weight and survival. Effects on the external genitalia were observed though abiraterone acetate was not teratogenic. In these fertility and developmental toxicity studies performed in the rat, all effects were related to the pharmacological activity of abiraterone. Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat, abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding is considered related to the pharmacological action of abiraterone and rat-specific. Abiraterone acetate was not carcinogenic in female rats. Environmental risk assessment (ERA) The active substance, abiraterone, shows an environmental risk for the aquatic environment, especially to fish (see section 6.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Akeega 50 mg/500 mg film-coated tablets Tablet core Colloidal anhydrous silica Crospovidone Hypromellose Lactose monohydrate Magnesium stearate Microcrystalline cellulose Sodium lauryl sulfate Film-coating Iron oxide black (E172) Iron oxide red (E172) Iron oxide yellow (E172) Sodium lauryl sulphate Glycerol monocaprylocaprate Polyvinyl alcohol Talc Titanium dioxide (E171) Akeega 100 mg/500 mg film-coated tablets Tablet core Colloidal anhydrous silica Crospovidone Hypromellose Lactose monohydrate Magnesium stearate Microcrystalline cellulose Sodium lauryl sulfate Film-coating Iron oxide red (E172) Iron oxide yellow (E172) Sodium lauryl sulphate Glycerol monocaprylocaprate Polyvinyl alcohol Talc Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 30 months. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs each containing 28 film-coated tablets in a PVdC/PE/PVC blister with an aluminum push-through foil. 6.6 Special precautions for disposal and other handling Based on its mechanism of action, this medicinal product may harm a developing foetus. Therefore, women who are or may become pregnant should handle Akeega with protection, e.g., gloves (see section 4.6). Any unused medicinal product or waste material should be disposed of in accordance with local requirements. This medicinal product may pose a risk to the aquatic environment (see section 5.3). 7. MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 8. MARKETING AUTHORISATION NUMBER(S) EU/1/23/1722/001 EU/1/23/1722/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency www.ema.europa.eu.

ANNEX II A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Janssen Cilag SpA Via C. Janssen, Borgo San Michele Latina 04100 Italy B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION ^ Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within six months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT ^ Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: ^ At the request of the European Medicines Agency; ^ Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. ^ Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Post-authorisation efficacy study (PAES): In order to further characterise the Q12024 efficacy of Akeega, to be used in combination with prednisone or prednisolone for the treatment of adult patients with metastatic castration resistant prostate cancer (mCRPC) and BRCA1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated, the MAH should submit the final overall survival data and other long-term endpoints from the MAGNITUDE study.

ANNEX III LABELLING AND PACKAGE LEAFLET A. LABELLING PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 50 mg/500 mg (28 days) 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further 4. PHARMACEUTICAL FORM AND CONTENTS 56 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Take Akeega at least two hours after eating. Do not eat any Akeega. Swallow the tablets whole. Do not break, crush, or chew tablets. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard unused contents appropriately in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/23/1722/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Akeega 50 mg/500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING OUTER WALLET 50 mg/500 mg (28 days) 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Take Akeega at least two hours after eating. Do not eat any Akeega. Swallow the tablets whole. Do not break, crush, or chew tablets. Read the package leaflet before use. Oral use. (1) Press and hold (see Figure 8) (2) Pull out (see Figure 9) 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard unused contents appropriately in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/23/1722/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN Akeega 50 mg/500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

MINIMUM PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING INNER WALLET 50 mg/500 mg (28 days) 1. NAME OF THE MEDICINAL PRODUCT 2. NAME OF THE MARKETING AUTHORISATION HOLDER Flip open (see Figure 11)

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 50 mg/500 mg (Blister sealed in inner wallet) 1. NAME OF THE MEDICINAL PRODUCT 2. NAME OF THE MARKETING AUTHORISATION HOLDER

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 100 mg/500 mg (28 days) 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further 4. PHARMACEUTICAL FORM AND CONTENTS 56 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Take Akeega at least two hours after eating. Do not eat any Akeega. Swallow the tablets whole. Do not break, crush, or chew tablets. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard unused contents appropriately in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/23/1722/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN Akeega 100 mg/500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING OUTER WALLET 100 mg/500 mg (28 days) 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Take Akeega at least two hours after eating. Do not eat any Akeega. Swallow the tablets whole. Do not break, crush, or chew tablets. Read the package leaflet before use. Oral use. (1) Press and hold (see Figure 8) (2) Pull out (see Figure 9) 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard unused contents appropriately in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/23/1722/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Akeega 100 mg/500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA MINIMUM PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING INNER WALLET 100 mg/500 mg (28 days) 1. NAME OF THE MEDICINAL PRODUCT 2. NAME OF THE MARKETING AUTHORISATION HOLDER Flip open (see Figure 11)

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 100 mg/500 mg (Blister sealed in inner wallet) 1. NAME OF THE MEDICINAL PRODUCT 2. NAME OF THE MARKETING AUTHORISATION HOLDER

B. PACKAGE LEAFLET Package leaflet: Information for the user Akeega 50 mg/500 mg film-coated tablets niraparib/abiraterone acetate Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. ^ Keep this leaflet. You may need to read it again. ^ If you have any further questions, ask your doctor or pharmacist. ^ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. ^ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4). What is in this leaflet 1. What Akeega is and what it is used for 2. What you need to know before you take Akeega 3. How to take Akeega 4. Possible side effects 5. How to store Akeega 6. Contents of the pack and other information 1. What Akeega is and what it is used for Akeega is a medicine that contains two active substances: niraparib and abiraterone acetate, and works in two different ways. Akeega is used to treat adult men with prostate cancer who have changes in certain genes and whose prostate cancer has spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone (also called metastatic castration-resistant prostate cancer). Niraparib is a type of cancer medicine called a PARP inhibitor. PARP inhibitors block an enzyme called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged DNA. When PARP is blocked, cancer cells cannot repair their DNA, resulting in tumour cell death and helping to control the cancer. Abiraterone stops your body from making testosterone; this can slow the growth of prostate cancer. When you take this medicine, your doctor will also prescribe another medicine called prednisone or prednisolone. This is to lower your chances of getting high blood pressure, having too much water in your body (fluid retention), or having reduced levels of a chemical known as potassium in your blood. 2. What you need to know before you take Akeega Do not take Akeega: ^ if you are allergic to niraparib or abiraterone acetate or any of the other ingredients of this medicine - listed in section 6. ^ if you are a woman who is or can become pregnant. ^ if you have severe liver damage. ^ in combination with Ra-223 treatment (which is used to treat prostate cancer). This is because of a possible increase in the risk of bone fracture or death. Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. Warnings and precautions Talk to your doctor or pharmacist before or while taking this medicine if you have: ^ low blood cell counts. Signs and symptoms you need to look out for include fatigue, fever or infection, and abnormal bruising or bleeding. Akeega may also lower your blood cell counts. Your doctor will test your blood regularly throughout your treatment. ^ high blood pressure or heart failure or low blood potassium (low blood potassium may increase the risk of heart rhythm problems), have had other heart or blood vessel problems, have an irregular or rapid heart rate, shortness of breath, gained weight rapidly, or swelling in the feet, ankles, or legs. Your doctor will measure your blood pressure regularly throughout your treatment. ^ headaches, vision changes, confusion, or seizure. These may be signs of a rare neurological side effect named posterior reversible encephalopathy syndrome (PRES) that has been associated with use of niraparib, an active ingredient of Akeega. ^ high fever, fatigue and other signs and symptoms of severe infection. ^ blood clots in the lungs, or have had them in the past. ^ liver problems. ^ low or high levels of sugar in the blood. ^ muscle weakness and/or muscle pain. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. If you develop low blood-cell counts for a long period of time while taking Akeega, this may be a sign of more serious problems with the bone marrow such as ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukaemia’ (AML). Your doctor may want to test your bone marrow to check for these problems. Before taking Akeega, also talk to your doctor or pharmacist about: ^ the effect Akeega may have on your bones. ^ taking prednisone or prednisolone (another medicine you must take with Akeega) If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking this medicine. Blood monitoring Akeega may affect your liver, but you may not notice any symptoms of liver problems. When you are taking this medicine, your doctor will therefore check your blood periodically to look for any effects on your liver. Children and adolescents This medicine is not for use in children and adolescents. If Akeega is accidentally swallowed by a child or adolescent, take them to the hospital immediately and take this package leaflet with you to show to the emergency doctor. Other medicines and Akeega Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Akeega can affect the way some other medicines work. Also, some other medicines can affect the way Akeega works. Treatment with medicines that stop the body from producing testosterone, may increase the risk of heart rhythm problems. Tell your doctor if you are receiving medicine: ^ to treat heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol); ^ known to increase the risk of heart rhythm problems (e.g., methadone), used for pain relief and part of drug addiction detoxification; moxifloxacin, an antibiotic; antipsychotics, used for serious mental illnesses. Tell your doctor if you are taking any of the medicines listed above. Akeega with food ^ This medicine must not be taken with food (see section 3, “Taking Akeega”), as this may increase your risk of side effects. Pregnancy and breast-feeding Akeega is not for use in women. ^ This medicine may cause harm to the unborn child if it is taken by women who are pregnant. ^ Women who are pregnant or who may become pregnant should wear gloves if they need to touch or handle Akeega. Contraception for men using Akeega ^ If you are having sex with a woman who can become pregnant, use a condom and another effective birth control method. Use contraception during treatment and for 4 months after stopping. Talk to your doctor if you have any questions about contraception. ^ If you are having sex with a pregnant woman, use a condom to protect the unborn child. Driving and using machines Taking Akeega may make you feel weak, unfocused, tired or dizzy. This may influence your ability to drive and use machines. Use caution when driving or using machines. Akeega contains lactose and sodium ^ Akeega contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. ^ This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. 3. How to take Akeega Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much to take The recommended starting dose is 200 mg/1000 mg once a day. Taking Akeega ^ Take this medicine by mouth. ^ Do not take Akeega with food. ^ Take Akeega tablets as a single dose once daily on an empty stomach at least one hour before or at least two hours after eating (see section 2, “Akeega with food”). ^ Swallow the tablets whole with water. Do not break, crush, or chew the tablets. This will ensure the medicine works as well as possible. ^ Akeega is taken with a medicine called prednisone or prednisolone. o Take the prednisone or prednisolone exactly as your doctor has told you. o You need to take prednisone or prednisolone every day while you are taking Akeega. o The amount of prednisone or prednisolone you take may need to be changed if you have a medical emergency. Your doctor will tell you if you need to change the amount of prednisone or prednisolone you take. Do not stop taking prednisone or prednisolone unless your doctor tells you to. Your doctor may also prescribe other medicines while you are taking Akeega. If you take more Akeega than you should If you take more tablets than you should contact your doctor. You may have an increased risk of side effects. If you forget to take Akeega If you forget to take Akeega or prednisone or prednisolone, take your usual dose as soon as you remember on the same day. If you forget to take Akeega or prednisone or prednisolone for more than one day - talk to your doctor straight away. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. If you stop taking Akeega Do not stop taking Akeega or prednisone or prednisolone unless your doctor tells you to. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop taking Akeega and seek medical attention immediately if you notice any of the following symptoms: Very common (may affect more than 1 in 10 people) ^ Bruising or bleeding for longer than usual if you hurt yourself - these may be signs of a low blood platelet count (thrombocytopenia). ^ Being short of breath, feeling very tired, having pale skin, or fast heartbeat - these may be signs of a low red blood cell count (anaemia). ^ Fever or infection – low white blood cell count (neutropenia) can increase your risk for infection. Signs may include fever, chills, feeling weak or confused, cough, pain or burning feeling when passing urine. Some infections can be serious and may lead to death. ^ Muscle weakness, muscle twitching or a pounding heart beat (palpitations). These may be signs that the level of potassium in your blood is low (hypokalaemia). ^ Increased level of the enzyme ‘alkaline phosphatase’ in the blood Not known (cannot be estimated) – not reported with the use of Akeega but reported with use of niraparib or abiraterone acetate (components of Akeega) ^ Allergic reaction (including severe allergic reaction that can be life-threatening). Signs include: raised and itchy rash (hives) and swelling-sometimes of the face or mouth (angioedema), causing difficulty in breathing, and collapse or loss of consciousness. ^ A sudden increase in blood pressure, which may be a medical emergency that could lead to organ damage or can be life-threatening. Other side effects Talk to your doctor if you get any other side effects. These can include: Very common (may affect more than 1 in 10 people): ^ urinary tract infection ^ low number of white blood cells (leukopenia), seen in blood tests ^ decreased appetite ^ difficulty sleeping (insomnia) ^ feeling dizzy ^ shortness of breath ^ constipation ^ feeling sick (nausea) ^ vomiting ^ back pain ^ joint pain ^ feeling very tired ^ feeling weak ^ weight loss ^ bone fractures Common (may affect up to 1 in 10 people): ^ pneumoniae ^ lung infection (bronchitis) ^ infection of the nose and throat (nasopharyngitis) ^ low number of a type of white blood cell (lymphopenia), seen in blood tests ^ high level of a type of fat (hypertriglyceridemia) in the blood ^ depression ^ feeling anxious ^ headache ^ fast heart beat ^ fast or uneven heart beat (palpitations) ^ irregular heart beat (atrial fibrillation) ^ heart failure, causing shortness of breath and swollen legs ^ heart attack ^ cough ^ blood clot in the lungs, causing chest pain and shortness of breath ^ inflamed lungs ^ stomach pain ^ indigestion ^ diarrhoea ^ bloating ^ sores in the mouth ^ dry mouth ^ inflamed liver (hepatitis) based on blood tests ^ skin rash ^ muscle aches ^ blood in the urine ^ swollen hands, ankles, or feet ^ increased level of ‘creatinine’ in the blood ^ increased level of the enzyme ‘aspartate aminotransferase’ in the blood ^ increased level of the enzyme ‘alanine aminotransferase’ in the blood Uncommon (may affect up to 1 in 100 people): ^ severe infection (sepsis) that spreads from the urinary tract throughout the body ^ inflamed eye (conjunctivitis) ^ feeling confused ^ difficulty thinking, remembering information, or solving problems (cognitive impairment) ^ change in sense of taste ^ chest discomfort, often brought on by physical activity ^ abnormal ECG (electrocardiogram), which could be a sign of heart problems ^ nose bleeds ^ inflammation of the protective linings in the body cavities, such as the nose, mouth, or digestive system ^ sudden liver failure ^ increased sensitivity of the skin to sunlight ^ increased level of ‘gamma-glutamyltransferase’ in the blood Not known (cannot be estimated) – not reported with the use of Akeega but reported with use of niraparib or abiraterone acetate (components of Akeega) ^ low numbers of all types of blood cells (pancytopenia) ^ brain condition with symptoms including seizures (fits), headache, confusion, and changes in vision (posterior reversible encephalopathy syndrome or PRES), which is a medical emergency that could lead to organ damage or can be life-threatening ^ adrenal gland problems (related to salt and water problems) where too little hormone is produced which may cause problems like weakness, tiredness, loss of appetite, nausea, dehydration and skin changes ^ inflamed lungs caused by an allergic reaction (allergic alveolitis) ^ muscle disease (myopathy), which may cause muscle weakness, stiffness or spasms ^ breakdown of muscle tissue (rhabdomyolysis), which may cause muscle cramps or pains, tiredness and dark urine Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V (www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc). By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Akeega Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the container (blister foil, inner wallet, outer wallet, and carton) after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Akeega contains ^ The active substances are niraparib and abiraterone acetate. Each film-coated tablet contains 50 mg niraparib and 500 mg abiraterone acetate. ^ The other ingredients of the tablet core are colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The film-coating contains iron oxide black (E172), iron oxide red (E172), iron oxide yellow (E172), sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide (E171) (see section 2, Akeega contains lactose and sodium). What Akeega looks like and contents of the pack Akeega film-coated tablets are yellowish orange to yellowish brown oval tablet, debossed with “N 50 A” on one side and plain on the other side. Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs of 28 film-coated tablets each. Marketing Authorisation Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium Manufacturer Janssen Cilag SpA Via C. Janssen, Borgo San Michele Latina 04100 Italy For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Lietuva Janssen-Cilag NV UAB "JOHNSON & JOHNSON" Tel/Tél: +3214649411 Tel: +37052786888 janssen@jacbe.jnj.com lt@its.jnj.com България Luxembourg/Luxemburg „Джонсън & Джонсън България” ЕООД Janssen-Cilag NV Тел.: +35924899400 Tél/Tel: +3214649411 jjsafety@its.jnj.com janssen@jacbe.jnj.com Česká republika Magyarország Janssen-Cilag s.r.o. Janssen-Cilag Kft. Tel: +420227012227 Tel.: +3618842858 janssenhu@its.jnj.com Danmark Malta Janssen-Cilag A/S AM MANGION LTD Tlf: +4545948282 Tel: +35623976000 jacdk@its.jnj.com Deutschland Nederland Janssen-Cilag GmbH Janssen-Cilag B.V. Tel: +492137955955 Tel: +31767111111 jancil@its.jnj.com janssen@jacnl.jnj.com Eesti Norge UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS Tel: +3726177410 Tlf: +4724126500 ee@its.jnj.com jacno@its.jnj.com Ελλάδα Österreich Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε. Janssen-Cilag Pharma GmbH Tηλ: +302108090000 Tel: +431610300 España Polska Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o. Tel: +34917228100 Tel.: +48222376000 contacto@its.jnj.com France Portugal Janssen-Cilag Janssen-Cilag Farmacêutica, Lda. Tél: 0800255075 / +33155004003 Tel: +351214368600 medisource@its.jnj.com Hrvatska România Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL Tel: +38516610700 Tel: +40212071800 jjsafety@JNJCR.JNJ.com Ireland Slovenija Janssen Sciences Ireland UC Johnson & Johnson d.o.o. Tel: 1800709122 Tel: +38614011800 medinfo@its.jnj.com Janssen_safety_slo@its.jnj.com Ísland Slovenská republika Janssen-Cilag AB Johnson & Johnson, s.r.o. c/o Vistor hf. Tel: +421232408400 Sími: +3545357000 janssen@vistor.is Italia Suomi/Finland Janssen-Cilag SpA Janssen-Cilag Oy Tel: 800.688.777 / +390225101 Puh/Tel: +358207531300 janssenita@its.jnj.com jacfi@its.jnj.com Κύπρος Sverige Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB Τηλ: +35722207700 Tfn: +4686265000 jacse@its.jnj.com Latvija United Kingdom (Northern Ireland) UAB "JOHNSON & JOHNSON" filiāle Latvijā Janssen Sciences Ireland UC Tel: +37167893561 Tel: +441494567444 lv@its.jnj.com medinfo@its.jnj.com This leaflet was last revised in MM/YYYY. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: www.ema.europa.eu

Package leaflet: Information for the user Akeega 100 mg/500 mg film-coated tablets niraparib/abiraterone acetate Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. ^ Keep this leaflet. You may need to read it again. ^ If you have any further questions, ask your doctor or pharmacist. ^ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. ^ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4). What is in this leaflet 1. What Akeega is and what it is used for 2. What you need to know before you take Akeega 3. How to take Akeega 4. Possible side effects 5. How to store Akeega 6. Contents of the pack and other information 1. What Akeega is and what it is used for Akeega is a medicine that contains two active substances: niraparib and abiraterone acetate, and works in two different ways. Akeega is used to treat adult men with prostate cancer who have changes in certain genes and whose prostate cancer has spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone (also called metastatic castration-resistant prostate cancer). Niraparib is a type of cancer medicine called a PARP inhibitor. PARP inhibitors block an enzyme called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged DNA. When PARP is blocked, cancer cells cannot repair their DNA, resulting in tumour cell death and helping to control the cancer. Abiraterone stops your body from making testosterone; this can slow the growth of prostate cancer. When you take this medicine, your doctor will also prescribe another medicine called prednisone or prednisolone. This is to lower your chances of getting high blood pressure, having too much water in your body (fluid retention), or having reduced levels of a chemical known as potassium in your blood. 2. What you need to know before you take Akeega Do not take Akeega: ^ if you are allergic to niraparib or abiraterone acetate or any of the other ingredients of this medicine - listed in section 6. ^ if you are a woman who is or can become pregnant. ^ if you have severe liver damage. ^ in combination with Ra-223 treatment (which is used to treat prostate cancer). This is because of a possible increase in the risk of bone fracture or death. Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. Warnings and precautions Talk to your doctor or pharmacist before or while taking this medicine if you have: ^ low blood cell counts. Signs and symptoms you need to look out for include fatigue, fever or infection, and abnormal bruising or bleeding. Akeega may also lower your blood cell counts. Your doctor will test your blood regularly throughout your treatment. ^ high blood pressure or heart failure or low blood potassium (low blood potassium may increase the risk of heart rhythm problems), have had other heart or blood vessel problems, have an irregular or rapid heart rate, shortness of breath, gained weight rapidly, or swelling in the feet, ankles, or legs. Your doctor will measure your blood pressure regularly throughout your treatment. ^ headaches, vision changes, confusion, or seizure. These may be signs of a rare neurological side effect named posterior reversible encephalopathy syndrome (PRES) that has been associated with use of niraparib, an active ingredient of Akeega. ^ high fever, fatigue and other signs and symptoms of severe infection. ^ blood clots in the lungs, or have had them in the past. ^ liver problems. ^ low or high levels of sugar in the blood. ^ muscle weakness and/or muscle pain. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. If you develop low blood cell counts for a long period of time while taking Akeega, this may be a sign of more serious problems with the bone marrow such as ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukaemia’ (AML). Your doctor may want to test your bone marrow to check for these problems. Before taking Akeega, also talk to your doctor or pharmacist about: ^ the effect Akeega may have on your bones. ^ taking prednisone or prednisolone (another medicine you must take with Akeega). If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking this medicine. Blood monitoring Akeega may affect your liver, but you may not notice any symptoms of liver problems. When you are taking this medicine, your doctor will therefore check your blood periodically to look for any effects on your liver. Children and adolescents This medicine is not for use in children and adolescents. If Akeega is accidentally swallowed by a child or adolescent, take them to the hospital immediately and take this package leaflet with you to show to the emergency doctor. Other medicines and Akeega Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Akeega can affect the way some other medicines work. Also, some other medicines can affect the way Akeega works. Treatment with medicines that stop the body from producing testosterone, may increase the risk of heart rhythm problems. Tell your doctor if you are receiving medicine: ^ to treat heart rhythm problems (e.g., quinidine, procainamide, amiodarone and sotalol); ^ known to increase the risk of heart rhythm problems (e.g., methadone), used for pain relief and part of drug addiction detoxification; moxifloxacin, an antibiotic; antipsychotics, used for serious mental illnesses. Tell your doctor if you are taking any of the medicines listed above. Akeega with food ^ This medicine must not be taken with food (see section 3, “Taking Akeega”), as this may increase your risk of side effects. Pregnancy and breast-feeding Akeega is not for use in women. ^ This medicine may cause harm to the unborn child if it is taken by women who are pregnant. ^ Women who are pregnant or who may become pregnant should wear gloves if they need to touch or handle Akeega. Contraception for men using Akeega ^ If you are having sex with a woman who can become pregnant, use a condom and another effective birth control method. Use contraception during treatment and for 4 months after stopping. Talk to your doctor if you have any questions about contraception. ^ If you are having sex with a pregnant woman, use a condom to protect the unborn child. Driving and using machines Taking Akeega may make you feel weak, unfocused, tired or dizzy. This may influence your ability to drive and use machines. Use caution when driving or using machines. Akeega contains lactose and sodium ^ Akeega contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. ^ This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. 3. How to take Akeega Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much to take The recommended starting dose is 200 mg/1,000 mg (two tablets) once a day. Taking Akeega ^ Take this medicine by mouth. ^ Do not take Akeega with food. ^ Take Akeega tablets as a single dose once daily on an empty stomach at least one hour before or at least two hours after eating (see section 2, “Akeega with food”). ^ Swallow the tablets whole with water. Do not break, crush, or chew the tablets. This will ensure the medicine works as well as possible. ^ Akeega is taken with a medicine called prednisone or prednisolone. o Take the prednisone or prednisolone exactly as your doctor has told you. o You need to take prednisone or prednisolone every day while you are taking Akeega. o The amount of prednisone or prednisolone you take may need to be changed if you have a medical emergency. Your doctor will tell you if you need to change the amount of prednisone or prednisolone you take. Do not stop taking prednisone or prednisolone unless your doctor tells you to. Your doctor may also prescribe other medicines while you are taking Akeega. If you take more Akeega than you should If you take more tablets than you should contact your doctor. You may have an increased risk of side effects. If you forget to take Akeega If you forget to take Akeega or prednisone or prednisolone, take your usual dose as soon as you remember on the same day. If you forget to take Akeega or prednisone or prednisolone for more than one day - talk to your doctor straight away. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. If you stop taking Akeega Do not stop taking Akeega or prednisone or prednisolone unless your doctor tells you to. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop taking Akeega and seek medical attention immediately if you notice any of the following symptoms: Very common (may affect more than 1 in 10 people) ^ Bruising or bleeding for longer than usual if you hurt yourself - these may be signs of a low blood platelet count (thrombocytopenia). ^ Being short of breath, feeling very tired, having pale skin, or fast heartbeat - these may be signs of a low red blood cell count (anaemia). ^ Fever or infection – low white blood cell count (neutropenia) can increase your risk for infection. Signs may include fever, chills, feeling weak or confused, cough, pain or burning feeling when passing urine. Some infections can be serious and may lead to death. ^ Muscle weakness, muscle twitching or a pounding heart beat (palpitations). These may be signs that the level of potassium in your blood is low (hypokalaemia). ^ Increased level of the enzyme ‘alkaline phosphatase’ in the blood Not known (cannot be estimated) – not reported with the use of Akeega but reported with use of niraparib or abiraterone acetate (components of Akeega) ^ Allergic reaction (including severe allergic reaction that can be life-threatening). Signs include: raised and itchy rash (hives) and swelling-sometimes of the face or mouth (angioedema), causing difficulty in breathing, and collapse or loss of consciousness. ^ A sudden increase in blood pressure, which may be a medical emergency that could lead to organ damage or can be life-threatening. Other side effects Talk to your doctor if you get any other side effects. These can include: Very common (may affect more than 1 in 10 people): ^ urinary tract infection ^ low number of white blood cells (leukopenia), seen in blood tests ^ decreased appetite ^ difficulty sleeping (insomnia) ^ feeling dizzy ^ shortness of breath ^ constipation ^ feeling sick (nausea) ^ vomiting ^ back pain ^ joint pain ^ feeling very tired ^ feeling weak ^ weight loss ^ bone fractures Common (may affect up to 1 in 10 people): ^ pneumoniae ^ lung infection (bronchitis) ^ infection of the nose and throat (nasopharyngitis) ^ low number of a type of white blood cell (lymphopenia), seen in blood tests ^ high level of a type of fat (hypertriglyceridemia) in the blood ^ depression ^ feeling anxious ^ headache ^ fast heart beat ^ fast or uneven heart beat (palpitations) ^ irregular heart beat (atrial fibrillation) ^ heart failure, causing shortness of breath and swollen legs ^ heart attack ^ cough ^ blood clot in the lungs, causing chest pain and shortness of breath ^ inflamed lungs ^ stomach pain ^ indigestion ^ diarrhoea ^ bloating ^ sores in the mouth ^ dry mouth ^ inflamed liver (hepatitis) based on blood tests ^ skin rash ^ muscle aches ^ blood in the urine ^ swollen hands, ankles, or feet ^ increased level of ‘creatinine’ in the blood ^ increased level of the enzyme ‘aspartate aminotransferase’ in the blood ^ increased level of the enzyme ‘alanine aminotransferase’ in the blood Uncommon (may affect up to 1 in 100 people): ^ severe infection (sepsis) that spreads from the urinary tract throughout the body ^ inflamed eye (conjunctivitis) ^ feeling confused ^ difficulty thinking, remembering information, or solving problems (cognitive impairment) ^ change in sense of taste ^ chest discomfort, often brought on by physical activity ^ abnormal ECG (electrocardiogram), which could be a sign of heart problems ^ nose bleeds ^ inflammation of the protective linings in the body cavities, such as the nose, mouth, or digestive system ^ sudden liver failure ^ increased sensitivity of the skin to sunlight ^ increased level of ‘gamma-glutamyltransferase’ in the blood Not known (cannot be estimated) – not reported with the use of Akeega but reported with use of niraparib or abiraterone acetate (components of Akeega) ^ low numbers of all types of blood cells (pancytopenia) ^ brain condition with symptoms including seizures (fits), headache, confusion, and changes in vision (posterior reversible encephalopathy syndrome or PRES), which is a medical emergency that could lead to organ damage or can be life-threatening ^ adrenal gland problems (related to salt and water problems) where too little hormone is produced which may cause problems like weakness, tiredness, loss of appetite, nausea, dehydration and skin changes ^ inflamed lungs caused by an allergic reaction (allergic alveolitis) ^ muscle disease (myopathy), which may cause muscle weakness, stiffness or spasms ^ breakdown of muscle tissue (rhabdomyolysis), which may cause muscle cramps or pains, tiredness and dark urine Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Akeega Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the container (blister foil, inner wallet, outer wallet, and carton) after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Akeega contains ^ The active substances are niraparib and abiraterone acetate. Each film-coated tablet contains 100 mg niraparib and 500 mg abiraterone acetate. ^ The other ingredients of the tablet core are colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The film-coating contains iron oxide red (E172), iron oxide yellow (E172), sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide (E171) (see section 2, Akeega contains lactose and sodium) What Akeega looks like and contents of the pack Akeega film-coated tablets are orange oval tablets, debossed with “N 100 A” on one side and plain on the other side. Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs of 28 film-coated tablets each. Marketing Authorisation Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium Manufacturer Janssen Cilag SpA Via C. Janssen, Borgo San Michele Latina 04100 Italy For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Lietuva Janssen-Cilag NV UAB "JOHNSON & JOHNSON" Tel/Tél: +3214649411 Tel: +37052786888 janssen@jacbe.jnj.com lt@its.jnj.com България Luxembourg/Luxemburg „Джонсън & Джонсън България” ЕООД Janssen-Cilag NV Тел.: +35924899400 Tél/Tel: +3214649411 jjsafety@its.jnj.com janssen@jacbe.jnj.com Česká republika Magyarország Janssen-Cilag s.r.o. Janssen-Cilag Kft. Tel: +420227012227 Tel.: +3618842858 janssenhu@its.jnj.com Danmark Malta Janssen-Cilag A/S AM MANGION LTD Tlf: +4545948282 Tel: +35623976000 jacdk@its.jnj.com Deutschland Nederland Janssen-Cilag GmbH Janssen-Cilag B.V. Tel: +492137955955 Tel: +31767111111 jancil@its.jnj.com janssen@jacnl.jnj.com Eesti Norge UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS Tel: +3726177410 Tlf: +4724126500 ee@its.jnj.com jacno@its.jnj.com Ελλάδα Österreich Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε. Janssen-Cilag Pharma GmbH Tηλ: +302108090000 Tel: +431610300 España Polska Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o. Tel: +34917228100 Tel.: +48222376000 contacto@its.jnj.com France Portugal Janssen-Cilag Janssen-Cilag Farmacêutica, Lda. Tél: 0800255075 / +33155004003 Tel: +351214368600 medisource@its.jnj.com Hrvatska România Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL Tel: +38516610700 Tel: +40212071800 jjsafety@JNJCR.JNJ.com Ireland Slovenija Janssen Sciences Ireland UC Johnson & Johnson d.o.o. Tel: 1800709122 Tel: +38614011800 medinfo@its.jnj.com Janssen_safety_slo@its.jnj.com Ísland Slovenská republika Janssen-Cilag AB Johnson & Johnson, s.r.o. c/o Vistor hf. Tel: +421232408400 Sími: +3545357000 janssen@vistor.is Italia Suomi/Finland Janssen-Cilag SpA Janssen-Cilag Oy Tel: 800.688.777 / +390225101 Puh/Tel: +358207531300 janssenita@its.jnj.com jacfi@its.jnj.com Κύπρος Sverige Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB Τηλ: +35722207700 Tfn: +4686265000 jacse@its.jnj.com Latvija United Kingdom (Northern Ireland) UAB "JOHNSON & JOHNSON" filiāle Latvijā Janssen Sciences Ireland UC Tel: +37167893561 Tel: +441494567444 lv@its.jnj.com medinfo@its.jnj.com This leaflet was last revised in MM/YYYY. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: www.ema.europa.eu

Example 3 – Approved Drug Product Label by Health Canada; approval date: 23 June 2023 PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION P^rAKEEGA^TM Niraparib and abiraterone acetate tablets 100 mg niraparib (as niraparib tosylate)/500 mg abiraterone acetate, 50 mg niraparib (as niraparib tosylate)/500 mg abiraterone acetate Oral administration Antineoplastic agent/Androgen biosynthesis inhibitor P^rAKEEGA™ (niraparib and abiraterone acetate), indicated for: ^ The treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) metastatic castration resistant prostate cancer (mCRPC), who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated. Patients must have confirmation of BRCA mutation before AKEEGA™ treatment is initiated. has been issued market authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for ^PrAKEEGA™ please refer to Health Canada’s Notice of Compliance with conditions - drug products web site: www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/notice-compliance/conditions.html” Janssen Inc. Date of Initial Authorization: Toronto, Ontario June 07, 2023 M3C 1L9 Submission Control Number: 265223 What is a Notice of Compliance with Conditions (NOC/c)? An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products authorized under Health Canada’s NOC/c policy are intended for the treatment, prevention, or diagnosis of a serious, life-threatening, or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame. TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed TABLE OF CONTENTS ..........................................................................................................2 PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................4 1 INDICATIONS ..........................................................................................................4 1.1 Pediatrics (<18 years of age) ................................................................................4 1.2 Geriatrics (≥65 years of age) ................................................................................4 2 CONTRAINDICATIONS .............................................................................................4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX .........................................................4 4 DOSAGE AND ADMINISTRATION .............................................................................5 4.1 Dosing Considerations ..........................................................................................5 4.2 Recommended Dose and Dosage Adjustment .....................................................5 4.3 Reconstitution ......................................................................................................7 4.4 Administration ......................................................................................................8 4.5 Missed Dose .........................................................................................................8 5 OVERDOSAGE .........................................................................................................8 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ..............................8 7 WARNINGS AND PRECAUTIONS ..............................................................................9 7.1 Special Populations ............................................................................................14 7.1.1 Pregnant Women .........................................................................................14 7.1.3 Pediatrics (<18 years of age) ........................................................................14 7.1.4 Geriatrics (≥65 years of age) ........................................................................14 8 ADVERSE REACTIONS ............................................................................................14 8.1 Adverse Reaction Overview ...............................................................................14 8.2 Clinical Trial Adverse Reactions ..........................................................................15 8.3 Less Common Clinical Trial Adverse Reactions ..................................................18 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data .........................................................................................................19 8.5 Post-Market Adverse Reactions .........................................................................19 9 DRUG INTERACTIONS ............................................................................................20 9.2 Drug Interactions Overview ...............................................................................20 9.3 Drug-Behavioural Interactions ...........................................................................21 9.4 Drug-Drug Interactions .......................................................................................21 9.5 Drug-Food Interactions ......................................................................................23 9.6 Drug-Herb Interactions .......................................................................................23 9.7 Drug-Laboratory Test Interactions .....................................................................23 10 CLINICAL PHARMACOLOGY ...................................................................................23 10.1 Mechanism of Action ...................................................................................23 10.2 Pharmacodynamics ......................................................................................24 10.3 Pharmacokinetics .........................................................................................26 11 STORAGE, STABILITY AND DISPOSAL .....................................................................28 12 SPECIAL HANDLING INSTRUCTIONS .......................................................................28 PART II: SCIENTIFIC INFORMATION ...................................................................................29 13 PHARMACEUTICAL INFORMATIONA ......................................................................29 14 CLINICAL TRIALS ....................................................................................................30 14.1 Clinical Trials by Indication ...........................................................................30 15 MICROBIOLOGY ....................................................................................................36 16 NON-CLINICAL TOXICOLOGY .................................................................................36 PATIENT MEDICATION INFORMATION ..............................................................................39

PART I: HEALTH PROFESSIONAL INFORMATION I ^PN rDICATIONS AKEEGA™ (niraparib and abiraterone acetate) is indicated with prednisone or prednisolone for: The treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) metastatic castration resistant prostate cancer (mCRPC), who are asymptomatic/mildly symptomatic , and in whom chemotherapy is not clinically indicated. Patients must have confirmation of BRCA mutation before AKEEGA™ treatment is initiated. Marketing authorization with conditions issued based on radiographic progression-free survival, time to symptomatic progression and time to cytotoxic chemotherapy (See 14 CLINICAL TRIALS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in subsequent analyses. The efficacy of AKEEGA™ in patients with visceral metastases is uncertain (See 14 CLINICAL TRIALS) Pediatrics (<18 years of age) No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. Geriatrics (≥65 years of age) No overall differences in safety and efficacy of niraparib and abiraterone acetate combination therapy were observed between these patients and younger patients, however, greater sensitivity of some older individuals cannot be ruled out (see 7 WARNINGS AND PRECAUTIONS). CONTRAINDICATIONS AKEEGA™ is contraindicated in: ^ Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions ^ AKEEGA™ may cause hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular) ^ AKEEGA™ should be used with caution in patients with a history of cardiovascular disease (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular) ^ AKEEGA™ should not be given to patients with moderate to severe hepatic impairment (see 7 WARNINGS AND PRECAUTIONS, Hepatic Impairment) ^ MDS/AML has been reported with PARP inhibitor treatment (see 7 WARNINGS AND PRECAUTIONS) DOSAGE AND ADMINISTRATION Dosing Considerations AKEEGA™ is a fixed-dose dual combination of niraparib and abiraterone acetate. Confirm presence of a BRCA mutation using a validated test prior to initiation of AKEEGA™ (see 14 CLINICAL TRIALS). Recommended Dose and Dosage Adjustment The recommended dosage of AKEEGA™ is 200 mg niraparib and 1000 mg abiraterone acetate (two 100 mg/500 mg tablets), as a single daily dose that must be taken on an empty stomach at approximately the same time every day (see 4 DOSAGE AND ADMINISTRATION, Administration). For dose reduction to 100 mg niraparib and 1000 mg abiraterone acetate, a low strength tablet (two 50 mg/ 500 mg tablets) is recommended (see 4 DOSAGE AND ADMINISTRATION, Dose Modification). If further dose reduction below 100 mg/day niraparib is required, discontinue AKEEGA. Dosage of Prednisone or Prednisolone AKEEGA™ is used with 10 mg prednisone or prednisolone daily. Treatment Withdrawal Treatment should be continued until disease progression, unequivocal clinical progression, or unacceptable toxicity. Dose Modification Hematologic Adverse Reactions The dose adjustment recommendations for anemia, thrombocytopenia and neutropenia are listed in Table 1 and in Table 2. Table 1: Dose Adjustment Recommendations for Anemia Grade 1 No change, consider weekly monitoring. Grade 2 At least weekly monitoring for 28 days, if baseline anemia was Grade ≤ 1. Grade ≥ 3 Withhold AKEEGA™¹ and switch to single agent abiraterone acetate plus prednisone (AAP). Provide supportive management with monitoring at least weekly until recovered to Grade ≤ 2. Consider resuming AKEEGA™ at one dose-level reduction [two low strength (50 mg/500 mg) tablets] if anemia persists based on clinical judgment. Second Withhold AKEEGA™ and switch to single agent AAP. Provide supportive management and monitor at occurrence least weekly until recovered to Grade ≤ 2. Further treatment with AKEEGA™ should restart at one dose- ≥ Grade 3 level reduction [two low strength (50 mg/500 mg) tablets]. Weekly monitoring is recommended for 28 days after resuming treatment with AKEEGA™. If patient was already on a reduced dose [two low strength (50 mg/500 mg) tablets], consider treatment discontinuation. Third Consider discontinuing treatment with AKEEGA™ based on clinical judgment. occurrence ≥ Grade 3 ¹ During AKEEGA™ treatment interruption, physician may consider giving abiraterone acetate and prednisone to maintain daily dose of abiraterone acetate (see abiraterone acetate product monograph). Table 2: Dose Adjustment Recommendations for Thrombocytopenia and Neutropenia Grade 1 No change, consider weekly monitoring Grade 2 At least weekly monitoring and consider withholding AKEEGA™ and switch to single agent AAP combination until recovery to Grade 1 or baseline.¹ Resume AKEEGA™ with recommendation of weekly monitoring for 28 days after restart. First Withhold AKEEGA™ and switch to single agent AAP combination. Monitor at least weekly) until occurrence ≥ platelets and neutrophils recover to Grade 1 or baseline.¹ Then resume AKEEGA™ or, if warranted, at Grade 3² one dose-level reduction [two low strength (50 mg/500 mg) tablets]. Weekly monitoring of blood counts is recommended for 28 days after restarting dose. Second Withhold AKEEGA™ and switch to single agent AAP combination. Monitor at least weekly until platelets occurrence ≥ and/or neutrophils recover to Grade 1. Further treatment with AKEEGA™ should restart at one dose- Grade 3 level reduction [two low strength (50 mg/500 mg) tablets]. Weekly monitoring is recommended for 28 days after resuming treatment with AKEEGA™. If patient was already on a reduced dose [two low strength (50 mg/500 mg) tablets], consider treatment discontinuation. Third Permanently discontinue AKEEGA™ and switch to single agent AAP combination occurrence ≥ Grade 3 ¹ During AKEEGA™ treatment interruption related to hematological toxicities, abiraterone acetate plus prednisone or prednisolone should be generally continued by the physician (see abiraterone acetate product monograph) ² If patient requires platelet transfusion or has neutropenic fever or neutropenia requiring granulocyte-colony stimulating factor for Grade ≥3 AE deemed to be related to AKEEGA™ toxicity, interrupt study drug and restart at 1 dose-level reduction after resolution to Grade 1 or baseline. If AKEEGA™ was previously dose-reduced for the same hematologic toxicity, discontinue AKEEGA™ Non-Hematologic Adverse Reactions For drug-related ≥Grade 3 toxicities, if the toxicity cannot be definitively attributed to either niraparib or abiraterone acetate only, then AKEEGA™ should be interrupted. Treatment with AKEEGA™ must not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or baseline. To resume treatment, initiate treatment with single AAP combination first. If there is continued resolution of the toxicity to baseline/Grade 1, then switch to treatment with AKEEGA™ at least 7 days after restarting AAP. If a patient was on a reduced dose of AKEEGA™ (100mg/1000mg), AKEEGA™ must be discontinued for a Grade ≥ 3 treatment-related adverse reaction lasting more than 28 days. Permanently discontinue AKEEGA™ for treatment-related hypertensive crisis. Hepatotoxicity For patients who develop ≥ Grade 3 hepatotoxicity (alanine aminotransferase [ALT] increases or aspartate aminotransferase [AST] increases above five times the upper limit of normal [ULN]), treatment with AKEEGA™ should be interrupted and liver function closely monitored. Re-treatment may take place only after return of liver function tests to the patient’s baseline and at a reduced dose level of one regular strength AKEEGA™ tablet (equivalent to 100 mg niraparib and 500 mg abiraterone acetate).For patients being re-treated, serum transaminases should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 100 mg/500 mg daily (1 tablet), treatment with AKEEGA™ should be discontinued. Permanently discontinue AKEEGA™ for patients who develop severe hepatotoxicity (ALT or AST 20 times the ULN). Permanently discontinue AKEEGA™ for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation (see 7 WARNINGS AND PRECAUTIONS). Recommended Monitoring See 7 WARNINGS AND PRECAUTIONS for required monitoring prior to, and during treatment with AKEEGA™. Special Populations Pediatrics (<18 years of age) Health Canada has not authorized an indication for pediatric use. Geriatrics (≥65 years of age) No dose adjustment is necessary for elderly patients (see 10.3 Pharmacokinetics). Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment (AST or ALT ≤ 3 x ULN or serum total bilirubin ≤ 1.5 x ULN). AKEEGA™ should not be used in patients with moderate to severe hepatic impairment (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX; 10.3 Pharmacokinetics). Renal Impairment No dose adjustment is necessary for patients with mild to moderate renal impairment (see 10.3 Pharmacokinetics). AKEEGA™ has not been studied in patients with severe renal impairment (Creatinine clearance <30mL/min). Reconstitution Not applicable Administration AKEEGA™ must be taken on an empty stomach. AKEEGA™ must be taken at least two hours after eating and food must not be eaten for at least one hour after taking AKEEGA™. The tablets must be swallowed whole with water (see 10.3 Pharmacokinetics–Absorption). Do not break, crush, or chew tablets. Gonadotropin releasing hormone (GnRH) agonists must be taken during treatment with AKEEGA™ or patients must have been previously treated with orchiectomy. Missed Dose If a dose of either AKEEGA™, prednisone or prednisolone is missed, it should be resumed the next day with the usual daily dose and normal daily schedule. Extra tablets must not be taken to make up for the missed dose. OVERDOSAGE There is no specific treatment in the event of AKEEGA™ overdose. In the event of an overdose, physicians should follow general supportive measures and treat patients symptomatically. For management of a suspected drug overdose, contact your regional poison control centre. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING Dosage Forms, Strengths, Composition and Packaging Route of Dosage Form Administration _{Strength/Composition} ^{Non-medicinal Ingredients oral} _tablets Colloidal anhydrous silica, crospovidone, glycerol monocaprylocaprate, hypromellose, iron oxide (E172), iron oxide red (E172), iron oxide yellow (E172), lactose Regular strength: monohydrate, magnesium stearate, polyvinyl alcohol, 100 mg niraparib (as silicified microcrystalline cellulose, sodium lauryl sulfate, niraparib tosylate)/500 mg talc, titanium dioxide (E171) abiraterone acetate Low strength: 50 mg niraparib (as niraparib tosylate)/500 mg abiraterone acetate AKEEGA™ tablets are available as regular strength (100 mg niraparib (as niraparib tosylate) and 500 mg abiraterone acetate) and low-dose strength (50 mg niraparib (as niraparib tosylate) and 500 mg abiraterone acetate): AKEEGA™ 100 mg niraparib (as niraparib tosylate) and 500 mg abiraterone acetate tablets: Orange, oval, tablets (22 mm x 11 mm), debossed with “N 100 A” on one side, and plain on the other side. AKEEGA™ 50 mg niraparib (as niraparib tosylate) and 500 mg abiraterone acetate tablets: Yellowish orange to yellowish brown, oval, tablets (22 mm x 11 mm), debossed with “N 50 A” on one side, and plain on the other side. AKEEGA™ tablets of both strengths will be available in 150 ml high-density polyethylene (HDPE) bottles with 60 tablets each. WARNINGS AND PRECAUTIONS Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. General AKEEGA™ is used with 10 mg prednisone or prednisolone daily. Gonadotropin releasing hormone (GnRH) agonists must be taken during treatment with AKEEGA™ or patients must have been previously treated with orchiectomy. AKEEGA™ must be taken on an empty stomach. AKEEGA™ must be taken at least two hours after eating and food must not be eaten for at least one hour after taking AKEEGA™. The tablets must be swallowed whole with water (see 4 DOSAGE AND ADMINISTRATION and 10.3 Pharmacokinetics-Absorption) Lactose Intolerance This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose galactose malabsorption should not take this medicine. Carcinogenesis and Mutagenesis Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) MDS/AML, including cases with fatal outcome, have been reported in ovarian, fallopian tube or primary peritoneal cancer trials among patients who received niraparib monotherapy (see ZEJULA® PM). In the MAGNITUDE study Cohort 1 (see 8 ADVERSE REACTIONS), with a median duration of follow-up of 26.8 months in the niraparib+AAP arm and 26.9 months in the placebo+AAP arm respectively, AML was reported in 0 subjects in the niraparib +AAP arm and 1 subject (0.5%) in the placebo+AAP arm. For suspected MDS/AML or prolonged hematological toxcities that has not resolved with treatment interruption or dose reduction, the patient should be referred to a hematologist for further evaluation. If MDS and/or AML is confirmed, treatment with AKEEGA™ should be permanently discontinued. Cardiovascular AKEEGA™ should be used with caution in patients with a history of cardiovascular disease. Before and during treatment of patients with a significant risk for congestive heart failure (e.g., a history of cardiac failure, or cardiac events such as ischemic heart disease), cardiac failure should be treated, and cardiac function optimized. Symptoms of congestive heart failure should be monitored every two weeks for three months, then monthly thereafter. The safety of AKEEGA™ in patients with clinically significant heart disease, as evidenced by myocardial infarction, arterial and venous thrombotic events in the past six months, severe or unstable angina, or NYHA Class II to IV heart failure or cardiac ejection fraction measurement of < 50%, is unknown as these patients were excluded from the MAGNITUDE study. Hypertension AKEEGA™ may cause hypertension. Pre-existing hypertension should be adequately controlled before starting AKEEGA™ treatment. Blood pressure should be monitored at least weekly for two months, monthly afterwards for the first year and every other month thereafter during treatment with AKEEGA™. Hypokalemia, Fluid retention AKEEGA™ may cause hypokalemia and fluid retention (see 8 ADVERSE REACTIONS) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see 10.2 Pharmacodynamics). Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by hypokalemia. QT prolongation has been observed in patients experiencing hypokalemia in association with AKEEGA™ treatment. Hypokalemia and fluid retention should be corrected and controlled. Fluid retention (weight gain, peripheral edema) should be monitored every two weeks for three months, then monthly thereafter and abnormalities corrected. Venous Thromboembolic Events Venous thromboembolic events (VTE), including pulmonary embolism, have occurred in patients treated with AKEEGA™ (see 8 ADVERSE REACTIONS). Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Driving and Operating Machinery Patients who take AKEEGA™ may experience asthenia, fatigue, dizziness. AKEEGA™ may influence the ability to drive or use machines. Patients should use caution when driving or operating a vehicle or potentially dangerous machinery. Endocrine and Metabolism Hypoglycemia Cases of hypoglycemia have been reported when abiraterone acetate plus prednisone or prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (see 9 DRUG INTERACTIONS); therefore, blood sugar should be monitored in patients with diabetes. Hematologic Hematologic Adverse Reactions Hematologic adverse reactions (anemia, neutropenia and thrombocytopenia) have been reported in patients treated with niraparib monotherapy and combination therapy (see 8 ADVERSE REACTIONS). In the MAGNITUDE study, the overall incidence of Grade ≥3 anemia, neutropenia and thrombocytopenia was 29.7%, 6.6% and 6.6% respectively, in Cohort 1 patients receiving niraparib+AAP. Testing complete blood counts weekly for the first month, bi-weekly for the next two months, followed by monthly monitoring for the first year and then every other month for the remainder of treatment is recommended (see 4 DOSAGE AND ADMINISTRATION). Based on individual laboratory values, weekly monitoring for the second month may be warranted. If a patient develops severe persistent hematologic toxicity including pancytopenia that does not resolve within 28 days following interruption, AKEEGA™ should be discontinued. Due to the risk of thrombocytopenia, other medicinal products known to reduce platelet counts should be used with caution in patients taking AKEEGA™. Hepatic/Biliary/Pancreatic Hepatic Impairment There are no data on the clinical safety and efficacy of AKEEGA™ administered to patients with moderate or severe hepatic impairment (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤3 x ULN or Child-Pugh Class B or C). AKEEGA™ should not be used in patients with moderate to severe hepatic impairment (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, 4 DOSAGE AND ADMINISTRATION, and 10.3 Pharmacokinetic Properties). Hepatotoxicity Marked increases in liver enzymes leading to treatment interruption or discontinuation occurred in clinical studies with abiraterone acetate, including in the MAGNITUDE study, (2 % of patients experienced a dose modification, one patient (0.5%) discontinued treatment in Cohort 1) (see 8 ADVERSE REACTIONS). Severe hepatotoxicity (including fatal outcomes) has been reported during post-marketing experience with abiraterone acetate monotherapy (see ZYTIGA® PM). Serum aminotransferase and total bilirubin levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum aminotransferases and bilirubin should be measured immediately. If at any time the ALT or AST rises above five times the upper limit of normal (ULN) or bilirubin rises 3 times the ULN, treatment with AKEEGA™ should be interrupted and liver function closely monitored. Permanently discontinue AKEEGA™ for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation. Retreatment may take place only after return of liver function tests to the patient’s baseline and at a reduced dose level (See 4 DOSAGE AND ADMINISTRATION) If patients develop severe hepatotoxicity (ALT or AST twenty times the ULN) anytime while on therapy, treatment with AKEEGA™ should be permanently discontinued. Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are no data to support the use of AKEEGA™ in this population. Immune In patients treated with abiraterone acetate monotherapy, cases of anaphylactic reactions requiring rapid medical interventions have been reported during post-marketing experience (see ZYTIGA® PM). Monitoring and Laboratory Tests ^ Complete blood counts should be obtained prior to starting treatment, weekly for the first month, bi-weekly for the next two months, followed by monthly monitoring for the first year and then every other month for the remainder of treatment (see 4 DOSAGE AND ADMINISTRATION). ^ Serum aminotransferases and total bilirubin should be measured prior to starting treatment, every two weeks for the first three months of treatment and monthly thereafter for the first year and then every other month for the duration of treatment. ^ Serum potassium should be monitored monthly for the first year and then every other month for the duration of treatment. ^ Blood pressure should be monitored at least weekly for two months, monthly afterwards for the first year and every other month thereafter during treatment with AKEEGA™. ^ In patients who develop hypokalemia whilst being treated with AKEEGA™, consider maintaining the patient’s potassium level at ≥ 4.0 mM (see 4 DOSAGE AND ADMINISTRATION ^ Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If AKEEGA™ is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess. In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of corticosteroids may be indicated before, during and after the stressful situation. Musculoskeletal Increased Fractures and Mortality in Combination with Radium dichloride Treatment with AKEEGA™ in combination with radium dichloride is not recommended. In a randomized clinical trial of patients with asymptomatic or mildly symptomatic bone- predominant metastatic castration resistant prostate cancer with bone metastases, the addition of radium 223 dichloride to abiraterone plus prednisone/prednisolone showed an increase in mortality and an increased rate of fracture (see ZYTIGA® PM). Myopathy/Rhabdomyolysis Cases of myopathy/rhabdomyolysis have been reported in patients treated with abiraterone acetate monotherapy (see ZYTIGA® PM). Caution is recommended in patients concomitantly treated with drugs known to be associated with myopathy/rhabdomyolysis. Neurologic Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES) is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). There have been reports of PRES in patients receiving niraparib as a monotherapy in the ovarian, fallopian tube or primary peritoneal cancer population (see ZEJULA® PM). In case of PRES, treatment with AKEEGA™ should be permanently discontinued and appropriate medical management should be instituted. Reproductive Health: Female and Male Potential It is not known whether components of AKEEGA™ or their metabolites are present in semen. If the patient is engaged in sex with a pregnant woman or a woman of childbearing potential, a condom is required along with another highly effective contraceptive method during treatment and for three months after the last dose of AKEEGA™. Studies in animals have shown reproductive toxicity See 7.1.1 Pregnant Women. ^ Fertility There are no clinical data on fertility with AKEEGA™. In animal studies, male fertility was reduced with niraparib or abiraterone acetate, but these effects were reversible following treatment cessation (see 16 NON-CLINICAL TOXICOLOGY). ^ Teratogenic Risk AKEEGA™ has the potential to cause fetal harm based on the mechanism of action of both components and findings from animal studies with abiraterone acetate (see 16 NON-CLINICAL TOXICOLOGY). Special Populations 1.1.1 Pregnant Women AKEEGA™ is not authorized for use in women (see 10.3 Pharmacokinetics). There are no data of the use of AKEEGA™ in pregnant women. AKEEGA™ has the potential to cause fetal harm based on the mechanism of action of both components and findings from animal studies with abiraterone acetate. Animal developmental and reproductive toxicology studies were not conducted with niraparib (see 16 NON-CLINICAL TOXICOLOGY– Reproductive and Developmental Toxicology). To avoid inadvertent exposure, women who are pregnant or women who may be pregnant should not handle AKEEGA™ tablets without protection, e.g., gloves. 7.1.2 Breast-feeding AKEEGA™ is not authorized for use in women. 7.1.3 Pediatrics (<18 years of age) No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 1.1.4 Geriatrics (≥65 years of age) In MAGNITUDE Cohort 1, 70.9% of subjects were aged ≥65 years and 26.5% were aged ≥75 years. No overall differences in safety and efficacy of niraparib and abiraterone acetate combination therapy were observed between these patients and younger subjects. However, greater sensitivity of older individuals ≥ 75 years cannot be ruled out. Increased vigilance in older individuals (≥75 years) could be recommended. ADVERSE REACTIONS Adverse Reaction Overview The overall safety profile of AKEEGA™ is based on data from a Phase 3, randomized, double- blind, placebo-controlled study, MAGNITUDE cohort 1 (HRR positive) who received niraparib plus abiraterone acetate and prednisone (AAP) (n=212) or placebo plus AAP (n=211) as single agent combinations orally once daily (see 14 CLINICAL TRIALS). The median duration of exposure to niraparib plus AAP was 13.8 months (range: 0- 29) . The baseline and disease characteristics were median age of 69 years (range 43-100) , the racial distribution was 74% Caucasian, 16.5% Asian, and 1.2% Black, and others or not reported (8.3%); Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0: 66%, ECOG PS1: 34% . At study entry, 83.5% of patients had bone involvement and 21.3% had visceral disease. All patients who had not received prior orchiectomy continued background androgen deprivation therapy with a GnRH analogue. Serious adverse events occurred in 36% of subjects treated with niraparib plus AAP and 25% of subjects treated with placebo plus AAP. Anemia (5.7%) was the serious adverse reaction reported in ≥2% of subjects who received niraparib plus AAP. Fatal adverse events occurred in 5.7% of subjects treated with niraparib plus AAP and 3.3% of subjects treated with placebo plus AAP. Fatal adverse reactions due to pneumonia occurred in 0.5 % of subjects who received niraparib plus AAP and none of the subjects who received placebo plus AAP. The most common adverse reactions of all Grades, occurring in >20% of patients in MAGNITUDE Cohort 1 were anemia, hypertension, constipation, fatigue, nausea and thrombocytopenia. The most frequently observed Grade≥3 adverse reactions were anemia, hypertension, thrombocytopenia, neutropenia and blood alkaline phosphatase increased. Dose interruptions of any component of combination therapy due to an adverse event occurred in 43% of subjects treated with niraparib plus AAP and 23% of patients treated with placebo plus AAP.22% of subjects in Cohort 1 needed dose interruptions of niraparib and use of single agent abiraterone acetate. The median length of treatment with single agent abiraterone acetate was 102 days (range: 6; 518). The most common adverse reactions leading to dose interruption in the niraparib plus AAP arm were anemia (22%), thrombocytopenia (9%) and neutropenia (7%). All other TEAEs leading to dose interruption occurred with <5% frequency. Dose reductions due to an adverse event occurred in 27% of patients in the niraparib plus AAP arm and 9.5% of subjects in the patients plus AAP arm in Cohort 1. The most common adverse reactions leading to dose reduction in the niraparib plus AAP arm were anemia (13%), thrombocytopenia (3%) and fatigue (2%). Permanent discontinuation due to an adverse event occurred in 10.8% of patients treated with niraparib plus AAP and 6.2% of subjects treated with placebo plus AAP in Cohort 1. The most common adverse events leading drug discontinuation in the niraparib plus AAP arm were COVID-19/COVID-19 pneumonia (2.8 %) and anemia (2.4%). Overall, the safety and tolerability profile of AKEEGA™ was in line with the known safety profile of its 2 single agents, with no new safety signals identified. Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The safety of niraparib plus AAP and AKEEGA™ in mCRPC patients with HRR mutations was assessed in the MAGNITUDE study, Cohorts 1 and 3 respectively (Table 3). Table 3: Adverse Drug Reactions in mCRPC Patients with HRR Gene Mutations, Cohort 1 (≥2% Increase in Frequency in niraparib+AAP Compared to Placebo +AAP) System/Organ Class Niraparib+ AAP Placebo + AAP N=212 N=211 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Adverse Reaction % % % % % % Blood and lymphatic system disorders Anemia 46.2 28.3 1.4 20.4 7.6 0 Thrombocytopenia 21.2 2.8 3.8 8.5 2.4 0 Neutropenia 13.7 5.2 1.4 5.7 1.4 0 Leukopenia 10.4 1.9 0 2.4 0.5 0 Lymphopenia 9.0 3.3 0.5 1.9 0.5 0.5 Infections and infestations Urinary tract infection 9.4 3.3 0 6.2 1.9 0 Metabolism and nutrition disorders Decreased appetite 14.2 0.5 0 6.2 0.5 0 Hypokalemia 13.7 2.8 0 9.5 2.8 0 Psychiatric disorders Insomnia 10.4 0 0 3.8 0 0 Nervous system disorders Dizziness 11.3 0.5 0 5.7 0 0 Cardiac disorders Arrhythmia^a 12.7 2.4 0 5.7 1.4 0 Venous Thromboembolism^b 8.0 5.2 0 3.3 1.4 0 Vascular disorders Hypertension 31.1 14.6 0 20.9 12.3 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 16.0 1.9 0 5.7 0.9 0 Cough 7.1 0 0 4.7 0 0 Pneumonitis 2.4 0 0 0 0 0 Gastrointestinal disorders Constipation 30.7 0 0 13.7 0 0 Nausea 23.6 0.5 0 13.7 0 0 Vomiting 13.2 0.5 0 6.6 0.5 0 Dyspepsia 6.1 0 0 2.8 0 0 Abdominal Pain Upper 4.7 2.8 Abdominal distention 3.8 0 0 0.5 0 0 Musculoskeletal and connective tissue disorders Arthralgia 13.2 0.5 0 9.5 0.5 0 Renal and urinary disorders Hematuria 6.6 0.9 0 3.8 0.5 0 Dysuria 4.7 0 0 1.9 0 0 General disorders and administration site conditions Fatigue 26.4 3.3 0 16.6 4.3 0 Asthenia 15.6 0.5 0 9.0 0.5 0 Investigations Blood alkaline phosphatase 9.9 4.2 0.9 6.6 2.4 0 increased Weight decreased 9.0 0.9 0 2.4 0 0 System/Organ Class Niraparib+ AAP Placebo + AAP N=212 N=211 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Adverse Reaction % % % % % % Blood creatinine increased 9.0 1.4 0 3.8 0 0.5 *CTCAE=Common Terminology Criteria for Adverse Events version 5.0 ^aGrouped terms for arrhythmia: tachcardia, palpitations, atrial fibrillations,sinus tachycardia, supraventricular extrasystoles, atrial tachycardia, cardio-respiratory arrest, ventricular extrasystoles, atrial flutter, bradycardia, heart rate increased, ventricular tachycardia ^bGrouped terms for thromboembolism (venous): embolism, pulmonary embolism, thrombosis, deep vein thrombosis, venous thrombosis Hematological Toxicities Hematological toxicities (anemia, thrombocytopenia, and neutropenia) including laboratory findings are the most frequent adverse reactions attributable to niraparib. These toxicities generally occurred within the first two months of treatment. In the MAGNITUDE study, the following hematologic parameters were inclusion criteria: absolute neutrophil count (ANC) ≥ 1,500 cells/μL; platelets ≥ 100,000 cells/μL and hemoglobin ≥ 9 g/dL. ^ Anemia Anemia was the most frequent adverse reaction (46.2%) and most observed Grade > 3 event (28.3%) in the MAGNITUDE study. Anemia generally occurred early during therapy (median time to onset of 57 days, range: 1; 636 days), however, 50% of these patients had ongoing, low-grade persistent anemia. Dose interruptions occurred in 22.2% of patients and dose reductions in 13%. Twenty-six percent of patients received at least one anemia related transfusion. Anemia caused treatment discontinuation in 2.4% of subjects. ^ Thrombocytopenia In the MAGNITUDE study, 21.2% of treated patients reported thrombocytopenia while 6.6% of patients experienced Grade 3-4 thrombocytopenia. Median time from first dose to first onset was 43 days. Thrombocytopenia was managed with dose modification (interruption 9.4% and reduction in 2.8%) and platelet transfusion (2.4%) where appropriate. Discontinuation occurred in 0.5% of patients and 1.4% of patients experienced a concurrent bleeding event. ^ Neutropenia In the MAGNITUDE study, 14% of patients experienced neutropenia with Grade 3-4 neutropenia reported in 6.6% of patients. Median time from first dose to first report of neutropenia was 50 days. Neutropenia led to treatment interruption in 6.6% of patients and dose reduction in 1.4%. In the MAGNITUDE study, 0.9% of patients had a concurrent infection. Non-Hematologic Adverse Reactions Hypertension Hypertension is an adverse reaction for both components of AKEEGA™ and patients with uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg) were excluded in all combination trials. Hypertension was reported in 31% of patients of whom 15% had Grade ≥ 3. The median time to onset of hypertension was 56 days. Cardiac Events In the MAGNITUDE study, the most frequent major adverse cardiovascular events [MACE (Ischemic Heart Disease, Cardiac Failure)] were ischemic heart disease (1.9%) and Cardiac failure was also reported in 1.9% of patients. Additionally, arrythmias were reported in 12.7% of patients. Hepatotoxicity Hepatotoxicity had been recognized as important identified risk for abiraterone acetate. Patients with moderate and severe hepatic impairment (NCI classification) and patients with Child-Turcotte-Pugh Class B and C were excluded from AKEEGA™ combination studies. In the MAGNITUDE study, patients with baseline hepatitis or significant abnormalities of liver function tests were excluded (Serum total bilirubin ≤1.5× ULN or direct bilirubin ≤1 x ULN and AST or ALT ≤3 × ULN). The overall incidence of hepatotoxicity in the MAGNITUDE study was 12% in both arms. Grade 3 events occurred in 1.4% of patients and a Grade 4 event occurred in only one patient (0.5%). The incidence of SAEs was 0.9%. The median time to onset of hepatotoxicity in the MAGNITUDE study was 30 days. Hepatotoxicity was managed with dose interruptions in 1.4% and dose reduction in 0.9% of patients. One patient (0.5%) in the MAGNITUDE study discontinued treatment due to hepatotoxicity. Less Common Clinical Trial Adverse Reactions The following are selected clinically significant adverse reactions reported in less than 1% of patients receiving niraparib plus AAP or AKEEGA™ and with higher incidences reported than with placebo +AAP: Cardiac disorders: QT Prolongation Infections and Infestations: Urosepsis, Conjunctivitis Investigations: Gamma-glutamyl transferase increased Metabolism and nutrition disorders: Hypertriglyceridemia Skin and Subcutaneous tissue disorders: Photosensitivity Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Table 4 presents hematology and chemistry laboratory abnormalities worsening from baseline from the placebo-controlled Cohort 1 in the MAGNITUDE study. Table 4: Summary of Laboratory Abnormalities Worsening From Baseline in Niraparib plus AAP Treated Patients at a Higher Incidence than Placebo +AAP; Cohort 1 All HRR Safety Analysis Set (MAGNITUDE) Placebo + AAP Niraparib + AAP Placebo + AAP Niraparib + AAP Grade 1-4 Grade 1-4 Grade 3-4 Grade 3-4 Analysis set: safety 211 212 211 212 CHEMISTRY Alkaline Phosphatase Increased 56 (26.5%) 73 (34.4%) 2 (0.9%) 7 (3.3%) Blood Bilirubin Increased 17 (8.1%) 22 (10.4%) 2 (0.9%) 0 Creatinine Increased 31 (14.7%) 61 (28.8%) 3 (1.4%) 1 (0.5%) Hyperkalemia 45 (21.3%) 53 (25.0%) 5 (2.4%) 5 (2.4%) Hypokalemia 38 (18.0%) 47 (22.2%) 6 (2.8%) 9 (4.2%) HEMATOLOGY Anemia 102 (48.3%) 147 (69.3%) 14 (6.6%) 56 (26.4%) Hemoglobin Increased 0 1 (0.5%) 0 0 Lymphocyte Count Decreased 49 (23.2%) 98 (46.2%) 20 (9.5%) 37 (17.5%) Neutrophil Count Decreased 31 (14.7%) 60 (28.3%) 5 (2.4%) 15 (7.1%) Platelet Count Decreased 40 (19.0%) 77 (36.3%) 4 (1.9%) 15 (7.1%) White Blood Cell Decreased 30 (14.2%) 83 (39.2%) 2 (0.9%) 10 (4.7%) Key: AAP = abiraterone acetate plus prednisone. Post-Market Adverse Reactions At the time of authorization, no post-market findings were identified. DRUG INTERACTIONS 1.2 Drug Interactions Overview No clinical trial evaluating drug interactions has been performed using AKEEGA™. Interactions that have been identified in studies with individual components of AKEEGA™ (niraparib or abiraterone acetate) determine the interactions that may occur with AKEEGA™. Niraparib (see ZEJULA® PM for Drug Interaction Overview) No formal drug interaction studies have been performed with niraparib. In Vitro Studies Substrate of CYPs: Niraparib is a substrate of carboxylesterases (CEs) and UDP- glucuronosyltransferases (UGTs) in vivo. Inhibition of CYPs: Neither niraparib nor the major primary metabolite M1 is an inhibitor of CYP1A1/2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The potential to inhibit CYP3A4 at the intestinal level has not been established at relevant niraparib concentrations. Therefore, caution is recommended when niraparib is combined with active substances with CYP3A4-dependent metabolism. Induction of CYPs: Neither niraparib nor M1 is a CYP3A4 inducer in vitro. Niraparib weakly induces CYP1A2 in vitro. Therefore, caution is recommended when niraparib is combined with active substances with CYP1A2-dependent metabolism. Inhibition of UGTs: Niraparib did not exhibit inhibitory effect against the UGT isoforms (UGT1A1,UGT1A4, UGT1A9, and UGT2B7) up to 200 μM in vitro. Therefore, the potential for a clinically relevant inhibition of UGTs by niraparib is minimal. Inhibition of transporter systems: Niraparib is a weak inhibitor of Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp) with an IC50 = 5.8 μM and 161 μM, respectively, but does not inhibit bile salt export pump (BSEP). The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or Multidrug And Toxin Extrusion (MATE)-1 or 2. Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2). Niraparib is an inhibitor of MATE-1 and -2 with IC₅₀ of 0.18 μM and ≤ 0.14 μM, respectively (see 9.4 Drug-Drug Interactions). In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an IC50 = 34.4 μM. Caution is recommended when niraparib is combined with active substances that undergo uptake transport by OCT1. Substrate of transporter systems: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE-1 or 2. The metabolite M1 is not a substrate of P-gp, BCRP, BSEP, or MATE-1 and 2. Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2). Abiraterone Acetate (see ZYTIGA® PM for Drug Interaction Overview) In Vitro Studies In vitro studies indicated that CYP3A4 (see 9.4 Drug-Drug Interactions) and sulfotransferase 2A1 (SULT2A1) are the major isoenzymes involved in the metabolism of abiraterone. Inhibition of CYPs: Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2C8 and CYP2D6 (see 9.4 Drug-Drug Interactions). In vitro studies with human hepatic microsomes demonstrated that abiraterone was a moderate inhibitor of CYP2C9, CYP2C19 and CYP3A4/5 (No clinical DDI studies have been performed to confirm these in vitro findings). Substrate of OATP1B1: In vitro, abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the concentrations of drugs that are eliminated by OATP1B1. There are no clinical data available to confirm transporter based interaction. Drug-Behavioural Interactions Photosensitivity has been observed in patients exposed to niraparib monotherapy (See ZEJULA® PM) and as a combination therapy with AKEEGA™. Patients should be counselled to avoid sun exposure when possible while on treatment with AKEEGA™. 1.4 Drug-Drug Interactions Potential for other medicinal ingredients to affect AKEEGA™ CYP3A4 inducers: Based on in vitro data, abiraterone is a substrate of CYP3A4. In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampicin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong inducers of CYP3A4 during treatment with AKEEGA™ are to be avoided. CYP3A4 inhibitors: In a clinical pharmacokinetic interaction study, healthy subjects were administered ketoconazole, a strong CYP3A4 inhibitor, 400 mg daily for 6 days. No clinically meaningful effect on the pharmacokinetics of abiraterone was demonstrated following co- administration of a single dose of abiraterone acetate, 1000 mg at day 4. Potential for AKEEGA™ to affect other drugs CYP2D6 substrates: In a clinical study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased by approximately 200%. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased by approximately 33%. Caution is advised when AKEEGA™ is administered with drugs activated by or metabolized by CYP2D6, particularly with drugs that have a narrow therapeutic index. Dose reduction of narrow therapeutic index drugs metabolized by CYP2D6 should be considered. CYP2C8 substrates: In a clinical pharmacokinetic interaction study in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of the CYP2C8 substrate pioglitazone, each decreased by 10%, when a single dose of pioglitazone was given together with a single dose of 1000 mg abiraterone acetate. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with AKEEGA™. The drugs listed in Table 5 are interactions for AKEEGA™. Table 5: Established or Potential Drug-Drug Interactions Common name Source Effect Clinical Comment of Evidenc e Drugs that may affect the exposure of AKEEGA™ Strong CYP3A4 inducers (e.g., CT* Decreased abiraterone Strong inducers of phenytoin, carbamazepine, exposure CYP3A4 during treatment rifampicin, rifabutin, rifapentine, with AKEEGA™ are to be phenobarbital, St. John's wort) avoided. Strong CYP3A4 inhibitors (e.g., CT* No clinically meaningful No dose adjustment ketoconazole) effect on the needed for AKEEGA™ pharmacokinetics of when given with strong abiraterone inhibitors of CYP3A4. Drugs for which the exposure may be affected by AKEEGA™ CYP2D6 substrates (e.g., CT* Inhibited metabolism of Caution is advised when metoprolol, propranolol, CYP2D6 substrates co-administering desipramine, venlafaxine, AKEEGA™ with medicinal haloperidol, risperidone, products activated by or propafenone, flecainide, metabolized by CYP2D6, codeine, oxycodone and particularly with drugs tramadol) that have a narrow therapeutic index. Dose reduction should be considered. CYP2C8 substrates: (e.g., CT* Inhibited metabolism of Patients should be pioglitazone and repaglinide) CYP2C8 substrates monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with AKEEGA™. MATE-1 and -2 substrates (e.g. T* Inhibited metabolism of Monitoring of the clinical metformin) MATE-1 and -2 substrates effects of MATE-1 and MATE-2 substrates with a narrow therapeutic index is recommended if used concomitantly with AKEEGA™. CT*= Clinical trial with abiraterone acetate, T*=Theoretical Drug interactions of AKEEGA™ with vaccines or immunosuppressant agents has not been studied. The data on niraparib, in combination with cytotoxic medicinal products, are limited. Caution should be taken if AKEEGA™ is used in combination with vaccines, immunosuppressant agents or with other cytotoxic medicinal products. The safety of immunization during treatment with AKEEGA™ with live or live-attenuated vaccines and the response to immunization with any vaccine are unknown. Drug-Food Interactions AKEEGA™ must not be taken with food (see 4 DOSAGE AND ADMINISTRATION and 10.3 Pharmacokinetics). Administration with food has the potential to result in increased and highly variable systemic exposures of AKEEGA™. Drug-Herb Interactions Concomitant use with St. John’s wort (Hypericum perforatum) or products containing St. John’s wort is to be avoided. Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established. CLINICAL PHARMACOLOGY Mechanism of Action The niraparib and abiraterone acetate tablet is a dual-action tablet combination of niraparib (an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair) and the abiraterone prodrug (abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. This combination targets two oncogenic dependencies in patients with mCRPC and HRR gene alterations. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib-induced cytotoxicity was observed in tumour cell lines with or without deficiencies in BRCA1/2. Niraparib reduced tumour growth in mouse xenograft models of human cancer cell lines with defective BRCA1/2 function and in patient-derived xenograft tumour models with homologous recombination deficiency that had either mutated or wild type BRCA1/2, and in tumours that are BRCA wild-type and without detectable homologous recombination deficiency. Abiraterone acetate is converted in vivo to abiraterone that selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). CYP17 enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal, and prostatic tumour tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone into testosterone precursors, DHEA, and androstenedione, respectively, by 17αhydroxylation and cleavage of the C17,20 bond. Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Treatment with abiraterone decreases serum testosterone to undetectable levels (using commercial assays) when given with GnRH agonists (or orchiectomy). In preclinical mouse models of prostate cancer, the combination of niraparib and abiraterone acetate demonstrated superior efficacy relative to either active substance administered alone. This was demonstrated in both the BRCA1/2 wild-type VCaP model, and the BRCA2 mutant LuCaP 96 model. Pharmacodynamics As niraparib and abiraterone acetate tablets contain niraparib and abiraterone acetate, the pharmacodynamic effects of each component should be considered. Cardiac Electrophysiology Niraparib (see ZEJULA® PM for Pharmacodynamics) The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo‑controlled study in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the study following the treatment of niraparib 300 mg once daily. Abiraterone Acetate (see ZYTIGA® PM for Pharmacodynamics) A multicentre, open-label, uncontrolled, single arm ECG assessment study was performed in 33 patients with metastatic castration-resistant prostate cancer who were medically (N=28) or surgically castrated (N=5). Patients had serial ECG recordings at baseline and on day 1 of the first and second 28-day cycles of treatment with abiraterone acetate 1g/day plus prednisone 5 mg twice daily. At steady-state on day 1 of cycle 2, the QTc interval was significantly shortened at most time points, with a maximum decrease from baseline of mean -10.7 (90% CI -14.8, -6.5) ms at 24 h post-dosing. Androgen deprivation is associated with QTc prolongation. In this study the QTc interval averaged 435−440 ms at baseline and 57.6% of subjects had baseline QTc values > 450 ms prior to initiation of abiraterone acetate. Because the subjects in this trial were already androgen-deprived, the results of this study cannot be extrapolated to non-castrated populations. Cardiovascular Effects (see ZEJULA® PM for Pharmacodynamics) Niraparib (see ZEJULA® PM for Pharmacodynamics) Niraparib has the potential to cause effects on pulse rate and blood pressure in patients, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Based on the PRIMA study conducted in patients with advanced ovarian cancer (NCT02655016), mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at most on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 22.4 and 14.0 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.4 and 19.6 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 15.9 and 13.9 mmHg in the niraparib and placebo arms, respectively. Based on the NOVA study conducted in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (NCT02354131), mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively. Mineralocorticoid receptor antagonists Patients in the pivotal clinical trial MAGNITUDE (64091742PCR3001) were not allowed to use the mineralocorticoid receptor antagonist spironolactone since spironolactone has the ability to bind and activate the androgen receptor, which could stimulate disease progression. The use of spironolactone with AKEEGA™ should be avoided. Pharmacokinetics Table 6: Summary of AKEEGA™ (200 mg niraparib and 1000 mg abiraterone acetate) Pharmacokinetic Parameters in mCRPC Patients Cmax,ss Tmax (h)* T1/2 (h) AUC0-24h,ss CL/F (L/h) Vd/F (L) (ng/mL) (ng∙h/mL) Mean for 831 3.00 62.3 13616 16.7 1117 niraparib Mean for 151 1.50 19.7 707 1673 25774 abiraterone *Median for T^max Co-administration of niraparib and abiraterone acetate has no impact on the exposure of the individual moieties. The AUC and Cmax are comparable for niraparib and abiraterone when administered as a combination when compared to respective monotherapy exposures. Absorption In mCRPC patients, under fasted and modified fasted conditions, upon administration of multiple doses of niraparib and abiraterone acetate tablets, the maximum plasma concentration was achieved within a median of 3 hours for niraparib, and a median of 1.5 hours for abiraterone. The food effect of the individual components has been extensively characterized. Given the normal variation in the content and composition of meals, taking niraparib and abiraterone acetate tablets with meals has the potential to result in increased and highly variable exposures of abiraterone. Niraparib and abiraterone acetate tablets must be taken at least two hours after eating and food must not be eaten for at least one hour after taking abiraterone acetate. Distribution: Based on population pharmacokinetic analysis, the apparent steady-state volume of distribution (Vss/F) of niraparib and abiraterone were 1,117 L and 25,774 L, respectively, indicative of extensive extravascular distribution. Niraparib was moderately protein-bound in h ¹⁴uman plasma (83 %), mainly with serum albumin. The plasma protein binding of Cabiraterone in human plasma is >99%. Metabolism: Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major circulating metabolites. Following oral administration of ¹⁴C- abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone by a CYP independent pathway. Abiraterone undergoes metabolism including sulphation, hydroxylation, and oxidation primarily in the liver. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and Noxide abiraterone sulphate, each represent approximately 43% of total radioactivity. The formation of N-oxide abiraterone sulphate is predominantly catalyzed by CYP3A4 and SULT2A1 while the formation of abiraterone sulphate is catalyzed by SULT2A1. Elimination Based on population pharmacokinetic analysis in patients with mCRPC, the apparent clearance (CL/F) of niraparib and abiraterone were estimated to be 16.7 L/h and 1673 L/h, respectively. The mean t½ of niraparib and abiraterone when given in combination were approximately 62 hours and 20 hours, respectively. Special Populations and Conditions Pediatrics: No studies have been conducted to investigate the pharmacokinetics of AKEEGA™ in pediatric patients. Geriatrics: Based on population pharmacokinetic analysis in patients with mCRPC, geriatric patients aged 75 to 90 years had 23% (90% CI of 16-30%) higher AUC_0-24h,ss and 16% (90% CI of 10-22%) higher C_max,ss of niraparib compared to patients aged 45 to 65 years. Based on population pharmacokinetic analysis in patients with mCRPC, geriatric patients aged 75 to 90 years had 25% (90% CI of 16-34%) higher AUC_0-24h,ss and 19% (90% CI of 1-40%) higher Cmax,ss of abiraterone compared to patients aged 43 to 65 years. Body weight: Based on the population pharmacokinetic analysis, body weight did not have a clinically relevant impact on the exposure of niraparib (range: 43.3-165 kg) and abiraterone (range: 46.0-165 kg). Ethnic Origin: Based on a population pharmacokinetic analysis that included 69% White, 11 % Asian, and 6% Hispanic patients, ethnicity does not have a clinically significant effect on the exposure to niraparib. Based on a population pharmacokinetic analysis that included 67% White, 17 % Asian, and 7% Hispanic patients, ethnicity does not have a clinically significant effect on the exposure to abiraterone. Hepatic Insufficiency: No hepatic impairment study was conducted using AKEEGA™. Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib and abiraterone acetate in combination, mild hepatic impairment (NCI-ODWG criteria, n=231) did not affect the exposure of niraparib In a clinical study of cancer patients using NCI-ODWG criteria to classify the degree of hepatic impairment, niraparib AUC_inf in patients with moderate hepatic impairment (n=8) was 1.56 (90% CI: 1.06 to 2.30) times the niraparib AUCinf in patients with normal hepatic function (n=9) following administration of a single 300 mg dose. The pharmacokinetics of abiraterone were examined in subjects with pre-existing mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Turcotte-Pugh Class A and B, respectively) and in 8 healthy control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased approximately 1.11-fold and 3.6-fold in subjects with mild and moderate pre- existing hepatic impairment, respectively. There is no clinical experience using AKEEGA™ in patients with moderate or severe hepatic impairment. No dose adjustment of AKEEGA™ is necessary for patients with preexisting mild hepatic impairment. AKEEGA™ should not be used in patients with moderate and severe hepatic impairment (see 4 DOSAGE AND ADMINISTRATION, 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7 WARNINGS AND PRECAUTIONS). For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required (see 4 DOSAGE AND ADMINISTRATION and 7 WARNINGS AND PRECAUTIONS). Renal Insufficiency: No renal impairment study was conducted using AKEEGA™. Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib and abiraterone acetate in combination, mild renal impairment (CrCl: 60 to 90 mL/min, n=337) had no clinically significant effect on the pharmacokinetics of niraparib. Patients with moderate renal impairment (CrCl: 30 to 60 mL/min, n=114) had 33% higher AUC_0-24h,ss and 25% higher C_max,ss of niraparib compared to patients with normal renal function. The pharmacokinetics of abiraterone were compared in patients with end-stage renal disease on a stable hemodialysis schedule (n=8) versus matched control subjects with normal renal function (n=8). Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis. No dose adjustment for the niraparib and abiraterone acetate tablets is necessary for patients with mild to moderate renal impairment. There is no clinical experience in patients with severe renal impairment. STORAGE, STABILITY AND DISPOSAL Store at room temperature (15-30°C) in original container. SPECIAL HANDLING INSTRUCTIONS Based on its mechanism of action, this medicinal product may harm a developing fetus; therefore, women who are or may become pregnant should not handle it without protection, e.g., gloves (see 4 CONTRAINDICATIONS, and 7.1.1 Pregnant Women). Any unused product or waste material should be disposed of in accordance with local requirements. PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substances Proper/Common name: niraparib tosylate Chemical name: 2-{4-[(3S)-piperidin-3-yl] phenyl}-2H-indazole 7-carboxamide 4- methylbenzenesulfonate hydrate (1:1:1) Molecular formula: C19H20N4O. C7H8O3S.H2O Molecular mass: 510.61 Structural formula: is a white to off-white, non- hygroscopic crystalline solid. Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range. Proper name: abiraterone acetate Chemical name: (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate Molecular formula: C26H33NO2 Molecular mass: 391.55 Structural formula: Physicochemical properties: Abiraterone acetate is a white to off-white crystalline powder. Abiraterone acetate is practically insoluble in aqueous media over a wide range of pH values (pH=2.0 to 12.9). The melting point is between 147ºC and 148ºC. The pKa is 5.19. CLINICAL TRIALS Clinical Trials by Indication The treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) metastatic castration-resistant prostate cancer (mCRPC), who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated. Patients must have confirmation of BRCA mutation before AKEEGA™ treatment is initiated. Table 7: Summary of Patient Demographics for Clinical Trials in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Dosage, route of Study # Study design administration and Study subjects Mean age duration (n) (Range) 64091742PCR3001 Phase 3 Cohort 1 and 2: 200mg Cohort 1 = 423 Cohort 1 = 69 (MAGNITUDE) Randomized, niraparib/placebo, Cohort 2=247 (43-100 years) double-blind, 1000mg abiraterone as ebo- single agent C Cohort 2= 71 plac ohort 3=95 (52-87 years) controlled combinations, and multicenter 10mg prednisone Cohort 3=69.2 study with 3 orally once daily. (47-90 years) Cohorts Cohort 3: 200mg niraparib, 1000mg abiraterone as fixed- dose combination tablets, and 10mg predinosone orally once Patients received concomitant background androgen deprivation therapy with a GnRH analogue if not surgically castrate. Study Design and Study Demographics (MAGNITUDE) The efficacy of AKEEGA™ was established in MAGNITUDE (Study 64091742PCR3001), a randomized, double-blind, placebo-controlled multicenter Phase 3 clinical study to assess the efficacy of niraparib in combination with abiraterone acetate plus prednisone (AAP), compared with placebo plus AAP in metastatic castration-resistant prostate cancer (mCRPC) patients randomized in 3 Cohorts. Key eligibility criteria included asymptomatic/mildy symptomatic patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior AAP (up to four months in the absence of disease progression) and, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, adequate hematological, hepatic, renal and cardiac function parameters (See Table 7 for Study Demographics). Asymptomatic/mildly symptomatic status was defined by a score of ≤3 on BPI-SF (Brief Pain Inventory Short Form), Question#3 worst pain over the past 24 hours at screening. Patients were required to have castrate levels of testosterone ≤50 ng/dL on a GnRHa or bilateral orchiectomy and continued background androgen deprivation therapy with a GnRH analogue if not surgically castrate. Subjects with active brain metastases, opiate use during screening, a history of adrenal dysfunction, history of current/prior AML/MDS, or prior AAP treatment outside mCRPC setting were excluded. Patients were stratified by past taxane-based chemotherapy exposure in metastatic castration sensitive prostate cancer setting (24.4%), past AR-targeted therapy exposure (4.9%), prior AAP use up to four months (26.2%). In Cohort 1, Patients were further stratified by Homologous recombination repair (HRR) gene alteration status (BRCA1/2 vs. all non-BRCA HRRm). Patients were prospectively screened for HRR alterations and then enrolled into either Cohort 1 and 3 (presence of HRR gene alterations) or Cohort 2 (absence of HRR gene alterations). Plasma, and/or tumor tissue (fresh or archival) samples for all patients were centrally tested with Foundation One® CDx or the Resolution CtDx HRD™ to determine HRR mutation status. These assays do not differentiate between germline and somatic mutations. Enrollment into the study based on local testing was infrequent. The same central tests were used to confirm HRR status for those subjects who enrolled based on local test results. Cohort 1 consisted of 423 patients with mCRPC and 9 pre-specified HRR gene alterations (HRRm). Cohort 1 and 2 patients were randomized (1:1) to receive either niraparib plus abiraterone acetate and prednisone or prednisolone (AAP) orally at a dose of 200 mg/1,000 mg once daily or placebo plus AAP once daily as single agent combinations. Treatment was continued until disease progression, unequivocal clinical progression, unacceptable toxicity, or death. Cohort 2 included 246 patients without HRR gene alterations. Since the pre-specified futility analysis for Cohort 2 was met, the independent data monitoring committee (IDMC) recommended unblinding and to stop enrolment in Cohort 2, with the unblinded patients allowed to remain on niraparib plus AAP or receive AAP alone. Cohort 3 was a separate single-arm open-label cohort with no hypothesis testing, which enrolled patients after completion of enrollment into Cohort 1 and 2. Cohort 3 included 95 mCRPC patients with the same HRR gene alterations as Cohort 1. Patients received treatment with the same dosing regimen as Cohort 1 with the fixed-dose combination tablet formulation of niraparib and abiraterone acetate. Demographic and baseline BRCAm patient characteristics in MAGNITUDE, Cohort 1 are summarized in Table 8 below. BRCAm patient demographics and baseline disease characteristics were generally balanced between the treatment arms, however, more patients with higher ECOG and BPI-SF score were in the niraparib plus AAP arm. Table 8: Key Baseline Disease Characteristics in BRCAm patients, MAGNITUDE Cohort 1 Placebo + AAP Niraparib + AAP Total Analysis set: randomized 112 113 225 Time from initial diagnosis to randomization (years) Mean (SD) 3.68 (3.506) 3.09 (2.796) 3.39 (3.176) Median 2.31 2.00 2.26 Range (0.5; 16.1) (0.5; 18.3) (0.5; 18.3) Time from mCRPC to first dose (years) Mean (SD) 0.46 (0.513) 0.34 (0.292) 0.40 (0.420) Median 0.28 0.27 0.27 Range (0.0; 2.9) (0.0; 2.3) (0.0; 2.9) Age (years) Median 68.0 67.0 68.0 Range (43; 88) (45; 100) (43; 100) < 65 37 (33.0%) 39 (34.5%) 76 (33.8%) ≥ 65-74 52 (46.4%) 44 (38.95) 96 (42.7%) ≥ 75 23 (20.5%) 30 (26.5%) 53 (23.6%) Gene Frequency BRCA1 4 (3.6%) 12 (10.6%) 16 (7.1%) BRCA2 89 (79.5%) 86 (76.1%) 175 (77.8%) Race Asian 20 (17.9%) 18 (15.9%) 38 (16.9%) Black or African American 0 3 (2.7%) 3 (1.3%) White 84 (75.0%) 78 (69.0%) 162 (72.0%) Unknown 8 (7.1%) 14 (12.4%) 22 (9.8%) Ethnicity Hispanic or Latino 13 (11.6%) 13 (11.5%) 26 (11.6%) Not Hispanic or Latino 91 (81.3%) 83 (73.5%) 174 (77.3%) Not reported 8 (7.1%) 17 (15.0%) 25 (11.1%) Metastasis stage at initial diagnosis M0 56 (50.0%) 38 (33.6%) 94 (41.8%) M1 50 (44.6%) 70 (61.9%) 120 (53.3%) Unknown 6 (5.4%) 5 (4.4%) 11 (4.9%) Gleason Score at initial diagnosis <7 8 (7.1%) 8 (7.1%) 16 (7.1%) 7 27 (24.1%) 16 (14.3%) 43 (19.2%) 3+4 7 (6.3%) 6 (5.4%) 13 (5.8%) 4+3 19 (17.0%) 10 (8.9%) 29 (12.9%) unknown 1 (0.9%) 0 1 (0.4%) >=8 72 (64.3%) 83 (74.1%) 155 (69.2%) Unknown 5 (4.5%) 5 (4.5%) 10 (4.5%) PSA at initial diagnosis (µg/l) N 101 104 205 Mean (SD) 252.83(693.7) 219.83 (553.9) 236.09 (625.3) Median 42.00 43.23 42.96 Range (0.1;5000.0) (0.1;3687.0) (0.1;5000.0) ECOG Performance Status 0 80 (71.4%) 69 (61.1%) 149 (66.2%) 1 32 (28.6%) 44 (38.9%) 76 (33.8%) Extent of Disease at study entry^a Bone 93 (83.0%) 99 (87.6%) 192 (85.3%) Placebo + AAP Niraparib + AAP Total Analysis set: randomized 112 113 225 Bone only 46 (41.1%) 38 (33.6%) 84 (37.3%) Visceral 22 (19.6%) 26 (23.0%) 48 (21.3%) Soft tissue 7 (6.3%) 5 (4.4%) 12 (5.3%) Nodal^b 50 (44.6%) 62 (54.9%) 112 (49.8%) Pelvic 34 (30.4%) 42 (37.2%) 76 (33.8%) Non-pelvic 34 (30.4%) 40 (35.4%) 74 (32.9%) Prostate^c 2 (1.8%) 1 (0.9%) 3 (1.3%) Number of bone lesions at study entry <=10 lesions^d 67 (59.8%) 68 (60.2%) 135 (60.0%) > 10 lesions 45 (40.2%) 45 (39.8%) 90 (40.0%) LDH at study entry (Enzyme U/l) N 111 111 222 Mean (SD) 241.09(190.5) 337.90(473.8) 289.50 (363.5) Median 197.00 204.00 201.50 Range (98.0;1530.0) (98.0;2959.0) (98.0;2959.0) BPI-SF pain score (item 3) 0 57 (50.9%) 57 (50.4%) 114 (50.7%) 1 to 3 40 (35.7%) 51 (45.1%) 91 (40.4%) > 3 15 (13.4%) 5 (4.4%) 20 (8.9%) Mean (SD) 1.35 (1.976) 1.09 (1.573) 1.22 (1.786) Median 0.00 0.00 0.00 Range (0.0; 9.0) (0.0; 10.0) (0.0; 10.0) Key: AAP=abiraterone acetate plus prednisone ^aSubjects having multiple lesions within each category are counted only once in the category but may be represented on more than one category ^bIncludes lymph nodes not specified as pelvic or non-pelvic. ^cprostate local recurrence/progression ^dincludes subjects with no bone lesion The median duration of treatment in Cohort 1 was 13.8 months (12 months in placebo +AAP) and Cohort 3 was 5.4 months respectively at the time of CCO (08 October 2021) . Overall, 95.3% and 93.7% of patients received at least 3 cycles of treatment in Cohort 1 and Cohort 3. Efficacy Endpoints: The primary endpoint was radiographic progression free survival (rPFS) as determined by blinded independent central radiology (BICR) review per prostate cancer working group 3 (PCWG3) (for bone lesions) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 (for soft tissue lesions). In patients with alterations in BRCA1 or BRCA2 genes (BRCAm subgroup), rPFS was formally statistically evaluated. Secondary statistically-planned efficacy outcome measures included time to cytotoxic chemotherapy (TCC), time to symptomatic progression (TSP), and overall survival (OS). Study Results: Treatment of BRCA-mutated mCRPC (MAGNITUDE) In the BRCAm subgroup, a statistically significant and clinically meaningful improvement in rPFS was observed in the niraparib + AAP group, with a 47% reduction in the risk of radiographic progression or death compared with the placebo + AAP group (HR = 0.533; 95% CI: [0.361, 0.789], two-sided p = 0.0014) at interim analysis 1 (Clinical cut-off on 08 October 2021). The rPFS efficacy was similar between the plasma circulating tumour DNA and tumour tissue DNA testing methods for the BRCAm subgroup. Interim analyses for the secondary endpoints TCC (24% maturity), TSP (30% maturity) and OS (25% maturity) did not meet the pre-specified boundary for statistical significance (CCO on 08 October 2021). At the time of interim analysis 1, efficacy in Cohort 3 is immature. Efficacy results of the BRCAm subgroup of Cohort 1 are summarized in Table 9 and Figure 5. Table 9: Efficacy Results from BRCAm mCRPC population in MAGNITUDE Cohort 1 _Endpoints ^N Placebo + AAP (_N ^ir =^a 1^p 1^a 3^r )^ib+AAP (N=112) Radiographic Progression-free Survival by BICR Event of disease progression or death (%) 45 (39.8%) 64 (57.1%) Median, months (95% CI) 16.56 (13.86, NE) 10.87 (8.31, 13.80) Hazard Ratio (95% CI) 0.533 (0.361, 0.789) p-value 0.0014 Time to initiation of Cytotoxic chemotherapy Event (%) 22 (19.5%) 33 (29.5%) Median, months (95% CI) NE (22.60, NE) 25.99 (20.73, NE) Hazard Ratio (95% CI) 0.578 (0.332, 1.006) p-value^b 0.0495 Time to Symptomatic progression ^c Event (%) 29 (25.7%) 38 (33.9%) Median, months (95% CI) NE (20.53, NE) 19.84 (17.54, NE) Hazard Ratio (95% CI) 0.683 (0.420, 1.111) p-value^{b a} 0.1224 CCO 08 October 2021 Note hazard ratio is estimated based on the stratified Cox's Proportional Hazards Model; p-value is from a stratified log-rank test. ^b nominal p-value ^c Time to Symptomatic progression was defined as the time from the date of randomization to the date of the first of any of the following: - EBRT for skeletal symptoms. - Tumor-related orthopedic surgical intervention. - Other cancer-related procedures (e.g., nephrostomy insertion, bladder catheter insertion, EBRT, or surgery for tumor symptoms other than skeletal). - Cancer-related morbid events (e.g., fracture [symptomatic and/or pathologic], cord compression, urinary obstructive events). - Initiation of a new systemic anti-cancer therapy because of cancer pain In exploratory subgroup analyses, treatment benefit in subjects with visceral metastases was uncertain due to the limited sample size. In Cohort 1, BRCA patients with visceral metastases (n=48), the rPFS HR= 1.02 [95% CI 0.50,2.06; the OS HR=2.3 [95% CI: 1.06, 5.1]. In the BRCA subgroup with visceral metastases, the median OS was 14 months in the niraparib+AAP arm compared to 25 months in the placebo+AAP arm at interim analysis (IA) 2 (CCO on 17 Jun 2022). Subgroup analyses are summarized in Table 10. Table 10: Exploratory subgroup analyses by visceral metastases status rPFS PA-IA1 OS IA2 Treatment Subgroup (N) (%) group N(events) HR(95% CI) N(events) HR(95% CI) All BRCA (N=225) Placebo+AAP 112(64) 0.533 112 (49) 0.881 Niraparib+AAP 113(45) (0.361,0.789) 113 (43) (0.582,1.335) BRCA non-Visceral Placebo+AAP 90(51) 0.386 90(40) 0.534 (N=177) (78.7%) Niraparib+AAP 87(25) 0.238,0.626) 87(23) ^{(0.320,0.893)} BRCA Visceral (N=48) Placebo+AAP 22(13) 1.020 22(9) 2.334 (21.3%) Niraparib+AAP 26(20) (0.504,2.061) 26(20) (1.059,5.143) No benefit for treatment with niraparib+ AAP was observed in Cohort 2 patients without ^H Au^R g^R u ^g s^e tⁿ 2^e 02 ^a 0^lt ,^e a^r s^a s^t e^io sⁿ si^s n^. g ^T d^h a^e ta ^pr f^e ro^-p m^la 2ⁿ 3ⁿ 3^ed su ^f b^u j^t e^il c^it t^y s w ^an it^a h^ly 1^s 1^is 3 ^fo co^r m ^Co p^h o^o s^r it^t e ² p ^w ro^a g^s r ^p e^e ss^r i^f o^o n^rm e^e ve^d n ^o tⁿ s ¹³ observed. With a HR=1.087 for the composite progression endpoint, futility was declared for ^{this cohort} MICROBIO.LOGY No microbiological information is required for this drug product. NON-CLINICAL TOXICOLOGY General Toxicology: Nonclinical studies with AKEEGA™ have not been performed. The nonclinical toxicology data are based on findings in studies with niraparib and abiraterone acetate individually. Aside from reproductive organ changes seen in all animal toxicology studies, nonclinical data reveal no special hazard for humans with AKEEGA™ based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In vitro, niraparib bound to the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited uptake of norepinephrine and dopamine in cells with IC50 values that were lower than the Cmin at steady-state in patients receiving niraparib 300 mg once daily. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites in cortex. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular or CNS). In safety pharmacology studies, intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3 and 10 mg/kg resulted in an increased range of arterial pressures of 13-20, 18-27 and 19-25% and increased range of heart rates of 2-11, 4-17 and 12-21% above pre-dose levels, respectively. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.7, 2 and 8 times the unbound Cmax at steady-state in patients receiving niraparib 300 mg once daily. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinical relevance of these findings is not known. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months’ duration in rats and dogs. The major primary target organ for toxicity in rats and dogs was the bone marrow, with associated changes in peripheral hematology parameters. Additionally, decreased spermatogenesis was seen in both species. These findings occurred at exposure levels below those seen clinically and were reversible within 4 weeks of cessation of dosing. In repeated dose toxicity studies in rats and monkeys with abiraterone acetate, circulating testosterone levels were significantly reduced at concentration levels of approximately one half the human clinical exposure. As a result, morphological and/or histopathological changes in the reproductive organs such as aspermia/hypospermia, atrophy/weight reductions in the male genital tract organs and testes, adrenal gland hypertrophy, Leydig cell hyperplasia, pituitary gland hyperplasia and mammary gland hyperplasia were observed. The changes in the reproductive organs and androgen sensitive organs are consistent with the pharmacology of abiraterone. All treatment related changes were partially or fully reversed after a four-week recovery period. After chronic treatment from 13-weeks onward, bile duct/oval cell hyperplasia, associated with increased serum alkaline phosphatase and/or total bilirubin levels, was seen in rat and monkey livers. After a four-week recovery period, serum parameters reversed, whereas bile duct/oval cell hyperplasia persisted. A dose dependent increase in cataracts was observed after 26-weeks of treatment in rats which were irreversible after a four-week recovery period. Carcinogenicity: Carcinogenicity studies have not been conducted with niraparib. Abiraterone acetate was not carcinogenic in a 6 month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat, abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding is considered related to the pharmacological action of abiraterone and rat specific. The clinical relevance of this finding is not known. Abiraterone acetate was not carcinogenic in female rats. Genotoxicity: Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test but was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Abiraterone acetate and abiraterone were devoid of genotoxic potential in the standard panel of genotoxicity tests, including an in vitro bacterial reverse mutation assay (the Ames test), an in vitro mammalian chromosome aberration test (using human lymphocytes) and an in vivo rat micronucleus assay. Reproductive and Developmental Toxicology: Reproductive and developmental toxicity studies have not been conducted with niraparib. While no direct fertility studies were conducted with niraparib in animals, repeat dose toxicity studies in rats and dogs showed a reduction in spermatogenesis, small testes, and germ cell depletion in the testes and epididymides and these changes were largely reversible within four-weeks of cessation of dosing. In fertility studies in rats with abiraterone acetate, reduced organ weights of reproductive system, sperm count, sperm motility, altered sperm morphology and reduced fertility were observed in male rats dosed for 4 weeks at ≥ 30 mg/kg/day. Mating of untreated female rats with males that received 30 mg/kg/day abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre- implantation loss. Female rats dosed for 2 weeks until day 7 of pregnancy at ≥ 30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and preimplantation loss. These effects in male and female rats were completely reversible in 4 to 16 weeks after abiraterone acetate was stopped. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended 1000 mg/day dose of abiraterone acetate based on body surface area. In developmental toxicity study in rats, abiraterone acetate did not have teratogenic potential, however, abiraterone acetate caused developmental toxicity when administered at doses ≥10 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects), urogenital effects (bilateral ureter dilation), decreased fetal ano-genital distance, decreased fetal body weight. The doses tested in rats caused maternal toxicity at systemic exposures lower than the human exposure.

PATIENT MEDICATION INFORMATION READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE ^PrAKEEGA™ Niraparib and abiraterone acetate tablets Read this carefully before you start taking AKEEGA™ and each time you get a refill. This leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare professional about your medical condition and treatment and ask if there is any new information about AKEEGA™. Serious Warnings and Precautions ^ AKEEGA™ may cause hypertension (high blood pressure), hypokalemia (low blood potassium) and peripheral edema (swelling of the legs or hands caused by fluid retention). These will need to be treated before starting AKEEGA™. Your healthcare professional will do tests to check these problems monthly. ^ Tell your healthcare professional if you have a history of heart failure, heart attack, or other heart problems. This will help avoid side effects and ensure proper use of AKEEGA™. ^ If you have moderate to serious liver problems, you should not take AKEEGA™. ^ Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) is a problem with the bone marrow. You may have low red, white, or platelet cell counts. This is serious and can lead to death. What is AKEEGA™ used for? For the following indication AKEEGA™ has been approved with conditions (NOC/c). This means it has passed Health Canada’s review and can be bought and sold in Canada, but the manufacturer has agreed to complete more studies to make sure the drug works the way it should. For more information, talk to your healthcare professional. ^ AKEEGA™ is used with another medicine called prednisone or prednisolone. It is used to treat adult patients with prostate cancer that has spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone (known as metastatic castration resistant prostate cancer). These adults must also: o not currently be recommended to receive chemotherapy by their healthcare professional; o have mild or no symptoms; and o have alterations in BRCA genes What is a Notice of Compliance with Conditions (NOC/c)? A Notice of Compliance with Conditions (NOC/c) is a type of approval to sell a drug in Canada. Health Canada only gives an NOC/c to a drug that treats, prevents, or helps identify a serious or life- threatening illness. The drug must show promising proof that it works well, is of high quality, and is reasonably safe. Also, the drug must either respond to a serious medical need in Canada, or be much safer than existing treatments. Drug makers must agree in writing to clearly state on the label that the drug was given an NOC/c, to complete more testing to make sure the drug works the way it should, to actively monitor the drug’s performance after it has been sold, and to report their findings to Health Canada. How does AKEEGA™ work? AKEEGA™ is a dual action medicine that contains two active substances: niraparib and abiraterone acetate. Niraparib is a type of anti-cancer medicine called a PARP inhibitor. PARP inhibitors block an enzyme called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged DNA so blocking it means that the DNA of cancer cells cannot be repaired. This results in tumour cell death, helping to control the cancer. Abiraterone acetate stops your body from making testosterone. This can slow the growth of prostate cancer as testosterone promotes cancer cell growth. What are the ingredients in AKEEGA™? Medicinal ingredients: niraparib (as niraparib tosylate), abiraterone acetate Non-medicinal ingredients: Colloidal anhydrous silica, crospovidone, glycerol monocaprylocaprate, hypromellose, iron oxide (E172), iron oxide red (E172), iron oxide yellow (E172), lactose monohydrate, magnesium stearate, polyvinyl alcohol, silicified microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide (E171) AKEEGA™ comes in the following dosage forms: tablets in the following strengths: ^ 100 mg niraparib (as niraparib tosylate) and 500 mg abiraterone acetate: orange oval tablets, debossed with “N100 A” on one side and plain on the other side. ^ 50 mg niraparib (as niraparib tosylate)and 500 mg abiraterone acetate: yellowish orange to yellowish brown oval tablets, debossed with “N 50 A” on one side and plain on the other side. Both these strengths are available in bottles containing 60 tablets each. Do not use AKEEGA™ if: ^ you are allergic to niraparib or abiraterone acetate or any of the other ingredients of this medicine (see What are the ingredients in AKEEGA™?). ^ you are a woman. AKEEGA™ is for use in male patients only. ^ you have moderate or severe liver disease. Your healthcare professional will decide whether AKEEGA™ can be used if you have mild liver problems. To help avoid side effects and ensure proper use, talk to your healthcare professional before you take AKEEGA™. Talk about any health conditions or problems you may have, including if you: ^ have low blood-cell count on testing. AKEEGA™ lowers your blood-cell counts, such as your red blood-cell count (anemia), white blood-cell count (neutropenia), or blood-platelet count (thrombocytopenia). ^ have or have had high blood pressure or other heart or blood vessel problems. For example, heart failure, irregular or rapid heart rate, shortness of breath. ^ have low blood potassium. Low blood potassium may increase the risk of heart rhythm problems. ^ have gained weight rapidly, or have swelling in the feet, ankles, or legs. ^ have liver problems. ^ have low levels of sugar in the blood. ^ have an intolerance to lactose. This is because AKEEGA™ contains lactose. ^ are 75 years of age or older. Other warnings you should know about: AKEEGA™ must be taken on an empty stomach since food can increase the blood level of AKEEGA™ and this may be harmful. Do NOT eat any solid or liquid food two hours before taking AKEEGA™ and for at least one hour after taking AKEEGA™. High blood pressure (hypertension) ^ AKEEGA™ may cause high blood pressure. ^ To reduce the chance of developing high blood pressure, heart problems or low blood potassium, your healthcare professional will prescribe either prednisone or prednisolone. You need to take one of these drugs daily while you are taking AKEEGA™. ^ You may also be advised by your healthcare professional to monitor your blood pressure at home. Your healthcare professional will give you instructions on when to contact them in case of a rise in blood pressure. Posterior Reversible Encephalopathy Syndrome (PRES) PRES is a rare neurological side effect. Cases of PRES has been reported with the niraparib component of AKEEGA™. Talk to your healthcare professional right away if you develop the following symptoms: headaches, vision changes, confusion, or seizure. Low blood sugar (hypoglycemia) ^ AKEEGA™ may affect your blood sugar levels if you have diabetes. Your blood sugar may drop if you take AKEEGA™ plus prednisone/prednisolone with some medicines for diabetes such as pioglitazone or repaglinide. ^ Tell your healthcare professional if you take a medicine for diabetes and notice a drop in your blood sugar while monitoring your blood sugar. Male patients ^ During treatment with AKEEGA™, use a condom along with another effective birth control method each time you have sex with a woman who is pregnant, may be pregnant or could get pregnant. Continue using condom and another effective birth control method for 3 months after your last dose. ^ If your sexual partner becomes pregnant or think they may be pregnant during your treatment with AKEEGA™, talk to your healthcare professional right away. ^ Treatment with AKEEGA™ may affect your ability to have children. Talk to your healthcare professional if you have concerns about this. Females ^ AKEEGA™ is not for use in women. ^ AKEEGA™ may harm an unborn baby. ^ Women who are pregnant or may be pregnant should not handle AKEEGA™ without protective gloves. Sensitivity to sunlight (photosensitivity) ^ Photosensitivity was reported in patients treated with niraparib, a component of AKEEGA™. ^ You should avoid sun exposure during treatment with AKEEGA™. When in the sunlight, wear a sunscreen with a high protection factor of at least SPF 15 and protective clothing. Check-ups and testing You will have regular visits with your healthcare professional, before, during and after treatment with AKEEGA™. They will: ^ Do blood tests to check your blood cell count, liver enzyme levels, blood potassium levels. ^ Check your blood pressure. ^ Monitor for side effects of your treatment with AKEEGA™ and prednisone or prednisolone. Driving and using machinery AKEEGA™ may cause weakness, fatigue and dizziness. Before you drive or do tasks that require special attention, wait until you know how you respond to AKEEGA™. Tell your healthcare professional about all the medicines you take, including any drugs, vitamins, minerals, natural supplements, or alternative medicines. The following may interact with AKEEGA™: ^ medicines typically used to treat epilepsy (seizures) such as phenytoin, carbamazepine, phenobarbital ^ medicines to treat bacterial infections such as rifampicin, rifabutin ^ an herbal treatment for depression called St. John’s wort ^ medicines to treat psoriasis, rheumatoid arthritis such as such as ciclosporin, tacrolimus, methotrexate ^ medicines for pain such as alfentanil, ergotamine, codeine, oxycodone, and tramadol ^ medicines for schizophrenia (mental disorder) such as pimozide, quetiapine, haloperidol, risperidol, or depression such as desipramine, venlafaxine, ^ medicines for treating malaria such as halofantrine, clozapine, ^ medicines used to treat asthma such as theophylline ^ medicines used to treat parkinsons disease (progressive movement disorder) such as ropinirole, ^ medicines used to treat high blood pressure such as metoprolol, propranolol, or abnormal heart rhythm such as propafenone, flecainide, or for high cholesterol such as rosuvastatin, simvastatin, atorvastatin, and methotrexate ^ medicines used to treat diabetes, such as pioglitazone, repaglinide and metformin ^ medicines used in cancer treatment such as irinotecan, radiotherapy You should not start or stop any medicine before you talk with the healthcare professional that prescribed AKEEGA™. How to take AKEEGA™: ^ Take AKEEGA™ exactly as your healthcare provider tells you. ^ Take your prescribed dose of AKEEGA™ once a day. ^ Take AKEEGA™ on an empty stomach. Do NOT eat food at least two hours before taking AKEEGA™ and at least one hour after taking AKEEGA™. Taking AKEEGA™ with food causes more of this medicine to be absorbed by the body than is needed and this may cause side effects. ^ Swallow AKEEGA™ tablets whole with water. Do NOT break, crush, or chew the tablets. ^ Do NOT stop taking your prescribed dose of AKEEGA™ without talking to your healthcare professional first. ^ AKEEGA™ is taken with a medicine called prednisone or prednisolone. Take the prednisone or prednisolone exactly as your healthcare professional tells you. They will tell you how much of this medicine to take and how to take it. ^ You must also start or continue a gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with AKEEGA™ unless you had surgical castration. This is a surgery to remove your testicles to lower the amount of testosterone in your body. Usual dose: Recommended adult dose: 200 mg niraparib and 1000 mg abiraterone acetate. To make this dose, take two 100 mg / 500 mg tablets. Your healthcare professional may change your dose, temporarily stop or completely stop treatment with AKEEGA™. This may happen if you have certain side effects while taking AKEEGA™. Overdose: If you think you, or a person you are caring for, have taken too much AKEEGA™, contact a healthcare professional, hospital emergency department, or regional poison control centre immediately, even if there are no symptoms. Missed Dose: If you miss a dose of AKEEGA™, prednisone or prednisolone, take your normal dose as soon as possible on the same day. Return to your normal daily dose and normal daily schedule on the following day. DO NOT take extra tablets to make up the missed dose. What are possible side effects from using AKEEGA™? These are not all the possible side effects you may have when taking AKEEGA™. If you experience any side effects not listed here, tell your healthcare professional. Side effects may include: ^ Decreased appetite ^ Difficulty sleeping ^ Feeling dizzy ^ Constipation ^ Shortness of breath ^ Nausea and vomiting ^ Joint pain ^ Feeling weak and very tired ^ Increased sensitivity to the sun Serious side effects and what to do about them Talk to your healthcare professional Stop taking drug and Symptom / effect O^{nly if severe In all cases} get immediate m_{edical help} VERY COMMON Anemia (low red blood cells): Being short of breath, feeling very tired, having pale skin, loss of energy or ^ extreme weakness, fast heartbeat. Serious side effects and what to do about them Talk to your healthcare professional Stop taking drug and Symptom / effect O^{nly if severe In all cases} get immediate m_{edical help} Hypertension (high blood pressure): shortness of breath, fatigue, dizziness or fainting, chest pain or pressure, swelling in your ankles and legs, bluish _^ colour to your lips and skin, racing pulse or heart palpitations Thrombocytopenia (low blood platelets): bruising or bleeding for longer than usual if you hurt yourself - ^ - these may be signs of a low blood platelet count. Neutropenia or Leukopenia (low white blood cells): Fever or infection, chills, aches and pain and flu-like ^ symptoms. Some infections can be serious and may lead to death. Hypokalemia (low level of potassium in the blood): Muscle weakness, muscle twitches or a pounding ^ heartbeat, cramping, constipation, fatigue, tingling or numbness. COMMON Palpitations (Fast, irregular heartbeats) _^ Urinary tract infection (infection in urinary system including kidneys, ureters, bladder, and urethra): Burning or pain during urination, _^ frequent urination, blood in urine, pain in the pelvis, strong smelling urine, cloudy urine. Thromboembolism (blood clot in a vein or artery): pain or tenderness or swelling in your arm or leg, skin that is red or warm, coldness, tingling or _{^ ^} numbness, pale skin, muscle pain or spasms, weakness UNCOMMON Arrhythmias, including QT prolongation and Torsades de Pointes (irregular heart-beat disorders): associated with feeling faint, lightheaded, chest pain, a racing ^ heartbeat, a slow heartbeat, shortness of breath, sweating, or a fluttering in your chest. VERY RARE Serious side effects and what to do about them Talk to your healthcare professional Stop taking drug and Symptom / effect O^{nly if severe In all cases} get immediate m_{edical help} Hypoglycemia (low blood sugar): Thirst, frequent urination, hunger, nausea and dizziness, fast heartbeat, tingling, trembling, nervousness, _^ sweating, low energy (low blood sugar) If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to interfere with your daily activities, tell your healthcare professional. Reporting Side Effects You can report any suspected side effects associated with the use of health products to Health Canada by: ^ Visiting the Web page on Adverse Reaction Reporting (www.canada.ca/en/health- canada/services/drugs-health-products/medeffect-canada.html) for information on how to report online, by mail or by fax; or ^ Calling toll-free at 1-866-234-2345. NOTE: Contact your health professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice. Storage: ^ Store AKEEGA™ tablets at room temperature at 15−30^oC in original container. ^ Keep out of reach and sight of children. ^ Do not use after the expiry date which is stated on the label. The expiry date refers to the last day of the month. Do not throw away any drugs via wastewater or household waste. Ask your pharmacist how to throw away drugs you no longer use. If you want more information about AKEEGA™: ^ Talk to your healthcare professional ^ Find the full product monograph that is prepared for healthcare professionals and includes this Patient Medication Information by visiting the Health Canada website: (www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug- product-database.html); the manufacturer’s website : www.janssen.com/canada, or contact the manufacturer, Janssen Inc., at: 1-800-567-3331 or 1-800-387-8781. This leaflet was prepared by Janssen Inc., Toronto, Ontario M3C 1L9 Last revised: June 07, 2023 All trademarks used under license. All other third party trademarks are trademarks of their respective owners. _s a _g ² _t ⁿ ( ^m w _e ^M _{Y T} ^Y A _{Y /} ^Y ) ^a _{e l} ^ol _.t ^m _oG M bi_r a_p ^w _{o Ta} a_r ^{l i} _e Ow_l ^e N ^f _a ^{WE .} _{E n}K _: ^{M t} _{: o} ^P _{X n} ^b g_t ^r _oM ^S _. ^e l ^e _r ^{r DT} _PA ^{L E} A^e _{e l} ^di _e m_a h_c ^. _hG ^S. _h c_f ^l _d )_we ^c _a ^E l^oe _Es ^t _e ^{n l o} _{t a} h ^e _{s -} ^m _{o r} ^rK _Ab ^h _{gt b}t _t ^{h t} _s ^{P a} t ⁱ _s ^o _{n : A} l_e ^a _h ^g _{n y} e ^t _pgw i^ne _{h d} n_{d a} ^l _u ^h _p ^D _A N_A ^e _t n_a ^{c P e} _{r e} ^t _s ^{. (} _e m^{k e} _a ^t _r ^c _{r h} c ^o _h ^a _r g ^a _{t o} C ^e _c e_d ^s _] ^{s i Y} _o ^t _c ⁿ _a ^et_f ^o _, h _{a s} ^{e s} r^t _n ⁿ _{o F} O ^a S ^– [ t^{h g} _n ^d _nl ^{a a} _{s n} ^a _r ^u _r ^e _h ^a _n ^M _{E I} ^e ) _i ^{n o D} _n] d^u _o ^c, _t ^h k ^t _f ^g _e ^t _c u ^e _s ^S _T ^o _r e ^g _n00 e_r ^t _{s t} ^e _t ^a _e ^t _c ^{ha o} _t ^r _{p da} ⁿ _eU _t a ⁽ _] ^a _r ⁿ _o ^er _r ^er_t ⁰ ₅ ⁰ _{5 i} ^1t _{e s} ^r _b ^u _{o e} ^o _r ^d _{a i} ^{c l} _r ^O _i ^s _{[ [} ^{d X} _y ^c s ^h _o ^o iⁿⁿ _sl ^da _{e T p o} ^{A e m} _o ^P _{/ s} ⁿ _a ^e _dNO ^b _{a g} a _. ^s _{a t} ^m _t ^e _e ^l _t O aN _e K^c _e ⁿ _{r /} ^c m ^. _c ⁿ _u ^I _TU ^{m n k l} _ot ^e _a ^d _{o .} C ^b _e ^c _l ^{y. e} _c ^o _c ⁿ I_d e_s ^B _{I ]} Y ^a _t ^{a e} _{n [ c} ^{T a D.} _e ^° _{0 as} e_v ⁿ _o ^. _n ^N _E ^uR _T ^b _a ^t _e ^{y l} _s o t ^{a : e} _e ^e _r ^l n ^s _of ^o _o ^{3 h} _– ^{m °} _5r o_l ^o C /^{e g s} _{s n} ^s _n ^. _c ^S _S ^s _{k I} ⁿN ^r _I ^{S O N} _Aa ^{D s} _n ^L _b a t ^bi_r ^o _{r t} ^e Dt_l ^e _{bw s s} ^{1 e t :} _{e r t} a^u _o ^o _it ^aj_{. n} e_s ^, _o ^t _n ⁹ _L 1 ^Jm 3^eR d^O _F ^oi_t ^bi _r ^el_t ^{h t} _c ^a _{p o} ^a _E ^a _r ^{a i} _{ri n} ^b _a ^u _d ^r _ue ^l _b ^r _o A^o _{h t} ^{a t} _S ^o _h ^ht w_i ^s _ew w ^u _Qw ^s _n ^o _r w ^a _J ^o _T ^C _{2 3} ⁰ M ₂ ^a _r ^t ©_l ^l _T ^a AO N ^a _tp n^a _{] r} ⁱ _t ^h n^g _n ⁰ ₀ ^B _{X e} s ™ ^X _eg ^er ₅ ⁰ ₁ m_t ^s _[ A _XG ^{X )} X _w ^r l^{o e} _{P] d} ^X _[ ^E _E ^X _X ^e _b ^bi_r ^e _{e n} o K ^X t_{r r} ^e _t A _I ^{N a} _h ^a _p ^{s – e} _t ^e _k D ^{c a} _r e ⁱ _t ^{h a} _ri ^r _{a e n} ^g _n ^{b s} _s ^er_{t a g} M – ^a ( t^{h b s i} _{( r} ^] _Y ^{m [} ₎ g_n ^{a e} _{r p}/₎ ^{w t} _s ^a _r ^{i e} _{t o} ^l _{e l} ^{a b} _{t e} ^t _a ⁵ ₅ ³ ₆ (_{] n g} ^y _s ^r _a ^t _e ^N _I ⁵ ₈ ⁵ _{8 l} e_n ^X _[ m^o _t ^h _c ^c _a D ³ ₅ ^{3 2} _{5 0} ² ₀ a_{P n} ⁱ _{a t} ^e M _t ^{a e} _c a _n e ^e _{g n} ^o _r o_r ^d _{n t} ^e A a_r / i_b ^t _{r n} ^{o a e} _{t g} ⁱ _b d_n ^ai _h c ^{a i} _t ⁿ i s _i ^{s bi} _{a r} ^{l a} _p ^s _{e ps} ^{t h} _{s t} ^t _e ^{l a} _{r e} ^{o i} _n ^l _{e b i} ⁿⁿ _{y b} a t t^{a t} _n ^s _o Aⁱ _b ⁰ _{6 s} a _g ² ( ^m _t a_ew _{) l} w t_r i^b _{r )} ^{ol a} _a._{t e p}w ^l _l ^{o a} _h a _{l r} ^o _T i_n ^e Ow_l ^e b N ^Sf _{a n d} ^{e e e} _r ⁿ _{a b}t_r ^{c e} _{e g}t_{r o}M_. l _l ^{di h a} _t ^{a s} h ^DTA^e _{e h} c ^o _{h n} ^{c – m} ₎ ^{c .} _hG ^S. _f o _d ^e _{e t} ^h w_l ^oe _e ^c _a ^E _Es ^t _{e t} ^l _u ^{s g} _n e_b ^{s t} _r ^{– m} _o ^{Kl tr} _Ab ^h _g a t ⁱ _s ^o _h ^– t^{h e} _r ^t _s ^{( a} _{t h} ^h _s ^{P g} _{n y} ^t _gw _d ^s i ^{e n} _a ^t _{n :} ^{g h} _{n p} ^e _r ] _g l_e n ^c a ^{e P} _e ^e _r ^{t s} _s ^. _{e p} ⁿ _h m^k _a ^{c (} _{r h} ^{a c} _n ^a _{r l} e ^t _s ^{( Y} _[ e _] ^s _o ^t _c ^{e t} _r ^o _{a ,} ^{e g} r _e ^{r g} _{o n} a ] ^/ _g ^m ₎ w_l ^o d ^–Y [ _l ^{a n} _a ^et_f ^h _s ^e _{p h e} ⁿ _{o P p} ^X _[ m^e _b i _{S t} ^{h g} _n ^d _{ns n i} ^{a n o} _r ^{u u} _r ^t o ^c _f o ^m _o ^{M . t} _c ^o _T e_r ^{a t} _{) s} ⁽ _t ^e _t ^{a n d} o _e ^{, t} _{k t c} ^ha _e ^u _o ^c _{e s} e_v ^u _{da ]} ^a _r X [ ^d _y ^{c e}r_i ^1t _s ^r _{b p} ^{b e y} _al ^{o o} _r ^{d g P} _{/ a} n ^: _s ^h _o ^o _s ^l _A ^ds iⁿⁿ _o a _{. a} ^a _e ^l _{T e t t} O ^{K m} _r ^u _{s a /} ^c _t ^e t ^m _t ^e _e ^aN _{. o} C ^o _o ^{n h} _r t ^e _cm ^. _c n I _t ^ae _c ^l _e ⁿ _ot ^{e a} _t ^k _a ^d _n ^{D °} ₀ ^{e b} _a ^c _l ^{a 3} _r a_i w ⁿ _o ^o _c ^{. t} _e ^ye _c ^T: _n ^N _{E e} ^{a e} _r ^. _e ^l _– ^{° o} _h ^M _T C ^{d a} /^{e S} _n ^e _n L ^l _{s b} ^o t ^{a e s} _n ^a t ^b _f ^o _o i _{n r} ^o _{r o} D^e _b ^h _{5 w} ¹ A t_a ^{w s} _s s ^. _c nG _{nn I} ⁿ _{N S n} ^{O, 9} _L ^N _A ^{a J} i^b _r ^o _r ^o _t ^h _{t s} ^r _c ^a _pt ^{e a} t r_{i l} u_s ^r _{s u} ^t _e ^l _e ^r _e ^E _E ^o _it ^aj_{. o} ^mK ^s _ew ^e _{s o} ^{t s} _n o_r ¹³ ₂ ^a _p ^ea _ri ^t _e ^l _a ^a _E ^a _r ⁱ _n ^b _{a d} A^o _{hb t} ^{a t} _{S o} W^r _PA ^u _Qw _n w ^a _J ^o _T ^C ₃ ⁰ M₂ © ^a _r ⁱ _n ^b _{ab t} ^{a C} _X ™ ^X A _{X g}/_g G ^X _X ^m _{) )} ^e _t ^m ₎ ^E _E ^X _X w K ^X _l ^o _l ^{a e} _b ^y _s w_l ^o A _I ^N t ^o t ^e _bt D _r a_h ^bi _{r r} a_{h r} c ^a _{p e} ^{c e} _t ^o _t e ^{a s} _ri ^e _e ^a _t ⁱ _b e ⁱ _h – ⁿ _s ^{s –} _c ⁿ i t^{h g} _n ^a ( _t ^{h a g e} _{n i} ^{s s e} _r ^bi_{r n} e_r ^o _{r e} h_t ^l _{A l} e_n ^t _s ^a _p ^t _s ^e _t ⁿ _e ^{D a} _y ⁿ _{A P} ⁽ _{] n} ^X _[ ^a _r ^{( i} _] ^ar_{i n} ^Y _[ ^b _a ^s _{a o} ^N _A i ⁱ _b ^P C m _{F a n} ^o _t O M ^{e e} _g ^t _{o E I n} ^o _r B ^e _s ^{D S o} _{T r} ^d _n ⁿ _eU t^e A _i ^{c l a} _r / i_b ^t _r ^O n ^e _dN nO a ^e _{g u} ^I _{T d}U d _{I n} ^{a B c}i a _t M^{e s} M_s u^R i _{a s} M r ^{/ s} _{T kI} ^{S b l a} _{e p} ^t _Y ^r _a ^D p^{t a} _{a r} ^t _s ^t _e ^o _{e e} i _{e i} ^{l n} _b ^{Y a} _Ym t ^YeR : _d a^O _{F n} ^c _a ^l _{b t} ^{a t} _n :_{t Pr} ^t A ⁰ ₆ ^o _L ^X _El ^l _{T A}O N e_t a_t e_c a ^e _n] o_{r t} ^{h e} _t ^{g a} _{n00 ri} ^er b_t ⁰ ₅ ⁰ _{5 a} ^s _{[ g} m_] Y _[ ^s _n ^oi_t ^bi_r ^a _t ^a _p] ⁿ _{t e} ^a _r ^{i h s} _n ^g _{n e} ^r _g ^er_t ⁰ ₅₀ 0_{1 P} ^m _] ^s _{[ d} ^{X e} _{[ t} ^e _k ^r _a M 5 ^N ₅ ³ I ⁵ _{6 8} ⁵ ₈ D ³ ₅ ^{3 2} _{5 0} ² ₀

5.8 Posterior Reversible Encephalopathy Syndrome 12 CLINICAL PHARMACOLOGY 5.9 Embryo-Fetal Toxicity 12.1 Mechanism of Action 6 ADVERSE REACTIONS 12.2 Pharmacodynamics 6^{.1 Clinical Trial Experience 12.3 Pharmacokinetics 7 DRUG INTERACTIONS 13 NONCLINICAL TOXICOLOGY 7} 7^. .¹ 2 ^E E^f f^f f^e e^c c^t ts ^o o^f f ^O A^th K^e E^r E ^D G^ru A^g o^s n ^on Ot ^A h^K e^E r D^EG ru^A gs ^{13.1 C} Fe^a r^r t^c ilⁱ iⁿ ty^{ogenesis, Mutagenesis, Impairment of} 8 USE IN SPECIFIC POPULATIONS 13.2 Animal Toxicology and/or Pharmacology 8^{.1 Pregnancy 14 CLINICAL STUDIES 8.2 Lactation 14.1 BRCA-mutated Metastatic Castration-Resistant 8} 8^. .³ 4 ^F P^e e^m di^a a^l t^e ri^s c ^a Uⁿ s^d e ^{Males of Reproductive Potential} 16 HOW S ^P U^ro P^s P^ta L^te IE ^C D^a /Sⁿ T^ce O^r R ^(m AG^CR E^P A^C N⁾ D HANDLING 8.5 Geriatric Use 17 PATIENT COUNSELING INFORMATION 8^{.6 Hepatic Impairment 8.7 Renal Impairment} *Sections or subsections omitted from the full prescribing information are not ^{10 OVE} listed. 11 DESC^R R^D I^O P^S T^A IO^G N^E __________________________________________________________________________________________

JAB7217 -174- FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA [see Dosage and Administration (2.1)]. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCA gene alteration [see Clinical Studies (14)]. Information on FDA-approved tests is available at: www.fda.gov/CompanionDiagnostics. Recommended Dosage The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity. Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take AKEEGA on an empty stomach. Do not eat food two hours before and one hour after taking AKEEGA. Swallow tablets whole with water. Do not break, crush, or chew tablets. If a patient misses a dose, instruct patients to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day. Dosage Modification for Adverse Reactions The recommended dosage modifications for AKEEGA are provided in Table 1. Treatment with AKEEGA should not be reinitiated until the toxicity has resolved to Grade 1 or baseline. Table 1: Dosage Modifications for Adverse Reactions Adverse Re caction Severity Dosage Modification Myelosuppression Hemoglobin <8 g/dL ^ Withhold AKEEGA and monitor [see Warnings and blood counts weekly. Precautions (5.1)] ^ When hemoglobin returns to ≥9 g/dL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. ^ Permanently discontinue AKEEGA if hemoglobin has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose JAB7217 -175- reduct aion to 100 mg/1,000 mg once daily. Platelet count <100,000/mcL First occurrence: ^ Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. ^ Resume AKEEGA at same or the reduced dose of 100 mg/1,000 mg once daily. ^ If platelet count is <75,000/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Second occurrence: ^ Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. ^ Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. ^ Permanently discontinue AKEEGA if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduct aion to 100 mg/1,000 mg once daily. ^{Neutrophil <1,000/mcL} _{^ Withhold AKEEGA and monitor} blood counts weekly. ^ When neutrophil counts return to ≥1,500/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. ^ Permanently discontinue AKEEGA if neutrophils have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduct aion to 100 mg/1,000 mg once daily. Hematologic adverse reaction ^ Consider platelet transfusion for requiring transfusion patients with platelet count ≤10,000/mcL. If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or JAB7217 -176- transfusion at a higher platelet count. ^ Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Hepatotoxicity ALT and/or AST greater than 5 × ^ Withhold AKEEGA and closely [see Warnings and ULN or total bilirubin greater monitor liver function. Precautions (5.4)] than 3 × ULN ^ Permanently discontinue AKEEGA if: ALT or AST > 20 times the ULN – OR– ALT > 3 X ULN and total bilirubin > 2 X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation -OR- Hepatotoxicity recurs at the reduced dose 100 mg/500 mg. ^ When AST and ALT resolves to less < 2.5 X ULN and total bilirubin < 1.5 X ULN, AKEEGA may be resumed at the reduced dose of 100 mg/500 mg once daily. When resumed, monitor serum transaminases every two weeks for three months, monthly thereafter, and as clinically indicated. Other non-hematological ^{Grade 3 or 4^} ^ Withhold AKEEGA until resolution adverse reactions that persist c of adverse reaction or for a despite medical management maximum of 28 days. [see Warnings and Precautions (5) and Adverse ^ If resolves in 28 days or less, Reactions (6.1)] AKEEGA may be resumed at the reduced dose. ^ Permanently discontinue AKEEGA if adverse reaction(s) has not resolved after 28 days or Grade 3 or 4 adverse reaction reoccurs after ^a dose reduction. If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, discontinue AKEEGA [see Warnings and Precautions (5.1, 5.2)]. ^ Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions ^c [see Warnings and Precautions (5.3)]. During AKEEGA treatment interruption, physician may consider giving abiraterone acetate and prednisone to maintain daily dose of abiraterone acetate (see abiraterone acetate prescribing information). JAB7217 -177- DOSAGE FORMS AND STRENGTHS Tablets ^ 50 mg niraparib/500 mg abiraterone acetate: yellowish orange to yellowish brown, oval, film-coated tablets debossed with “N 50 A” on one side and plain on the other side. ^ 100 mg niraparib/500 mg abiraterone acetate: orange, oval, film-coated tablets debossed with “N 100 A” on one side and plain on the other side. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg) in combination with prednisone 10 mg once daily in BRCAm subgroup of Cohort 1 (N=113) of MAGNITUDE. Myelosuppression AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia and thrombocytopenia occurred in 2.7% and 0% of patients, respectively. Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.3)]. Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fatal outcome, has been observed in ovarian cancer patients treated with niraparib, a component of AKEEGA. MDS/AML was reported in 0 patients in MAGNITUDE Cohort 1. All patients who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed. JAB7217 -178- Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA arm. The safety of AKEEGA in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. Hepatotoxicity AKEEGA may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate- associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. Treatment discontinuation due to ALT and AST increases or abnormal hepatic function occurred in 0% of patients. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring and may require dosage modifications [see Dosage and Administration (2.4)]. Permanently discontinue AKEEGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 x ULN at any time after receiving AKEEGA. JAB7217 -179- Adrenocortical Insufficiency AKEEGA may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations. Hypoglycemia AKEEGA may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia. Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration- resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. Posterior Reversible Encephalopathy Syndrome Posterior Reversible Encephalopathy Syndrome (PRES) has been observed in ovarian cancer patients treated with niraparib, a component of AKEEGA. PRES was reported in 0 patients in MAGNITUDE Cohort 1. In other clinical trials, PRES has been reported in patients receiving niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA. JAB7217 -180- Monitor all patients treated with AKEEGA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA and administer appropriate treatment. The safety of reinitiating AKEEGA in patients previously experiencing PRES is not known. Embryo-Fetal Toxicity The safety and efficacy of AKEEGA have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1)]. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)]. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.1, 8.3)]. Individuals who are or may become pregnant should handle AKEEGA with protection, e.g., gloves [see How Supplied/Storage and Handling (16)]. ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Myelodysplastic syndrome/acute myeloid leukemia [see Warnings and Precautions (5.2)] Hypokalemia, fluid retention, and cardiovascular adverse reactions [see Warnings and Precautions (5.3)] Hepatotoxicity [see Warnings and Precautions (5.4)] Adrenocortical insufficiency [see Warnings and Precautions (5.5)] Hypoglycemia [see Warnings and Precautions (5.6)] Increased fractures and mortality in combination with Radium 223 Dichloride [see Warnings and Precautions (5.7)] Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.8)] Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. JAB7217 -181- BRCA-mutated Metastatic Castration-Resistant Prostate Cancer The safety of AKEEGA in patients with BRCAm mCRPC was evaluated in Cohort 1 of MAGNITUDE [see Clinical Studies (14.1)]. Patients were randomized to receive either AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg once daily) (n=113), or placebo and abiraterone (n=112) until unacceptable toxicity or progression. Patients in both arms also received prednisone 10 mg daily. The median duration of exposure for AKEEGA was 18 months (range: 0 to 37 months). Serious adverse reactions occurred in 41% of patients who received AKEEGA. Serious adverse reactions reported in >2% of patients included COVID-19 (8%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%). Dose reductions of any component of AKEEGA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dose reductions in > 2% of patients included anemia (12%), thrombocytopenia (4.4%), and fatigue (1.8%). Dosage interruptions of any component of AKEEGA due to an adverse reaction occurred in 48% of patients. Adverse reactions which required dosage interruption in > 2% of patients included anemia (6%), COVID-19 (6%), fatigue (3.5%) and nausea (3.5%). Permanent discontinuation of any component of AKEEGA due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of AKEEGA in > 2% of patients included COVID-19 (4.4%), anemia (2.7%), asthenia (2.7%), and vomiting (2.7%). The most common adverse reactions (>10%) in patients who received AKEEGA were musculoskeletal pain, fatigue, constipation, hypertension, nausea, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, bone pain, weight decreased, arrhythmia, fall, and pyrexia. The most common select laboratory abnormalities (>10%) that worsened from baseline in patients who received AKEEGA were hemoglobin decreased, platelets decreased, neutrophils decreased, creatinine increased, potassium decreased, AST increased, ALT increased, and bilirubin increased. Tables 2 and 3 summarize adverse reactions and laboratory abnormalities for patients with BRCAm mCRPC in MAGNITUDE, respectively.

JAB7217 -182- Table 2: Adverse Reactions (>10%) in Patients with BRCAm mCRPC Who Received AKEEGA in MAGNITUDE Placebo with Abiraterone AKEEGA with Prednisone Acetate and Prednisone N=113 N=112 Adverse Reaction All Grades Grade 3-4 All Grades Grade 3-4 % % % % Musculoskeletal ^{a a} pain 44 4 42 5 Fatigue 43 5 30 4 Constipation a 34 1 20 0 Hypertension 33 14 27 17 Nausea 33 1 21 0 Edema^a 17 0 9 0 Dyspnea^a 15 1 8 3 Decreased appetite 15 2 8 0 Vomiting 15 0 7 1 Dizziness^a 14 0 10 0 COVID-19^{a a} 13 7 9 4 Abdominal p aain 12 2 12 1 Hemorrhage 12 2 8 1 Headache a 12 1 9 0 Urinary a tract infection 12 3 9 1 Cough 12 0 6 0 Insomnia 12 0 5 0 Weight decreased 10 1 4 1 Arrhythmia^a 10 2 5 1 Fall 10 1 13 4 P ^ayrexia^a 10 2 6 0 Includes multiple similar terms. Table 3: Select Laboratory Abnormalities (>10%) That Worsened from Baseline in Patients with BRCAm mCRPC Who Received AKEEGA in MAGNITUDE 1 Placebo with Abirateron 1e AKEEGA with Prednisone Acetate and Prednisone N=113 N=112 Laboratory Abnormality All Grades Grade 3-4 All Grades Grade 3-4 (%) (%) (%) (%) Hematology Hemoglobin decreased ^{67 26 53 7} Lymphocyte decreased 55 22 32 13 WBC decreased 48 6 18 0.9 Platelets decreased 37 8 22 1.8 Neutrophils decreased 32 7 16 2.7 Chemistry ALP increased 34 1.8 29 1.8 Creatinine increased 30 0 13 1.8 Potassium increased 25 0.9 21 3.6 Potassium decreased 20 5 20 5 AST increased 20 1.8 25 2.7 ALT increased 18 0.9 17 4.5 B ¹ilirubin increased 12 ⁰ 10 0.9 The denominator used to calculate the rate varied from 111 to 112 for placebo with abiraterone acetate and prednisone and 113 for AKEEGA with prednisone based on the number of patients with a baseline value and at least one post-treatment value. JAB7217 -183- Other Clinical Trial Experience The following adverse reactions have been reported with the individual components of AKEEGA but were not observed in MAGNITUDE Cohort 1: myopathy, rhabdomyolysis, adrenal insufficiency, allergic alveolitis, pancytopenia, febrile neutropenia, anaphylactic reaction, posterior reversible encephalopathy (PRES), hypertensive crisis, and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). DRUG INTERACTIONS Effect of Other Drugs on AKEEGA Effect of CYP3A4 Inducers Avoid coadministration with strong CYP3A4 inducers [see Clinical Pharmacology (12.3)]. Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of abiraterone. Effects of AKEEGA on Other Drugs CYP2D6 Substrates Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious or life- threatening adverse reactions. If alternative treatments cannot be used, consider a dose reduction when of the concomitant CYP2D6 substrate drug. Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA increases the concentration of CYP2D6 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. CYP2C8 Substrates Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions. Abiraterone is a CYP2C8 inhibitor. AKEEGA increases the concentration of CYP2C8 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. JAB7217 -184- USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The safety and efficacy of AKEEGA have not been established in females. Based on findings from animal studies and mechanism of action [see Clinical Pharmacology (12.1)], AKEEGA can cause fetal harm and potential loss of pregnancy. There are no human data on the use of AKEEGA in pregnant women. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)]. Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose (see Data). Data Animal Data Niraparib Niraparib is genotoxic and targets actively dividing cells. Animal developmental and reproductive toxicology studies were not conducted with niraparib. Abiraterone Acetate In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ^10 mg/kg/day, decreased fetal ano-genital distance at ^30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ^10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients receiving 1,000 mg daily of abiraterone acetate. Lactation Risk Summary The safety and efficacy of AKEEGA have not been established in females. There is no information available on the presence of niraparib or abiraterone in human milk, or on the effects on the breastfed child or milk production. JAB7217 -185- Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.1)]. Infertility Based on animal studies, AKEEGA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. Pediatric Use Safety and effectiveness of AKEEGA in pediatric patients have not been established. Geriatric Use Of the 113 patients with BRCA gene alteration(s) who received AKEEGA in MAGNITUDE, 34.5% of patients were less than 65 years, 38.9% of patients were 65 years to 74 years, and 26.5% were 75 years and over. There was an insufficient number of patients with BRCA gene alteration(s) treated with AKEEGA in MAGNITUDE to accurately characterize efficacy or safety by age. Hepatic Impairment Avoid use of AKEEGA in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage modification is necessary for patients with mild hepatic impairment. Renal Impairment Monitor patients with severe renal impairment for increased adverse reactions and modify dosage as recommended for adverse reactions [see Clinical Pharmacology (12.3)]. No dosage modification is recommended for patients with mild to moderate renal impairment. 10 OVERDOSAGE In the event of an overdose, administration of AKEEGA should be stopped and general supportive measures undertaken, including monitoring for arrhythmias and cardiac failure and assessing liver function. There is no specific treatment in the event of AKEEGA overdose. JAB7217 -186- DESCRIPTION AKEEGA^TM (niraparib and abiraterone acetate) tablet contains niraparib tosylate and abiraterone acetate. Niraparib Niraparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name for niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7- carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C₂₆H₃₀N₄O₅S and it has a molecular weight of 510.61 g/mol. The molecular structure is shown below: Niraparib crystalline solid. Niraparib tosylate monohydrate is highly soluble in aqueous media over the pH range 1.2 to 6.8 (1.65-1.77 mg/mL determined at 37 ± 1°C), based on the proposed highest dose equivalent to 200 mg niraparib free base. Abiraterone Acetate Abiraterone acetate is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55 g/mol. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is: Abiraterone acetate powder. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. AKEEGA tablet is supplied as 50 mg/500 mg niraparib/abiraterone acetate and 100 mg/500 mg niraparib/abiraterone acetate film-coated tablets for oral administration. JAB7217 -187- Each AKEEGA tablet (50 mg/500 mg) contains 76.9 mg niraparib tosylate monohydrate equivalent to 50 mg niraparib free base as the active ingredient and 500 mg of abiraterone acetate. Each AKEEGA tablet (100 mg/500 mg) contains 153.7 mg niraparib tosylate monohydrate equivalent to 100 mg niraparib free base as the active ingredient and 500 mg of abiraterone acetate. AKEEGA tablet core contains the following inactive ingredients: Colloidal Anhydrous Silica, Crospovidone, Hypromellose, Lactose Monohydrate, Magnesium Stearate, Silicified Microcrystalline Cellulose, Sodium Lauryl Sulfate. The 50 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. The 100 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient‑derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2. Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.9)]. Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of abiraterone on serum testosterone levels. JAB7217 -188- Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients. In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone. Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of AKEEGA have not been fully characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) [see Nonclinical Toxicology (13.2)]. Niraparib increased mean pulse rate by 22.4 to 24.1 beats/min, mean systolic blood pressure by 24.5 mmHg, and mean diastolic pressure by 16.5 mmHg relative to 14.0 to 15.8 beats per min, 18.3 to 19.6 mmHg, and 11.6 mmHg in the placebo arm. Cardiac Electrophysiology No large (>20 ms) increases in the mean QTc interval were detected following the treatment of niraparib 300 mg once daily or 1,000 mg of abiraterone acetate once daily. Pharmacokinetics Niraparib Following the administration of AKEEGA, the mean (coefficient of variation [CV%]) C_max,ss was 831 ng/mL (32%) and AUC_0-24h,ss was 13,616 ng∙h/mL (36%). The accumulation ratio following daily administration of AKEEGA was 3.5-, and 2.6-fold for niraparib AUC_0-24h and Cmax. Niraparib exhibits dose proportional increase in Cmax and AUC in the dose range of 30 mg (0.15 times the recommended dosage) to 400 mg (2 times the recommended dosage). Abiraterone Acetate Following the administration of AKEEGA, the mean (CV%) C_max,ss was 151 ng/mL (59%) and AUC_0-24h,ss was 707 ng∙h/mL (59%) for abiraterone. The accumulation ratio following daily administration of AKEEGA was 2-, and 1.8-fold for abiraterone AUC_0-24h and C_max. No major deviation from dose proportionality was observed for abiraterone acetate in the dose range of 250 mg (0.25 times the recommended dosage) to 1000 mg (the recommended dosage). Absorption Niraparib The median Tmax was 3 hours after dosing. The absolute bioavailability of niraparib is approximately 73%. JAB7217 -189- Abiraterone Acetate The median Tmax of abiraterone was 1.5 hours after dosing. Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (C_max) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. Distribution Niraparib The apparent volume of distribution of niraparib was 1,117 L. Niraparib is 83% bound to human plasma proteins. Abiraterone Acetate The apparent volume of distribution of abiraterone was 25,774 L. Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. Elimination Niraparib The mean t½ of niraparib when given in combination was approximately 62 hours (CV%: 42%) and apparent CL/F was 16.7 L/h (CV%: 27%). Abiraterone Acetate The mean t½ of abiraterone when given in combination was approximately 20 hours (CV%: 7.8%) and apparent CL/F was 1673 L/h (CV%: 24%). Metabolism Niraparib Niraparib is metabolized by carboxylesterases. Abiraterone Acetate Abiraterone acetate is rapidly converted in vivo to abiraterone. CYP3A4 and SULT2A1 are the enzymes involved in the metabolism of abiraterone. Excretion Niraparib About 48% (33% to 60%) of the radiolabeled dose was recovered in urine and 39% (28% to 47%) in feces. Unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. JAB7217 -190- Abiraterone Acetate Approximately 88% of the radiolabeled dose is recovered in feces and 5% in urine. Unchanged abiraterone acetate and abiraterone accounted for 55% and 22% of the administered dose recovered in the feces, respectively. Specific Populations No clinically significant effects on the PK of niraparib and abiraterone were observed based on body weight (43.3-165 kg for niraparib and 46.0-165 kg for abiraterone), age (45-90 years for niraparib and 43-90 years for abiraterone), race/ethnicity (White, Asian, and Hispanic) and mild to moderate renal impairment (CLcr: 30-90 mL/min). Severe renal impairment (CLcr: 15-30 mL/min) has not been studied. Hepatic Impairment Niraparib Mild hepatic impairment did not affect the exposure of niraparib. Moderate hepatic impairment (Total bilirubin > 1.5 to 3.0 x ULN and any aspartate aminotransferase value) increased niraparib AUC by 56% compared to that of patients with normal hepatic function. Abiraterone Acetate Mild (Child-Pugh score of 5 to 6; Child-Turcotte-Pugh Class A) hepatic impairment increased abiraterone (AUC) by 1.1-fold and moderate (Child-Pugh score of 7 to 9; Child-Turcotte-Pugh Class B) hepatic impairment increased abiraterone (AUC) by 3.6-fold compared to subjects with normal hepatic function. Severe (Child-Pugh score of 10 to 15; Child-Turcotte-Pugh Class C) hepatic impairment increased abiraterone AUC by 7-fold and the fraction of free drug increased by 2-fold in subjects compared to subjects with normal hepatic function. Drug Interactions Studies Niraparib In Vitro Studies Inhibition of Cytochrome P450 (CYP) Enzymes: Niraparib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Induction of CYP Enzymes: Niraparib is not a CYP3A4 inducer. Niraparib induces CYP1A2 in vitro. Inhibition of Uridine 5’-Diphospho-Glucuronosyltransferases (UGTs): Niraparib did not inhibit UGT1A1, UGT1A4, UGT1A9, and UGT2B7. Inhibition of Transporter Systems: Niraparib inhibits BCRP, but does not inhibit P-gp, BSEP, or MRP2. Niraparib inhibits MATE 1 and 2. Substrate of Transporter Systems: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE1 or 2. JAB7217 -191- Abiraterone Acetate Clinical Studies Effect of Strong CYP3A4 Inducers on Abiraterone: Coadministration of rifampin (strong CYP3A4 inhibitor) decreased abiraterone mean AUC by 55%. Effect of Strong CYP3A4 Inhibitors on Abiraterone: Coadministration of ketoconazole (strong CYP3A4 inhibitor) had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effect of Abiraterone Acetate on CYP2D6 Substrates: The Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3-fold. Effect of Abiraterone Acetate on CYP1A2 Substrates: When abiraterone acetate (plus prednisone) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. Effect of Abiraterone Acetate on CYP2C8 Substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of abiraterone acetate. In vitro Studies Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5. Transporter Systems: Abiraterone acetate and abiraterone are not substrates of P-gp. Abiraterone acetate is an inhibitor of P-gp. Abiraterone and its major metabolites are inhibitors of OATP1B1. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Niraparib Carcinogenicity studies have not been conducted with niraparib. Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months’ duration in rats and dogs. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses ≥10 JAB7217 -192- mg/kg and ≥1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC0-24h) at the dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped. Abiraterone Acetate A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure (1,000 mg daily) based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. Abiraterone acetate and abiraterone were not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivo rat micronucleus assay. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans at 1,000 mg daily. In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at ≥30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area. In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. JAB7217 -193- Animal Toxicology and/or Pharmacology Niraparib In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC₅₀ values that were lower than the C_min at steady-state in patients receiving the 300 mg dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular, central nervous system). Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3, and 10 mg/kg resulted in an increased range of arterial pressures of 13% to 20%, 18% to 27%, and 19% to 25%, respectively, and increased range of heart rates of 2% to 11%, 4% to 17%, and 12% to 21%, respectively, above pre-dose levels. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.5, 1.5, and 5.8 times the unbound Cmax at steady state in patients receiving the 300 mg dose. In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid plasma C_max ratios of niraparib administered at 10 mg/kg orally to two rhesus monkeys were 0.10 and 0.52. Abiraterone Acetate A dose-dependent increase in cataracts was observed in rats after daily oral abiraterone acetate administration for 26 weeks starting at ^50 mg/kg/day (similar to the human clinical exposure (AUC) at 1,000 mg dose daily). In a 39-week monkey study with daily oral abiraterone acetate administration, no cataracts were observed at higher doses (2 times greater than the clinical exposure (AUC) at 1,000 mg dose daily). CLINICAL STUDIES BRCA-mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) The efficacy of AKEEGA was investigated in Cohort 1 of MAGNITUDE (NCT03748641), a randomized double-blind, placebo-controlled, multi-cohort, multi-center study in which 423 patients with homologous recombination repair (HRR) gene-mutated (HRRm) mCRPC were randomized (1:1) to receive niraparib 200 mg and abiraterone 1,000 mg (N=212) or placebo and abiraterone (N=211) until unacceptable toxicity or progression. All patients received prednisone 10 mg daily and a GnRH analog or had prior bilateral orchiectomy. Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior abiraterone acetate plus prednisone (up to four months) and ongoing ADT, were eligible. Patients could have received prior docetaxel or androgen-receptor (AR) targeted therapies in either the metastatic castration-sensitive prostate cancer (mCSPC) or non- metastatic castration-resistant prostate cancer (nmCRPC) setting. Randomization was stratified by prior docetaxel for mCSPC (yes or no), prior AR targeted therapy for mCSPC or nmCRPC (yes or no), prior abiraterone acetate for mCRPC (yes or no), and BRCA-status (BRCAm vs. other). Of the 423 patients enrolled, 225 (53%) had BRCA gene mutations (BRCAm); 113 received niraparib 200 mg and abiraterone acetate 1,000 mg and 112 received placebo and abiraterone acetate 1,0000mg. Mutation status of BRCA genes was determined prospectively using the Foundation One CDx tissue assay or other plasma or tissue clinical trial assays. JAB7217 -194- Among the 225 patients with BRCAm, the median age was 68 years (range 43-100) and 66% were 65 years of age or older; 72% were White, 17% Asian, and 1% Black, and 10% other or not reported; 12% were Hispanic or Latino; and baseline ECOG performance status (PS) was 0 (66%) or 1 (34%). Twenty-four percent had received prior docetaxel, 5% received prior AR- targeted therapy for mCSPC or nmCRPC, and 26% received prior abiraterone acetate plus prednisone for up to 4 months for mCRPC. Thirty-seven percent had bone-only metastases and 21% had visceral metastases. Seven percent had BRCA1 mutations, 78% had BRCA2 mutations, and 15% had BRCA mutations in combination with mutations in other HRR genes. The major efficacy outcome measure was radiographic progression free survival (rPFS) determined by blinded independent central radiology (BICR) review evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (soft tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Overall survival (OS) was an additional efficacy outcome measure. A statistically significant improvement in rPFS for niraparib plus abiraterone compared to placebo plus abiraterone was observed in BRCAm patients. The efficacy results are presented in Table 4 and Figures 6 and 7. Table 4: Efficacy Results from the BRCAm Subgroup of the MAGNITUDE Study AKEEGA Placebo Endpoints a (N=113) (N=112) Radiographic Progression-free Survival Event of disease progression or death (%) 45 (40%) 64 (57%) Median, mon bths (95% CI) 16.6 (13.9, NE) 10.9 (8.3, 13.8) Hazard c Ratio (95% CI) 0.533 (0.361, 0.789) p-value d 0.0014 Time to Symptomatic Progression Event (%) 38 (34%) 58 (52%) Median, months (95% CI) NE (36.2, NE) 21.7 (17.6, 35.8) Hazard Ratio (95% CI) d 0.562 (0.371, 0.849) Time to Cytotoxic Chemotherapy Event (%) 35 (31%) 51 (46%) Median, months (95% CI) NE (31.4, NE) 28.2 (20.7, NE) Hazard Ratio (9 d5% CI) 0.598 (0.387, 0.924) Overall Survival Event (%) 60 (53%) 70 (63%) Median, months (95% CI) 30.4 (27.6, NE) 28.6 (23.8, 33.0) a Hazard Ratio (95% CI) 0.788 (0.554, 1.120) b rPFS results based on blinded independent central review at primary analysis. c Cox proportional hazards model stratified by prior docetaxel (yes vs. no) and prior abiraterone (yes vs. no). Stratified log-rank test two-sided p-value d Final analysis NE = not estimable A prespecified multivariate Cox regression analysis of OS in the BRCA subgroup adjusting for externally validated and clinically relevant baseline prognostic factors (PSA, LDH, ECOG, bone lesion number, and Visceral Disease) demonstrated improvement in OS (HR=0.663; 95% CI: 0.464, 0.947) when treated by niraparib and abiraterone acetate. JAB7217 -195- 16 HOW SUPPLIED/STORAGE AND HANDLING AKEEGA^TM (niraparib and abiraterone acetate) tablets are available in the strengths and packages listed below: AKEEGA 50 mg/500 mg film-coated tablets Yellowish orange to yellowish brown, oval, film-coated tablets debossed with “N 50 A” on one side and plain on the other side. They are available in bottles of 60 tablets. NDC 57894-050-60 AKEEGA 100 mg/500 mg film-coated tablets Orange, oval, film-coated tablets debossed with “N 100 A” on one side and plain on the other side. They are available in bottles of 60 tablets. NDC 57894-100-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Based on its mechanism of action, AKEEGA may harm a developing fetus. Individuals who are or may become pregnant should handle AKEEGA tablets with protection, e.g., gloves [see Use in Specific Populations (8.1)]. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hematologic Adverse Reactions Advise patients that periodic monitoring of their blood counts is recommended. Advise patients to contact their healthcare provider for new onset of pallor, weakness, dyspnea, fatigue, bleeding, fever, or symptoms of infection [see Warnings and Precautions (5.1)]. Hypertension Advise patients to undergo blood pressure and heart rate monitoring at least weekly for the first 2 months, then monthly for the first year of treatment and every other month thereafter. Advise patients to contact their healthcare provider if blood pressure is elevated [see Warnings and Precautions (5.2)]. Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions Inform patients that AKEEGA is associated with, hypokalemia that may lead to QT prolongation. Advise patients that serum potassium will be monitored clinically at least monthly during the first year of treatment and then every other month for the duration of treatment. Signs and symptoms of fluid retention, such as peripheral edema, should be monitored every two weeks for three months, then monthly thereafter. Advise patients to adhere to corticosteroids and to report symptoms of hypokalemia or edema to their healthcare provider [see Warnings and Precautions (5.3)]. JAB7217 -196- Pulmonary Embolism Advise patients to immediately report any signs or symptoms of chest pain, shortness of breath, tachypnea, and tachycardia [see Warnings and Precautions (5.5)]. Hepatotoxicity and Hepatic Impairment Inform patients that AKEEGA is associated with severe hepatotoxicity. Inform patients that their liver function will be monitored using blood tests. Advise patients to immediately report symptoms of hepatotoxicity to their healthcare provider [see Warnings and Precautions (5.6)]. Corticosteroid Withdrawal and Coverage of Stress Situations Inform patients that AKEEGA with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their healthcare provider [see Warnings and Precautions (5.9)]. Dosage and Administration Inform patients that AKEEGA is taken orally once daily with prednisone daily (according to their healthcare provider’s instructions) and to not interrupt or stop either of these medications without consulting their healthcare provider [see Dosage and Administration (2.1)]. Inform patients coadministered a gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with AKEEGA [see Dosage and Administration (2.3)]. Inform patients that in the event of a missed daily dose of AKEEGA, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose [see Dosage and Administration (2.2)]. Instruct patients to take AKEEGA tablets as a single dose once daily on an empty stomach. Instruct patients to not eat food 2 hours before and 1 hour after taking AKEEGA. AKEEGA taken with food causes increased exposure and may result in adverse reactions. Instruct patients to swallow tablets whole with water and not to crush or chew the tablets [see Dosage and Administration (2.3)]. Embryo-Fetal Toxicity Inform patients that AKEEGA may harm a developing fetus and can cause loss of pregnancy [see Warnings & Precautions (5.12), Use in Specific Populations (8.1)]. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.3)]. Advise individuals who are pregnant or may become pregnant to handle AKEEGA tablets with protection, e.g., gloves [see Use in Specific Populations (8.1) and How Supplied/Storage and Handling (16)]. JAB7217 -197- Infertility Advise male patients that AKEEGA may impair fertility [see Use in Specific Populations (8.3)]. Product of France 5 Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044, USA For patent information: www.janssenpatents.com © YYYY Janssen Pharmaceutical Companies

JAB7217 -198- PATIENT INF TO MRMATION AKEEGA (TBD) (niraparib and abiraterone acetate) Tablets What is AKEEGA? AKEEGA is a prescription medicine used along with prednisone to treat adults with prostate cancer who have changes in certain genes and whose prostate cancer has spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone (also called metastatic castration-resistant prostate cancer). Your healthcare provider will perform a test to make sure AKEEGA is right for you. It is not known if AKEEGA is safe and effective in females. It is not known if AKEEGA is safe and effective in children. AKEEGA is a dual action medicine that contains two active substances: niraparib and abiraterone acetate. ^ Niraparib is a type of anti-cancer medicine called a PARP inhibitor. PARP inhibitors block an enzyme called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged DNA so blocking it means that the DNA of cancer cells cannot be repaired. This results in tumor cell death, helping to control the cancer. ^ Abiraterone acetate stops your body from making testosterone; this can slow the growth of prostate cancer. Before and while taking AKEEGA, tell your healthcare provider about all your medical conditions, including if you: ^ have low blood-cell counts. AKEEGA may lower your blood-cell counts, such as your red blood-cell count (anemia), white blood-cell count (neutropenia), or blood-platelet count (thrombocytopenia). Signs and symptoms that you need to look out for include fatigue, fever or infection, and abnormal bruising or bleeding. Your doctor will test your blood regularly throughout your treatment. ^ have high blood pressure or heart failure or low blood potassium (low blood potassium may increase the risk of heart rhythm problems), have had other heart or blood vessel problems, have an irregular or rapid heart rate, shortness of breath, gained weight rapidly, or swelling in the feet, ankles, or legs. Your doctor will measure your blood pressure regularly throughout your treatment. ^ have headaches, vision changes, confusion, or seizure, please contact your doctor. A rare neurological side effect named Posterior Reversible Encephalopathy Syndrome (PRES) has been associated with the niraparib component of AKEEGA. ^ have blood clots in the lungs, or have had them in the past. ^ have liver problems. ^ have low or high levels of sugar in the blood. ^ have muscle weakness and/or muscle pain. ^ have a partner who is pregnant or may become pregnant. AKEEGA can cause harm to your unborn baby and loss of pregnancy (miscarriage). Caregivers should handle AKEEGA tablets with protection, such as gloves. ^ Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after the last dose of AKEEGA. Talk with your healthcare provider if you have questions about birth control. Tell your healthcare provider about all the medicines you take or treatments you receive, including prescription and over-the-counter medicines, vitamins, and herbal supplements. AKEEGA can interact with many other medicines. Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist when you get a new medicine. You should not start or stop any medicine before you talk with the healthcare provider that prescribed AKEEGA. How should I take AKEEGA? ^ Take AKEEGA and prednisone exactly as your healthcare provider tells you. ^ Your healthcare provider may change your dose if needed. Reference ID: 5225301 JAB7217 -199- ^ Do not change or stop taking your prescribed dose of AKEEGA without talking with your healthcare provider first. ^ Take AKEEGA tablets as a single dose one time a day on an empty stomach. Do not eat food 2 hours before and 1 hour after taking AKEEGA. Taking AKEEGA with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects. ^ Swallow AKEEGA tablets whole. Do not break, crush, or chew tablets. ^ If you miss a dose of AKEEGA or prednisone, take your normal dose as soon as possible on the same day. Return to your normal schedule on the following day. You should not take extra tablets to make up the missed dose. ^ You should start or continue a gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with AKEEGA unless you have had a surgery to lower the amount of testosterone in your body (surgical castration). ^ If you take too much AKEEGA, call your healthcare provider. ^ AKEEGA is taken with a medicine called prednisone. o Take the prednisone exactly as your doctor has told you. o You need to take prednisone every day while you are taking AKEEGA. The amount of prednisone you take may need to change if you have a medical emergency. Your doctor will tell you if you need to change the amount of prednisone you take. Do not stop taking prednisone unless instructed by your doctor to do so. What is the most important information I should know about AKEEGA? AKEEGA may cause serious side effects including: ^ Low blood cell counts Low blood cell counts (low red blood cells, low white blood cells, and low platelets) are common during treatment with AKEEGA. Symptoms may include: o weakness o fever o feeling tired o shortness of breath o weight loss o blood in urine or stool o frequent infections o bruising or bleeding more easily Your healthcare provider will do blood tests to check your blood cell counts before and during treatment with AKEEGA. ^ High blood pressure (hypertension), low blood potassium levels (hypokalemia), fluid retention (edema), and irregular heartbeats This can be life threatening. To decrease the chance of this happening, you must take prednisone with AKEEGA exactly as your healthcare provider tells you. Tell your healthcare provider if you get any of the following symptoms: o dizziness o confusion o fast or irregular heartbeats o muscle weakness o feel faint or lightheaded o pain in your legs o headache o swelling in your legs or feet o swollen hands, ankles or feet Your healthcare provider will check your blood pressure, do blood tests to check your potassium levels, and check for any signs and symptoms of fluid retention. ^ Blood clots in the lungs (pulmonary embolism). Immediately contact your healthcare provider if you experience any signs or symptoms of chest pain, shortness of breath, rapid breathing, and fast heartbeat. ^ Severe liver problems. You may develop changes in liver function blood tests. Your healthcare provider will do blood tests to check your liver before treatment with AKEEGA and during treatment with AKEEGA. Liver failure may occur, which can lead to death. Tell your healthcare provider right away if you notice any of the following changes: o yellowing of the skin or eyes o severe nausea or vomiting o darkening of the urine ^ Adrenal problems. Adrenal problems may happen if you stop taking prednisone, get an infection, or are under stress. Reference ID: 5225301 JAB7217 -200- The most common side effects of AKEEGA include: o low number of red blood cells o feeling very tired (anemia) o low number of ‘platelets’ (cells that help blood o constipation clot) o high blood pressure o feeling weak (asthenia) o nausea AKEEGA may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of AKEEGA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088. How should I store AKEEGA? ^ Store AKEEGA at room temperature between 68°F to 77°F (20°C to 25°C). ^ Store AKEEGA in the original package. ^ Any unused product or waste material should be disposed of in accordance with local requirements. Keep AKEEGA and all medicines out of the reach of children. General information about the safe and effective use of AKEEGA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AKEEGA for a condition for which it was not prescribed. Do not give AKEEGA to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about AKEEGA that is written for health professionals. What are the ingredients in AKEEGA? Active ingredients: niraparib tosylate and abiraterone acetate Inactive ingredients: 100 mg/500 mg film-coated tablets: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate. The film- coating contains iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. 50 mg/500 mg film-coated tablets: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate. The film- coating contains iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. Manufactured for: Janssen Biotech, Inc., Horsham, PA 19044, USA For patent information: www.janssenpatents.com © 20YY Janssen Pharmaceutical Companies F^{or more information, call Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or go to www.tradename.com.} Reference ID: 5225301 JAB7217 -201- Example 5: August 11, 2023 Approved Drug Product Label from the Food and Drug Administration (FDA) NDA 216793 NDA APPROVAL Janssen Biotech, Inc. c/o Janssen Research & Development, LLC Attention: Joseph Lallier Director, Global Regulatory Affairs 920 Route 202, P.O. Box 300 Raritan, NJ 08869 Dear Joseph Lallier: Please refer to your new drug application (NDA) dated February 28, 2023, received February 28, 2023, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Akeega (niraparib/abiraterone acetate fixed-dose combination) 50/500 mg and 100/500 mg film-coated tablets. This NDA provides for the use of Akeega (niraparib/abiraterone acetate fixed- dose combination) 50/500 mg and 100/500 mg film-coated tablets for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration- resistant prostate cancer (mCRPC). APPROVAL & LABELING We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed- upon labeling. CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at FDA.gov.¹ Content of labeling must be identical to the enclosed labeling (text for the Prescribing Information and Patient Package Insert) as well as annual reportable changes not included in the enclosed labeling. Information on submitting SPL files using eLIST may be found in th 2e guidance for industry SPL Standard for Content of Labeling Technical Qs and As. 1 www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database www.fda.gov/RegulatoryInformation/Guidances/default.htm. Reference ID: 5225301 JAB7217 -202- NDA 216793 Page 2 The SPL will be accessible via publicly available labeling repositories. CARTON AND CONTAINER LABELING Submit final printed carton and container labeling that are identical to the carton and container labeling submitted on August 4, 2023, as soon as they are available, but no more than 30 days after they are printed. Please submit these labeling electronically according to the guidance for industry SPL Standard for Content of Labeling Technical Qs & As. For administrative purposes, designate this submission “Final Printed Carton and Container Labeling for approved NDA 216793.” Approval of this submission by FDA is not required before the labeling is used. DATING PERIOD Based on the stability data submitted to date, the expiry dating period for Akeega (niraparib and abiraterone acetate) tablets shall be 30 months from the date of manufacture when stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C.355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable. We are waiving the pediatric study requirement for this application because necessary studies are impossible or highly impracticable since the disease is extremely rare in children and adolescents. POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS UNDER SECTION 506B We remind you of your postmarketing commitment: 4482-1 Conduct an analytical and clinical validation study using clinical trial data, adequate to support the availability of an in vitro diagnostic device using ctDNA samples from plasma that is essential to the safe and effective use of niraparib plus abiraterone acetate for patients diagnosed with mCRPC, whose ctDNA samples harbor BRCA1 or BRCA2 mutations. U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov Reference ID: 5225301 JAB7217 203 NDA 216793 Page 3 The timetable you submitted on July 20, 2023, states that you will conduct this study according to the following schedule: Final Report Submission: 12/2024 Submit clinical protocols to your IND 131190 for this product. Submit nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final reports to this NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each commitment in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients/subjects entered into each study/trial. All submissions, including supplements, relating to these postmarketing commitments should be prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.” PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. For information about submitting promotional materials, see the final guidance for industry Providing Regulatory Submissions in Electronic and Non- Electronic Format 3—Promotional Labeling and Advertising Materials for Human Prescription Drugs. As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the Prescribing Information, at the time of initial dissemination or publicatio 4n, accompanied by a Form FDA 2253. Form FDA 2253 is available at FDA.gov. Information and Instructions for completing the form can be found at FDA.gov.⁵ REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). COMPENDIAL STANDARDS A drug with a name recognized in the official United States Pharmacopeia or official National Formulary (USP-NF) generally must comply with the compendial standards for strength, quality, and purity, unless the difference in strength, quality, or purity is plainly stated on its label (see FD&C Act § 501(b), 21 USC 351(b)). FDA typically cannot share application-specific information contained in submitted regulatory filings with third parties, which includes USP-NF. To help ensure that a drug continues to comply with 3 For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/media/128163/download_. 4 www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf 5 www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov Reference ID: 5225301 JAB7217 204 NDA 216793 Page 4 compendial standards, application holders may work directly with USP-NF to revise official USP 6 monographs. More information on the USP-NF is available on USP’s website . If you have any questions, contact Alice Lee, Senior Regulatory Project Manager, at (301) 796-8881 or at Alice.Lee@fda.hhs.gov. Sincerely, {See appended electronic signature page} Daniel Suzman, MD Deputy Director Division of Oncology 1 Office of Oncologic Diseases Center for Drug Evaluation and Research ENCLOSURE(S): ^ Content of Labeling o Prescribing Information o Patient Package Insert ^ Carton and Container Labeling 6 www.uspnf.com/ U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov Reference ID: 5225301 JAB72 17 205 /s/ 5 10 Example 6: The USPI and Patient Package Insert for the Approved Drug Product as approved by the Food and Drug Administration (FDA) on August 11, 2023 Reference ID: 5225301 JAB7217 -207- M^{echanism of Action BRCA-mutated Metastatic Castration-Resistant Pharmacodynamics} Prostate Cancer (mCRPC) P^{harmacokinetics HOW SUPPLIED/STORAGE AND HANDLING NONCLINICAL TOXICOLOGY PATIENT COUNSELING INFORMATION Carcinogenesis, Mutagenesis, Impairment of} *Sections or subsections omitted from the full pr Fertility escribing information are not A^{nimal Toxicology and/or Pharmacology} listed. ^{CLINICAL STUDIES}

JAB7217 -208- FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA [see Dosage and Administration (2.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCA gene alteration [see Clinical Studies (14)]. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity. Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take AKEEGA on an empty stomach. Do not eat food two hours before and one hour after taking AKEEGA. Swallow tablets whole with water. Do not break, crush, or chew tablets. If a patient misses a dose, instruct patients to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day. 2.3 Dosage Modification for Adverse Reactions The recommended dosage modifications for AKEEGA are provided in Table 1. Treatment with AKEEGA should not be reinitiated until the toxicity has resolved to Grade 1 or baseline. If the toxicity is attributed to one component of AKEEGA, the other component of AKEEGA may be continued as a single agent at the current dose until the adverse reaction resolves and AKEEGA can be resumed (see Table 1). Table 1: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Myelosuppression Hemoglobin <8 g/dL ^ Withhold AKEEGA and monitor [see Warnings and Precautions blood counts weekly. (5.2)] ^ When hemoglobin returns to 2:9 g/dL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts JAB7217 -209- weekly for 28 days and as clinically indicated. ^ Permanently discontinue AKEEGA if hemoglobin has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduct aion to 100 mg/1,000 mg once daily. Platelet count <100,000/mcL First occurrence: ^ Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to 2:100,000/mcL. ^ Resume AKEEGA at same or the reduced dose of 100 mg/1,000 mg once daily. ^ If platelet count is <75,000/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Second occurrence: ^ Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to 2:100,000/mcL. ^ Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. ^ Permanently discontinue AKEEGA if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period or if th e patient has already undergone dose reduction to 100 mg/1,000 mg once daily.^{a Neutrophil <1,000/mcL} _{^ Withhold AKEEGA and monitor} blood counts weekly. ^ When neutrophil counts return to 2:1,500/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. ^ Permanently discontinue AKEEGA if neutrophils have not returned to acceptable levels within 28 days of JAB7217 -210- the dose interruption period or if the patient has already undergone dose reduct aion to 100 mg/1,000 mg once daily. Hematologic adverse reaction ^ Consider platelet transfusion for requiring transfusion patients with platelet count S10,000/mcL. If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count. ^ Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Hepatotoxicity ALT and/or AST greater than 5 × ^ Withhold AKEEGA and closely [see Warnings and Precautions ULN or total bilirubin greater than monitor liver function. (5.4)] 3 × ULN ^ Permanently discontinue AKEEGA if: ALT or AST 2: 20 times the ULN – OR– ALT > 3 X ULN and total bilirubin > 2 X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation -OR- Hepatotoxicity recurs at the reduced dose 100 mg/500 mg. ^ When AST and ALT resolves to less S 2.5 X ULN and total bilirubin S 1.5 X ULN, AKEEGA may be resumed at the reduced dose of 100 mg/500 mg once daily. When resumed, monitor serum transaminases every two weeks for three months, monthly thereafter, and as clinically indicated. Other non-hematological ^{Grade 3 or 4b} ^ Withhold AKEEGA until resolution adverse reactions that persist of adverse reaction or for a maximum despite medical management[see of 28 days. Warnings and Precautions (5) and Adverse Reactions (6.1)] ^ If resolves in 28 days or less, AKEEGA may be resumed at the reduced dose. ^ Permanently discontinue AKEEGA if adverse reaction(s) has not resolved after 28 days or Grade 3 or 4 adverse reaction reoccurs after dose reduction. ^a If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, discontinue AKEEGA [see Warnings and Precautions (5.1)]. b Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions [see Warnings and Precautions (5.3)]. JAB7217 -211- 3 DOSAGE FORMS AND STRENGTHS Tablets ^ 50 mg niraparib/500 mg abiraterone acetate: yellowish orange to yellowish brown, oval, film-coated tablets debossed with “N 50 A” on one side and plain on the other side. ^ 100 mg niraparib/500 mg abiraterone acetate: orange, oval, film-coated tablets debossed with “N 100 A” on one side and plain on the other side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA. All patients treated with niraparib who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed. 5.2 Myelosuppression AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA and refer the patient to a JAB7217 -212- hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.3)]. 5.3 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA arm. The safety of AKEEGA in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. 5.4 Hepatotoxicity AKEEGA may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate- associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring and may require dosage modifications [see Dosage and Administration (2.3)]. Permanently discontinue AKEEGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction JAB7217 -213- or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST 2:20 x ULN at any time after receiving AKEEGA. 5.5 Adrenocortical Insufficiency AKEEGA may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations. 5.6 Hypoglycemia AKEEGA may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia. 5.7 Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo- controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA, in combination with prednisone. JAB7217 -214- 5.8 Posterior Reversible Encephalopathy Syndrome AKEEGA may cause Posterior Reversible Encephalopathy Syndrome (PRES). PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA. Monitor all patients treated with AKEEGA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA and administer appropriate treatment. The safety of reinitiating AKEEGA in patients previously experiencing PRES is not known. 5.9 Embryo-Fetal Toxicity The safety and efficacy of AKEEGA have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1)]. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)]. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately 2: 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.1, 8.3)]. Females who are or may become pregnant should handle AKEEGA with protection, e.g., gloves [see How Supplied/Storage and Handling (16)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: ^ Myelodysplastic syndrome/acute myeloid leukemia [see Warnings and Precautions (5.1)] ^ Myelosuppression [see Warnings and Precautions (5.2)] ^ Hypokalemia, fluid retention, and cardiovascular adverse reactions [see Warnings and Precautions (5.3)] ^ Hepatotoxicity [see Warnings and Precautions (5.4)] ^ Adrenocortical insufficiency [see Warnings and Precautions (5.5)] ^ Hypoglycemia [see Warnings and Precautions (5.6)] ^ Increased fractures and mortality in combination with Radium 223 Dichloride [see Warnings and Precautions (5.7)] ^ Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.8)] JAB7217 -215- 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg) in combination with prednisone 10 mg once daily in BRCA-mutated patients in Cohort 1 (N=113) of MAGNITUDE. BRCA-mutated Metastatic Castration-Resistant Prostate Cancer of AKEEGA in patients with BRCAm mCRPC was evaluated in Cohort 1 of [see Clinical Studies (14.1)]. Patients were randomized to receive either (niraparib 200 mg and abiraterone acetate 1,000 mg once daily) (n=113), or placebo and abiraterone acetate (n=112) until unacceptable toxicity or progression. Patients in both arms also received prednisone 10 mg daily. The median duration of exposure for AKEEGA was 18 months (range: 0 to 37 months). Serious adverse reactions occurred in 41% of patients who received AKEEGA. Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%). Permanent discontinuation of any component of AKEEGA due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of AKEEGA in > 2% of patients included COVID-19 (4.4%), anemia (2.7%), asthenia (2.7%), and vomiting (2.7%). Dosage interruptions of any component of AKEEGA due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruption in > 2% of patients included anemia (23%), thrombocytopenia (12%), neutropenia (7%), COVID-19 (6%), fatigue (3.5%), asthenia (3.5%), nausea (3.5%), pneumonia (2.7%), hematuria (2.7%), and vomiting (2.7%). Dose reductions of any component of AKEEGA due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dose reductions in > 2% of patients included anemia (12%), thrombocytopenia (4.4%), and fatigue (2.7%). The most common adverse reactions (>10%) in patients who received AKEEGA were musculoskeletal pain, fatigue, constipation, hypertension, nausea, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, weight decreased, arrhythmia, fall, and pyrexia. The most common select laboratory abnormalities (>10%) that worsened from baseline in patients who received AKEEGA were hemoglobin decreased, platelets decreased, neutrophils decreased, creatinine increased, potassium decreased, AST increased, ALT increased, and bilirubin increased. 10 JAB7217 -216- Tables 2 and 3 summarize adverse reactions and laboratory abnormalities for patients with BRCAm mCRPC in MAGNITUDE, respectively. Table 2: Adverse Reactions (>10%) in Patients with BRCAm mCRPC Who Received AKEEGA in MAGNITUDE Placebo with Abiraterone AKEEGA with Prednisone Acetate and Prednisone N=113 N=112 Adverse Reaction All Grades Grade 3 or 4 All Grades Grade 3 or 4 % % % % Musculoskeleta ^{a a} l pain 44 4 42 5 Fatigue 43 5 30 4 Constipation a 34 1 20 0 Hypertension 33 14 27 17 Nausea a 33 1 21 0 Edema 17 0 9 0 Dyspnea^a 15 1 8 3 Decreased appetite 15 2 8 0 Vomiting a 15 0 7 1 Dizziness a 14 0 10 0 COVID-19 a 13 7 9 4 Abdominal pain 12 2 12 1 Hemorrhage^a 12 2 8 1 Headache a 12 1 9 0 Urinary tract infection 12 3 9 1 Cough^a 12 0 6 0 Insomnia 12 0 4 0 Weight decr aeased 10 1 4 1 Arrhythmia 10 2 4 1 Fall a 10 1 13 4 Pyrexia 10 2 6 0 ^a Includes multiple similar terms. Clinically relevant adverse events that occurred in <10% of patients receiving niraparib and abiraterone acetate plus prednisone were rash (7%), ALT increased (5%), AST increased (5% ), cerebrovascular accident (4.4%), pulmonary embolism (2.7%), deep vein thrombosis (2.7%), and acute kidney injury (2.7%). Table 3: Select Laboratory Abnormalities (>10%) That Worsened from Baseline in Patients with BRCAm mCRPC Who Received AKEEGA in MAGNITUDE 1 Placebo with Abirateron 1e AKEEGA with Prednisone Acetate and Prednisone N=113 N=112 Laboratory Abnormality All Grades Grade 3 or 4 All Grades Grade 3 or 4 (%) (%) (%) (%) Hematology Hemoglobin decreased 67 26 53 7 Lymphocyte decreased 55 22 32 13 WBC decreased 48 6 18 0.9 JAB7217 -217- Platelets decreased 37 8 22 1.8 Neutrophils decreased 32 7 16 2.7 Chemistry ALP increased 34 1.8 29 1.8 Creatinine increased 30 0 13 1.8 Potassium increased 25 0.9 21 3.6 Potassium decreased 20 5 20 5 AST increased 20 1.8 25 2.7 ALT increased 18 0.9 17 4.5 Bilirubin increased 12 0 10 0.9 1 The denominator used to calculate the rate varied from 111 to 112 for placebo with abiraterone acetate and prednisone and 113 for AKEEGA with prednisone based on the number of patients with a baseline value and at least one post-treatment value. Other Clinical Trial Experience The following adverse reactions have been reported with the individual components of AKEEGA but were not observed in MAGNITUDE Cohort 1: myopathy, rhabdomyolysis, adrenal insufficiency, allergic alveolitis, febrile neutropenia, anaphylactic reaction, posterior reversible encephalopathy (PRES), hypertensive crisis, and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on AKEEGA Effect of CYP3A4 Inducers Avoid coadministration with strong CYP3A4 inducers [see Clinical Pharmacology (12.3)]. Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of abiraterone. 7.2 Effects of AKEEGA on Other Drugs CYP2D6 Substrates Avoid coadministration unless otherwise recommended in the Prescribing Information fo r CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug. Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA increases the concentration of CYP2D6 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. CYP2C8 Substrates Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions. JAB7217 -218- Abiraterone is a CYP2C8 inhibitor. AKEEGA increases the concentration of CYP2C8 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The safety and efficacy of AKEEGA have not been established in females. Based on findings from animal studies and mechanism of action [see Clinical Pharmacology (12.1)], AKEEGA can cause fetal harm and potential loss of pregnancy. There are no human data on the use of AKEEGA in pregnant women. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)]. Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposure approximately 2: 0.03 times the human exposure (AUC) at the recommended dose (see Data). Data Animal Data Niraparib Niraparib is genotoxic and targets actively dividing cells. Animal developmental and reproductive toxicology studies were not conducted with niraparib. Abiraterone Acetate In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ^10 mg/kg/day, decreased fetal ano-genital distance at ^30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ^10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients receiving 1,000 mg daily of abiraterone acetate. JAB7217 -219- 8.2 Lactation Risk Summary The safety and efficacy of AKEEGA have not been established in females. There is no information available on the presence of niraparib or abiraterone in human milk, or on the effects on the breastfed child or milk production. 8.3 Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.1)]. Infertility Based on animal studies, AKEEGA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness of AKEEGA in pediatric patients have not been established. 8.5 Geriatric Use Of the 113 patients with BRCA gene alteration(s) who received AKEEGA in MAGNITUDE, 34.5% of patients were less than 65 years, 38.9% of patients were 65 years to 74 years, and 26.5% were 75 years and over. There was an insufficient number of patients with BRCA gene alteration(s) treated with AKEEGA in MAGNITUDE to accurately characterize efficacy or safety by age. 8.6 Hepatic Impairment Avoid use of AKEEGA in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. No dosage modification is necessary for patients with mild hepatic impairment. 8.7 Renal Impairment Monitor patients with severe renal impairment for increased adverse reactions and modify dosage as recommended for adverse reactions [see Clinical Pharmacology (12.3)]. No dosage modification is recommended for patients with mild to moderate renal impairment. JAB7217 -220- 10 OVERDOSAGE In the event of an overdose, administration of AKEEGA should be stopped and general supportive measures undertaken, including monitoring for arrhythmias and cardiac failure and assessing liver function. There is no specific treatment in the event of AKEEGA overdose. 11 DESCRIPTION AKEEGA^TM (niraparib and abiraterone acetate) tablets contain niraparib tosylate (as the monohydrate) and abiraterone acetate. Niraparib Niraparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name for niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4- methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C26H30N4O5S and it has a molecular weight of 510.61 g/mol. The molecular structure is shown below: Niraparib tosylate crystalline solid. Niraparib tosylate monohydrate is highly soluble in aqueous media over the pH range 1.2 to 6.8 (1.65-1.77 mg/mL determined at 37 ± 1°C). Abiraterone Acetate Abiraterone acetate is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17a-hydroxylase/C17,20-lyase). Its molecular formula is C26H33NO2 and it has a molecular JAB7217 -221- weight of 391.55 g/mol. Abiraterone acetate is designated chemically as (3B)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is: Abiraterone acetate is a powder. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. AKEEGA tablets are supplied as 50 mg/500 mg niraparib/abiraterone acetate and 100 mg/500 mg niraparib/abiraterone acetate film-coated tablets for oral administration. Each AKEEGA tablet (50 mg/500 mg) contains 50 mg of niraparib (equivalent to 76.9 mg niraparib tosylate) and 500 mg of abiraterone acetate. Each AKEEGA tablet (100 mg/500 mg) contains 100 mg of niraparib (equivalent to 153.7 mg niraparib tosylate) and 500 mg of abiraterone acetate. AKEEGA tablet core contains the following inactive ingredients: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate. ^ The 50 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. ^ The 100 mg/500 mg tablets are finished with film-coating comprising th e following inactive ingredients: iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib-induced cytotoxicity was observed in tumor JAB7217 -222- cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient- derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2. Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 a-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17a-hydroxy derivatives by 17a-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.9)]. Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone decreased serum testosterone and other androgens in patients in the placebo- controlled clinical trial. It is not necessary to monitor the effect of abiraterone on serum testosterone levels. Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients. In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone. 12.2 Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of AKEEGA have not been fully characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) [see Nonclinical Toxicology (13.2)]. Niraparib increased mean pulse rate by 22.4 to 24.1 beats/min, mean systolic blood pressure by 24.5 mmHg, and mean diastolic pressure by 16.5 mmHg relative to 14.0 to 15.8 beats per min, 18.3 to 19.6 mmHg, and 11.6 mmHg in the placebo arm. Cardiac Electrophysiology No large (>20 ms) increases in the mean QTc interval were detected following the treatment of niraparib 300 mg once daily or 1,000 mg of abiraterone acetate once daily. JAB7217 -223- 12.3 Pharmacokinetics Niraparib Following the administration of AKEEGA, the mean (coefficient of variation [CV%]) C g/mL (32%) and AUC was 13,616 n ^max was 831 n ^,ss ily administration of AKE⁰ E^-2 g·h/mL (36%). The accumulation ratio following da ⁴ G^h, A^ss was 3.5-, and 2.6-fold for niraparib AUC^0-24h and C^max. Niraparib exhibits dose proportional increase in Cmax and AUC in the dose range of 30 mg (0.15 times the recommended dosage) to 400 mg (2 times the recommended dosage). Abiraterone Acetate Following the administration of AKEEGA, the mean (CV%) Cmax,ss was 151 ng/mL (59%) and AUC0-24h,ss was 707 ng·h/mL (59%) for abiraterone. The accumulation ratio following daily administration of AKEEGA was 2-, and 1.8-fold for abiraterone AUC0-24h and Cmax. No major deviation from dose proportionality was observed for abiraterone acetate in the dose range of 250 mg (0.25 times the recommended dosage) to 1,000 mg (the recommended dosage). Absorption Niraparib The median Tmax was 3 hours after dosing. The absolute bioavailability of niraparib is approximately 73%. Abiraterone Acetate The median Tmax of abiraterone was 1.5 hours after dosing. Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (C^max) increase in mean systemic exposure ^of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. Distribution Niraparib The apparent volume of distribution of niraparib was 1,117 L. Niraparib is 83% bound to human plasma proteins. Abiraterone Acetate The apparent volume of distribution of abiraterone was 25,774 L. Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. JAB7217 -224- Elimination Niraparib The mean t^½ of niraparib when given in combination was approximately 62 hours (CV%: 42%) and apparent CL/F was 16.7 L/h (CV%: 27%). Abiraterone Acetate The mean t½ of abiraterone when given in combination was approximately 20 hours (CV%: 7.8%) and apparent CL/F was 1673 L/h (CV%: 24%). Metabolism Niraparib Niraparib is metabolized by carboxylesterases. Abiraterone Acetate Abiraterone acetate is rapidly converted in vivo to abiraterone. CYP3A4 and SULT2A1 are the enzymes involved in the metabolism of abiraterone. Excretion Niraparib About 48% (33% to 60%) of the radiolabeled dose was recovered in urine and 39% (28% to 47%) in feces. Unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. Abiraterone Acetate Approximately 88% of the radiolabeled dose is recovered in feces and 5% in urine. Unchanged abiraterone acetate and abiraterone accounted for 55% and 22% of the administered dose recovered in the feces, respectively. Specific Populations No clinically significant effects on the PK of niraparib and abiraterone were observed based o n body weight (43.3-165 kg for niraparib and 46-165 kg for abiraterone), age (45-90 years for niraparib and 43-90 years for abiraterone), race/ethnicity (White, Asian, and Hispanic) and mild to moderate renal impairment (CLcr: 30-90 mL/min). Severe renal impairment (CLcr: 15- 30 mL/min) has not been studied. Hepatic Impairment Niraparib Mild hepatic impairment did not affect the exposure of niraparib. Moderate hepatic impairment (Total bilirubin > 1.5 to 3 x ULN and any aspartate aminotransferase value) increased niraparib AUC by 56% compared to that of patients with normal hepatic function. JAB7217 -225- Abiraterone Acetate Mild (Child-Pugh score of 5 to 6; Child-Turcotte-Pugh Class A) hepatic impairment increased abiraterone (AUC) by 1.1-fold and moderate (Child-Pugh score of 7 to 9; Child-Turcotte-Pugh Class B) hepatic impairment increased abiraterone (AUC) by 3.6-fold compared to subjects with normal hepatic function. Severe (Child-Pugh score of 10 to 15; Child-Turcotte-Pugh Class C) hepatic impairment increased abiraterone AUC by 7-fold and the fraction of free drug increased by 2-fold in subjects compared to subjects with normal hepatic function. Drug Interactions Studies Niraparib In Vitro Studies ^ Inhibition of Cytochrome P450 (CYP) Enzymes: Niraparib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. ^ Induction of CYP Enzymes: Niraparib is not a CYP3A4 inducer. Niraparib induces CYP1A2 in vitro. ^ Inhibition of Uridine 5’-Diphospho-Glucuronosyltransferases (UGTs): Niraparib did not inhibit UGT1A1, UGT1A4, UGT1A9, and UGT2B7. ^ Inhibition of Transporter Systems: Niraparib inhibits BCRP, but does not inhibit P-gp, BSEP, or MRP2. Niraparib inhibits MATE 1 and 2. ^ Substrate of Transporter Systems: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE1 or 2. Abiraterone Acetate Clinical Studies ^ Effect of Strong CYP3A4 Inducers on Abiraterone: Coadministration of rifampin (strong CYP3A4 inhibitor) decreased abiraterone mean AUC by 55%. ^ Effect of Strong CYP3A4 Inhibitors on Abiraterone: Coadministration of ketoconazole (strong CYP3A4 inhibitor) had no clinically meaningful effect on the pharmacokinetics of abiraterone. ^ Effect of Abiraterone Acetate on CYP2D6 Substrates: The C omethorphan (CYP2D6 substrate) were increased 2.8^m and AUC of dextr -^ax and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3-fold. JAB7217 -226- ^ Effect of Abiraterone Acetate on CYP1A2 Substrates: When abiraterone acetate (plus prednisone) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. ^ Effect of Abiraterone Acetate on CYP2C8 Substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of abiraterone acetate. In vitro Studies ^ Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5. ^ Transporter Systems: Abiraterone acetate and abiraterone are not substrates of P-gp. Abiraterone acetate is an inhibitor of P-gp. Abiraterone and its major metabolites were inhibitors of OATP1B1. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Niraparib Carcinogenicity studies have not been conducted with niraparib. Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months’ duration in rats and dogs. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses 2:10 mg/kg and 2:1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.5 and 0.02 times, respectively, the human exposure (AUC0-24h) at the dose of 200 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped. Abiraterone Acetate A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 21 JAB7217 -227- 0.8 times the human clinical exposure (1,000 mg daily) based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. Abiraterone acetate and abiraterone were not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivo rat micronucleus assay. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at 2:50 mg/kg/day in rats and 2:250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans at 1,000 mg daily. In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at 2:30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at 2:30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre- implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area. In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. 13.2 Animal Toxicology and/or Pharmacology Niraparib In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC values that were lower than the C at steady-state in patients dose. Nirapa⁵ r⁰ receiving the 200 mg ib has the potential to cause effec^m tⁱ sⁿ in patients related to inhibition of these transporters (e.g., cardiovascular, central nervous system). Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3, and 10 mg/kg resulted in an increased range of arterial pressures of 13% to 20%, 18% to 27%, and 19% to 25%, respectively, and increased range of heart rates of 2% to 11%, 4% to 17%, and 12% to 21%, respectively, above pre-dose levels. The unbound plasma concentrations of niraparib in dogs at these dose levels were 22 JAB7217 -228- approximately 1.2, 3.9, and 15.5 times the unbound Cmax at steady state in patients receiving the 200 mg dose. In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid plasma Cmax ratios of niraparib administered at 10 mg/kg orally to two rhesus monkeys were 0.10 and 0.52. Abiraterone Acetate A dose-dependent increase in cataracts was observed in rats after daily oral abiraterone acetate administration for 26 weeks starting at ^50 mg/kg/day (similar to the human clinical exposure (AUC) at 1,000 mg dose daily). In a 39-week monkey study with daily oral abiraterone acetate administration, no cataracts were observed at higher doses (2 times greater than the clinical exposure (AUC) at 1,000 mg dose daily). 14 CLINICAL STUDIES 14.1 BRCA-mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) The efficacy of AKEEGA was investigated in Cohort 1 of MAGNITUDE (NCT03748641), a randomized double-blind, placebo-controlled, multi-cohort, multi-center study in which 423 patients with homologous recombination repair (HRR) gene-mutated (HRRm) mCRPC were randomized (1:1) to receive niraparib 200 mg and abiraterone 1,000 mg (N=212) or placebo and abiraterone (N=211) until unacceptable toxicity or progression. All patients received prednisone 10 mg daily and a GnRH analog or had prior bilateral orchiectomy. Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior abiraterone acetate plus prednisone (up to four months) and ongoing ADT, were eligible. Patients could have received prior docetaxel or androgen-receptor (AR) targeted therapies in either the metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) setting. Randomization was stratified by prior docetaxel for mCSPC (yes or no), prior AR targeted therapy for mCSPC or nmCRPC (yes or no), prior abiraterone acetate for mCRPC (yes or no), and BRCA- status (BRCAm vs. other). Of the 423 patients enrolled, 225 (53%) had BRCA gene mutations (BRCAm). Mutation status o f BRCA genes was determined prospectively using the Foundation One CDx tissue assay or other clinical trial assays. Among the 225 patients with BRCAm, the median age was 68 years (range 43-100) and 66% were 65 years of age or older; 72% were White, 17% Asian, and 1% Black, and 10% other or not reported; 12% were Hispanic or Latino; and baseline ECOG performance status (PS) was 0 (66%) or 1 (34%). Twenty-four percent had received prior docetaxel, 5% received prior AR-targeted therapy for mCSPC or nmCRPC, and 26% received prior abiraterone acetate plus prednisone for up to 4 months for mCRPC. Thirty-seven percent had bone-only metastases and 21% had visceral metastases. Seven percent had BRCA1 mutations, 78% had BRCA2 mutations, and 15% had BRCA mutations in combination with mutations in other HRR genes. JAB7217 -229- The major efficacy outcome measure was radiographic progression free survival (rPFS) determined by blinded independent central radiology (BICR) review evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (soft tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Overall survival (OS) was an additional efficacy outcome measure. A statistically significant improvement in rPFS for niraparib plus abiraterone compared to placebo plus abiraterone was observed in BRCAm patients, and the Cohort 1 intention to treat (ITT) population. In an exploratory analysis in the subgroup of 198 (47%) patients with non-BRCA mutations, the rPFS hazard ratio was 0.99 (95% CI: 0.67, 1.44) and the OS hazard ratio was 1.13 (95% CI: 0.77, 1.64), indicating that the improvement in the ITT population was primarily attributed to the results seen in the subgroup of patients with BRCAm. The efficacy results are presented in Table 4 and Figures 1 and 2 for patients in Cohort 1 with BRCA mutations. Table 4: Efficacy Results from the BRCAm Subgroup of the MAGNITUDE Study AKEEGA (N=113) Placebo Endpoints a (N=112) Radiographic Progression-free Survival Event of disease progression or death (%) 45 (40%) 64 (57%) Median, months (95% CI) 16.6 (13.9, NE) 10.9 (8.3, b 13.8) Hazard c Ratio (95% CI) 0.53 (0.36, 0.79) p-value 0.0014 ^a rPFS results based on blinded independent central review at primary analysis. ^b Cox proportional hazards model stratified by prior docetaxel (yes vs. no) and prior abiraterone (yes vs. no). ^c Stratified log-rank test two-sided p-value NE = not estimable At the protocol pre-specified final OS analysis in Cohort 1, 60 (53%) deaths and 70 (63%) deaths were observed in the AKEEGA arm and placebo arm, respectively, for patients with BRCAm. In an exploratory OS analysis in the subgroup of patients with BRCAm, the median in the AKEEGA arm was 30.4 (95% CI: 27.6, NE) and 28.6 months (95% CI: 23.8, 33.0) in the placebo arm, with an OS hazard ratio of 0.79 (95% CI: 0.55, 1.12). JAB7217 -230- Figure 1: Kaplan-Meier Plot of BICR Assessed Radiographic Progression-Free Survival in the BRCAm Population (MAGNITUDE, primary analysis) JAB7217 -231- Figure 2: Kaplan-Meier Plot of Overall Survival in the BRCAm Population (MAGNITUDE, final analysis) 16 HOW SUPPLIED/STORAGE AND HANDLING AKEEGA^TM (niraparib and abiraterone acetate) tablets are available in the strengths and packages listed below: ^ AKEEGA 50 mg/500 mg film-coated tablets Yellowish orange to yellowish brown, oval, film-coated tablets debossed with “N 50 A” on one side and plain on the other side. They are available in bottles of 60 tablets. NDC 57894-050-60 ^ AKEEGA 100 mg/500 mg film-coated tablets Orange, oval, film-coated tablets debossed with “N 100 A” on one side and plain on the other side. They are available in bottles of 60 tablets. NDC 57894-100-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. JAB7217 -232- Based on its mechanism of action, AKEEGA may harm a developing fetus. Females who are or may become pregnant should handle AKEEGA tablets with protection, e.g., gloves [see Use in Specific Populations (8.1)]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hematologic Adverse Reactions ^ Advise patients that periodic monitoring of their blood counts is recommended. Advise patients to contact their healthcare provider for new onset of pallor, weakness, dyspnea, fatigue, bleeding, fever, or symptoms of infection [see Warnings and Precautions (5.1, 5.2)]. Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions ^ Inform patients that AKEEGA is associated with, hypokalemia that may lead to QT prolongation. Advise patients that hypertension, hypokalemia, and fluid retention will be monitored at least weekly for the first two months, then once a month. Advise patients to adhere to corticosteroids and to report symptoms of hypokalemia or edema to their healthcare provider [see Warnings and Precautions (5.3)]. Hepatotoxicity and Hepatic Impairment ^ Inform patients that AKEEGA is associated with severe hepatotoxicity. Inform patients that their liver function will be monitored using blood tests. Advise patients to immediately report symptoms of hepatotoxicity to their healthcare provider [see Warnings and Precautions (5.4)]. Adrenocortical Insufficiency ^ Inform patients that AKEEGA with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their healthcare provider [see Warnings and Precautions (5.5)]. Hypoglycemia ^ Inform patients that AKEEGA is associated with hypoglycemia. Advise patients with diabetes to monitor blood glucose during and after discontinuation of treatment with AKEEGA [see Warnings and Precautions (5.6)]. Posterior Reversible Encephalopathy Syndrome ^ Inform patients that they are at risk of developing posterior reversible encephalopathy syndrome (PRES) that can present with signs and symptoms including seizure, headaches, altered mental status, or vision changes. Advise patients to contact their healthcare provider if they develop any of these signs or symptoms [see Warnings and Precautions (5.8)]. JAB7217 -233- Dosage and Administration ^ Inform patients that AKEEGA is taken orally once daily with prednisone daily (according to their healthcare provider’s instructions) and to not interrupt or stop either of these medications without consulting their healthcare provider [see Dosage and Administration (2.2)]. ^ Inform patients coadministered a gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with AKEEGA [see Dosage and Administration (2.2)]. ^ Inform patients that in the event of a missed daily dose of AKEEGA, they should take their normal dose as soon as possible on the same day and resume their next dose at the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose [see Dosage and Administration (2.2)]. ^ Instruct patients to take AKEEGA tablets as a single dose once daily on an empty stomach. Instruct patients to not eat food 2 hours before and 1 hour after taking AKEEGA. AKEEGA taken with food causes increased exposure and may result in adverse reactions. Instruct patients to swallow tablets whole with water and not to break, crush, or chew the tablets [see Dosage and Administration (2.2)]. Embryo-Fetal Toxicity ^ Inform patients that AKEEGA may harm a developing fetus and can cause loss of pregnancy [see Warnings & Precautions (5.9) and Use in Specific Populations (8.1)]. ^ Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.3)]. ^ Advise females who are pregnant or may become pregnant to handle AKEEGA tablets with protection, e.g., gloves [see Use in Specific Populations (8.1) and How Supplied/Storage and Handling (16)]. Infertility ^ Advise male patients that AKEEGA may impair fertility [see Use in Specific Populations (8.3)]. Product of France Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044, USA For patent information: www.janssenpatents.com © 2023 Janssen Pharmaceutical Companies JAB7217 -234- PATIENT T I MNFORMATION AKEEGA (a kee' gah) (niraparib and abiraterone acetate) tablets What is the most important information I should know about AKEEGA? AKEEGA may cause serious side effects including: ^ Bone marrow problems called myelodysplastic syndrome (MDS) or a type of cancer of the blood called acute myeloid leukemia (AML). MDS or AML that may lead to death has happened in people treated with niraparib, one of the medicines in AKEEGA. If you develop MDS or AML, your healthcare provider will stop treatment with AKEEGA. Symptoms of low blood cell counts (low red blood cells, low white blood cells, and low platelets) are common during treatment with AKEEGA but can also be a sign of serious bone marrow problems, including MDS and AML. Tell your healthcare provider if you have any of the following symptoms during treatment with AKEEGA: o pale skin o fever o weakness o frequent infections o shortness of breath o blood in urine or stool o feeling tired o weight loss o bruising or bleeding more easily Your healthcare provider will do blood tests to check your blood cell counts: o weekly during the first month of treatment, o every 2 weeks for the next 2 months of treatment, o monthly for the remainder of the year, o then every other month and as needed during treatment with AKEEGA. See “What are the possible side effects of AKEEGA?” for more information about side effects. What is AKEEGA? AKEEGA is a prescription medicine used with prednisone to treat adults with prostate cancer: ^ who have a certain type of abnormal BRCA gene, and ^ whose prostate cancer has spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone (metastatic castration-resistant prostate cancer). Your healthcare provider will perform a test to make sure AKEEGA is right for you. It is not known if AKEEGA is safe and effective in females. It is not known if AKEEGA is safe and effective in children. Before taking AKEEGA, tell your healthcare provider about all of your medical conditions, including if you: ^ have high blood pressure or heart problems ^ have low blood potassium levels ^ have liver or kidney problems ^ have a history of adrenal problems ^ have diabetes ^ are receiving any other treatment for prostate cancer ^ are pregnant or plan to become pregnant. AKEEGA can cause harm to your unborn baby and loss of pregnancy (miscarriage). Females who are or may become pregnant should handle AKEEGA tablets with protection, such as gloves. ^ have a partner who is pregnant or may become pregnant. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after the last dose of AKEEGA. ^ are breastfeeding or plan to breastfeed. It is not known if AKEEGA passes into your breastmilk. JAB7217 -235- Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. AKEEGA may affect the way other medicines work, and other medicines may affect how AKEEGA works. How should I take AKEEGA? ^ Take AKEEGA and prednisone exactly as your healthcare provider tells you. ^ Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with AKEEGA if you have certain side effects. ^ Do not change or stop taking your prescribed dose of AKEEGA or prednisone without talking with your healthcare provider first. ^ Take your prescribed dose of AKEEGA 1 time a day. ^ Take AKEEGA on an empty stomach. Do not eat food 2 hours before and 1 hour after taking AKEEGA. Taking AKEEGA with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects. ^ Swallow AKEEGA tablets whole with water. Do not break, crush, or chew tablets. ^ If you miss a dose of AKEEGA, take the dose as soon as possible on the same day. Return to your normal schedule on the following day. Do not take extra tablets to make up the missed dose. ^ You should start or continue a gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with AKEEGA unless you have had a surgery to lower the amount of testosterone in your body (surgical castration). ^ If you take too much AKEEGA, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of AKEEGA? AKEEGA may cause serious side effects, including: ^ See “What is the most important information I should know about AKEEGA?” ^ Low blood potassium levels (hypokalemia), fluid retention (edema), high blood pressure (hypertension) and heart problems. To decrease the chance of this happening, you must take prednisone with AKEEGA exactly as your healthcare provider tells you. Your healthcare provider will check your blood pressure, do blood tests to check your potassium levels, and check for any signs and symptoms of fluid retention at least weekly for the first 2 months of treatment, then 1 time a month during treatment with AKEEGA. Tell your healthcare provider if you have any of the following symptoms: o dizziness o confusion o fast or irregular heartbeats o muscle weakness o feel faint or lightheaded o pain in your legs o headache o swelling in your hands, ankles, legs or feet ^ Liver problems. Severe liver problems, liver failure and death has happened in people treated with abiraterone acetate, one of the medicines in AKEEGA. Your healthcare provider will do blood tests to check your liver function before starting treatment with AKEEGA, every 2 weeks for the first 3 months of treatment, and then monthly thereafter during treatment with AKEEGA. Tell your healthcare provider right away if you develop any symptoms of liver problems, including: o yellowing of the skin or eyes o severe nausea or vomiting o darkening of the urine ^ Adrenal problems. Adrenal problems may happen if you stop taking prednisone, get an infection, or are under stress. Tell your healthcare provider right away if you develop any symptoms of adrenal problems, including: o feeling tired o nausea or vomiting o weakness o weight loss o feeling dizzy or lightheaded ^ Low blood sugar (hypoglycemia). AKEEGA may cause low blood sugar in people taking medicines for diabetes. Severe low blood sugar has happened in people who take certain medicines for diabetes and were treated with abiraterone acetate, one of the medicines in AKEEGA. You and your healthcare provider should check your blood sugar levels during treatment and after you stop treatment with AKEEGA. Your healthcare provider may need to

Claims

JAB7217 -236- change the dose of your diabetes medicine to decrease your risk of low blood sugar. Tell your healthcare provider right away if you have any of the following signs or symptoms of low blood sugar, including: o headache o irritability o drowsiness o hunger o weakness o fast heartbeat o dizziness o sweating o confusion o feeling jittery ^ Increased risk of bone fracture and death when abiraterone acetate, one of the medicines in AKEEGA, and prednisone or prednisolone is used in combination with a type of radiation called Radium 223 (Ra-223) dichloride. You should not receive treatment with Ra-223 dichloride for at least 5 days after your last dose of AKEEGA with prednisone. Tell your healthcare provider about any other treatments you are taking for prostate cancer. ^ Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a condition that affects the brain and may happen during treatment with AKEEGA. If you have headache, vision changes, confusion, or seizure with or without high blood pressure, please contact your healthcare provider. The most common side effects of AKEEGA include: ^ muscle and bone pain ^ swelling in your legs or feet ^ bleeding ^ tiredness ^ shortness of breath ^ urinary tract infection ^ changes in liver function blood tests ^ decreased appetite ^ cough ^ constipation ^ vomiting ^ trouble sleeping ^ high blood pressure ^ dizziness ^ decreased weight ^ nausea ^ Coronavirus disease 2019 ^ irregular heartbeat ^ _{changes in kidney function blood tests} ^{(COVID-19) (arrhythmia)} ^ increased potassium level in the blood ^{^ headache ^ falls} ^ _{decreased potassium level in the} ^{^ stomach area pain ^ fever} blood AKEEGA may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of AKEEGA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AKEEGA? ^ Store AKEEGA at room temperature between 68°F to 77°F (20°C to 25°C). Keep AKEEGA and all medicines out of the reach of children. General information about the safe and effective use of AKEEGA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AKEEGA for a condition for which it was not prescribed. Do not give AKEEGA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about AKEEGA that is written for health professionals. What are the ingredients in AKEEGA? Active ingredients: niraparib tosylate and abiraterone acetate Inactive ingredients: Core tablet: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate. 50 mg/500 mg film-coated tablets: The film-coating contains iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. 100 mg/500 mg film-coated tablets: The film-coating contains iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. Manufactured for: Janssen Biotech, Inc., Horsham, PA 19044, USA For patent information: www.janssenpatents.com © 2023 Janssen Pharmaceutical Companies For more information, call Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or go to www.akeegahcp.com. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 8/2023 JAB7217 -237- CLAIMS What is claimed is: 1. A drug product with at least one indication approved for marketing by a governmental authority, wherein said drug product comprises niraparib and abiraterone acetate. 2. The drug product of claim 1, wherein the at least one approved indication is metastatic castration resistant prostate cancer (mCRPC). 3. The drug product of claim 1 or 2, wherein the drug product is indicated with prednisone for the treatment of a patient with deleterious or suspected deleterious BReast Cancer- mutated (BRCAm) mCRPC, as detected by a test. 4. The drug product of claim 3, wherein the drug product is administered to deliver orally once daily a dosage of 200 mg of niraparib and 1,000 mg of abiraterone acetate, and is administered in combination with a daily dose of 10 mg of prednisone. 5. The drug product claim 3, wherein the drug product is administered orally once daily with a reduced dosage of 100 mg of niraparib and 1,000 mg of abiraterone acetate, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. 6. The drug product of any one of claims 3-5, wherein the drug product is administered on an empty stomach. 7. The drug product of any one of claims 3-6, wherein food is not eaten two hours before and one hour after taking the drug product. 8. The drug product of any one of claims 3-7, wherein the patient concurrently receives a gonadotropin-releasing hormone (GnRH) analog, or the patient has had bilateral orchiectomy. 9. The drug product of claim 8, wherein the GnRH analog is selected from triptorelin, nafarelin, goserelin, leuprorelin or leuprolide, histrelin, gonadorelin, and buserelin. 10. The drug product of any one of claims 3-9, wherein the drug product is not administered to a patient with moderate or severe hepatic impairment. 11. The drug product of any one of claims 3-10, wherein the drug product is not co- administered with the CYP3A4 inducer rifampicin. 12. The drug product of any one of the preceding claims, wherein said drug product comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and (i) 100 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (regular strength); or JAB7217 -238- (ii) 50 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (lower strength). 13. The drug product of any one of claims 4-12, wherein said drug product elicits a median Overall Survival (OS) of 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by an approved test. 14. The drug product of claim 13, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from Prostate-Specific Antigen (PSA), Lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) grade, bone lesion number, and Visceral Disease. 15. The drug product of any one of claims 4-14, wherein the drug product elicits an improved median Time to Symptomatic Progression (TSP) with a HR of 0.562 (95% CI: 0.371, 0.849) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test, when compared to a patient receiving placebo and abiraterone acetate plus prednisone. 16. The drug product of any one of claims 4-15, wherein the drug product elicits an improved median Time to Cytotoxic Chemotherapy (TCC) with a HR of 0.598 (95% CI: 0.387, 0.924) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test, when compared to a patient receiving placebo and abiraterone acetate plus prednisone. 17. The drug product of any one of claims 4-16, wherein the drug product elicits a median radiographic Progression Free Survival (rPFS) of 19.5 months with a HR of 0.553 (95%: 0.392, 0.782) in a patient with deleterious or suspected deleterious BRCAm mCRPC, as detected by a test. 18. The drug product of any one of claims 1-17, wherein the drug product comprises 159.40 mg niraparib tosylate monohydrate equivalent to 100 mg niraparib free base as the active ingredient, and 500 mg of abiraterone acetate. 19. The drug product of any one of claims 1-17, wherein the drug product comprises 79.70 mg niraparib tosylate monohydrate equivalent to 50 mg niraparib free base as the active ingredient, and 500 mg of abiraterone acetate. 20. The drug product of any one of claims 12-19, wherein the pharmaceutical composition is an oral dosage form selected from a film-coated tablet, a tablet, a capsule, granules, and a sachet. 21. The drug product of claim 20, wherein the pharmaceutical composition is a film-coated tablet further comprising colloidal anhydrous silica, crospovidone, hypromellose, lactose JAB7217 -239- monohydrate, magnesium stearate, silicified microcrystalline cellulose, and sodium lauryl sulfate; and a film-coating. 22. The drug product of claim 21, wherein the film-coated tablet comprises100 mg niraparib and 500 mg abiraterone acetate; and the film-coating comprises iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. 23. The drug product of claim 21, wherein the film-coated tablet comprises 50 mg niraparib and 500 mg abiraterone acetate; and the film-coating comprises iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide. 24. The drug product of any one of the preceding claims, wherein the drug product is approved for marketing in the European Economic Area (EEA), or Canada. 25. The drug product of any one of the preceding claims, wherein the drug product is a generic, an ANDA, a sNDA, an NDA product, or a 505(b)(2) drug product. 26. A method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test, the method comprising administering the drug product as defined in any one of the preceding claims, in combination with prednisone, to said patient. 27. The method for treating mCRPC of claim 26, wherein the method for treating comprises administering orally once daily the drug product that contains 200 mg of niraparib and 1,000 mg of abiraterone acetate, along with a separate daily dose of 10 mg of prednisone, until disease progression or unacceptable toxicity. 28. The method for treating mCRPC of claim 26, wherein the method for treating comprises administering orally once daily a reduced dosage of the drug product that contains 100 mg of niraparib and 1,000 mg of abiraterone acetate, along with a separate daily dose of 10 mg of prednisone, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non- hematological grade 3 or 4 adverse reactions. 29. The method for treating mCRPC of any one of claims 26-28, wherein the method for treating comprises the improvement of the median OS to 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). 30. The method for treating mCRPC of claim 29, wherein the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. JAB7217 -240- 31. The method for treating mCRPC of any one of claims 26-30, wherein the treatment comprises the improvement of median TSP with a HR of 0.562 (95% CI: 0.371, 0.849). 32. The method for treating mCRPC of any one of claims 26-31, wherein the treatment comprises the improvement of median TCC with a HR of 0.598 (95% CI: 0.387, 0.924). 33. The method for treating mCRPC of any one of claims 26-32, wherein the treatment comprises the improvement of median rPFS to 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). 34. A method of selling a drug product comprising niraparib and abiraterone acetate as defined in any one of claims 1-25, said method comprising selling such drug product. 35. The method of selling of claim 34, wherein the drug product is a generic, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product. 36. The method of selling of claim 34 or 35, wherein the reference listed drug for such drug product improves OS, rPFS, TCC, TSP, or TPP. 37. The method of selling of claim 36, wherein the median OS is 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). 38. The method of selling of claim 37, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. 39. The method of selling of any one of claims 36-38, wherein the median TSP is improved with a HR of 0.562 (95% CI: 0.371, 0.849). 40. The method of selling of any one of claims 36-39, wherein the median TCC is improved with a HR of 0.598 (95% CI: 0.387, 0.924). 41. The method of selling of any one of claims 36-40, wherein the median rPFS is 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). 42. A method of offering for sale a drug product comprising niraparib and abiraterone acetate as defined in any one of claims 1-25, said method comprising offering for sale such drug product. 43. The method of offering for sale of claim 42, wherein the drug product is a generic, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product. 44. The method of offering for sale of claim 42 or 43, wherein the reference listed drug for such drug product improves OS, rPFS, TCC, TSP, or TPP. JAB7217 -241- 45. The method of offering for sale of claim 44, wherein the median OS is 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). 46. The method of offering for sale of claim 45, wherein the median OS has a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease. 47. The method of offering for sale of any one of claims 44-46, wherein the median TSP is improved with a HR of 0.562 (95% CI: 0.371, 0.849). 48. The method of offering for sale of any one of claims 44-47, wherein the median TCC is improved with a HR of 0.598 (95% CI: 0.387, 0.924). 49. The method of offering for sale of any one of claims 44-48, wherein the median rPFS is 19.5 months with a HR of 0.553 (95%: 0.392, 0.782). 50. A drug product as defined in any one of preceding claims 1-25, for use in a method for treating mCRPC in a patient with deleterious or suspected deleterious BRCAm, as detected by a test, the method comprising administering said drug product, in combination with prednisone. 51. The drug product as defined in any one of preceding claims 1-25, for the use in a method of claim 50, wherein the method for treating comprises administering orally once daily a dosage of 200 mg of niraparib and 1,000 mg of abiraterone acetate of the drug product, and 10 mg of prednisone, until disease progression or unacceptable toxicity. 52. The drug product as defined in any one of preceding claims 1-25, for the use in a method of claim 50, wherein the method for treating comprises administering orally once daily a reduced dosage of 100 mg of niraparib and 1,000 mg of abiraterone acetate of the drug product, and 10 mg of prednisone, in case of myelosuppression with: (i) a platelet count < 100,000/mcL, or (ii) a neutrophil count < 1,000/mcL or hemoglobin count < 8 g/dL; or in case of other non-hematological grade 3 or 4 adverse reactions. 53. The drug product as defined in any one of preceding claims 1-25, for the use in a method of any one of claims 50-52, wherein the method for treating comprises the improvement of the median OS to 30.4 months with a HR of 0.788 (95% CI: 0.554, 1.120). 54. The drug product as defined in any one of preceding claims 1-25, for the use in a method of claim 53, wherein the median OS is further improved with a HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for externally validated and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and Visceral Disease.