EA046078B1 - ANTIANDROGENS FOR THE TREATMENT OF METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER - Google Patents

Description

Cross reference to related applications

This application claims the benefit of U.S. Provisional Patent Application No. 62/901,694, filed September 17, 2019; 62/836,920 filed April 22, 2019; US Provisional Patent Application No. 62/833,371, filed April 12, 2019; US Provisional Patent Application No. 62/822,312, filed March 22, 2019; 62/803,096, filed February 8, 2019; and US Provisional Patent Application No. 62/798,836, filed January 30, 2019; the contents of which are fully included in this document by reference to the family of analogous patents.

Technical field

Disclosed herein are methods of treating metastatic castration-sensitive prostate cancer with antiandrogens, including, but not limited to, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro [3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

Prerequisites for creating the invention

Prostate cancer is the second most commonly diagnosed cancer and the sixth leading cause of cancer death in men; it accounts for 14% (903,500) of total new cancer cases and 6% (258,400) of total cancer deaths in men worldwide. The course of prostate cancer from diagnosis to death is best classified into a series of clinical stages based on the extent of disease, hormonal status, and the presence or absence of detectable metastases: localized disease, rising prostate-specific antigen (PSA) levels after radiation therapy or surgery without detectable metastases, and clinical metastases in the uncastrated or neutered stage. Although surgery, radiation therapy, or a combination of both treatments may be curative in patients with localized disease, a significant proportion of these patients experience disease recurrence, as evidenced by rising PSA levels, which may lead to the development of metastases, especially in the high risk - transition to the fatal stage of the disease.

Based on current guidelines, androgen deprivation therapy (ADT) with or without docetaxel is considered appropriate active control therapy for patients with metastatic hormone-sensitive prostate cancer. However, there is a clear unmet medical need for alternative treatment options in mCSPC. Treatments that can slow disease progression and associated morbidities will provide significant clinical benefits for this patient population. The methods described address these and other important needs.

Summary of the invention

Disclosed herein are methods of treating metastatic castration-sensitive prostate cancer comprising, comprising, or substantially providing for the administration of a therapeutically effective amount of an antiandrogen to a male subject with metastatic castration-sensitive prostate cancer. In these methods, the antiandrogen can be: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]-2-fluoro -N-methylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4- [7-[4-cyano-3-(trifluoromethyl)phenyl]-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or Na{^)- 1-[3-(3-chloro-4cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide. In some embodiments, administration of an antiandrogen provides an increase in overall survival of a male subject relative to the overall survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, wherein the comparison group was administered placebo in combination with androgen deprivation therapy. In other embodiments, the comparison group received no treatment. In additional embodiments, administration of an antiandrogen provides an increase in progression-free survival in a male subject relative to progression-free survival in a comparison group of male subjects with metastatic castration-sensitive prostate cancer, wherein the comparison group was administered placebo in combination with androgen deprivation therapy. In other embodiments, the comparison group received no treatment.

In some embodiments, the male subject has received at least one prior cancer therapy prior to administration of the antiandrogen, wherein the prior cancer therapy is radiation, surgery, or docetaxel therapy. In some embodiments, the male subject has not previously received any treatment.

In some embodiments, the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro -N-methylbenzamide. In further embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-N-methylbenzamide

- 1 046078 is administered to a male human daily. In other further embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo5.7-diazaspiro|3.4|oct-5-yl |-2-(()tor-N-methylbenzamide is orally administered to a male human. In some embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is orally administered to a male human subject on a continuous daily dosing schedule.In further embodiments, an antiandrogen is substantially, and in particular 4 -[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, administered orally to humans male at a dose of about 30 mg per day to about 480 mg per day.In other additional embodiments, the implementation of an antiandrogen per se, and in particular 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a male subject at a dose of about 180 mg per day to about 480 mg per day. In certain embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-N-methylbenzamide is administered orally to a male human at a dose of: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In certain embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-Fluoro-N-methylbenzamide is administered orally to a male human at a dose of about 240 mg per day. In some embodiments, a dose of substantially an antiandrogen, and in particular, 4-[7-(6-cyano-5-tri(tormethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4] oct-5-yl]-2-fluoro-N-methylbenzamide, reduce to 180 mg per day or 120 mg per day if a male subject experiences grade 3 or higher toxicity.

In certain embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-N-methylbenzamide should not be administered concomitantly with: (a) a medicinal product that is an active inhibitor of CYP2C8 or CYP3A4; (b) a drug that is primarily metabolized by CYP3A4, CYP2C19 or CYP2C9; (c) a drug that is a UDP-glucuronosyltransferase (UGT) substrate; or (d) a drug that is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transporting polypeptide 1B1 (OATP1B1).

In some embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-N-methylbenzamide is administered in combination with androgen deprivation therapy. In further embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-N-methylbenzamide is administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist. In other additional embodiments, the at least one GnRH agonist or antagonist is or contains leuprolide, buserelin, na(erelin, histrelin, goserelin, deslorelin, degarelix, osarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP -100, KLH-2109, or triptorelin. In certain embodiments, a substantially antiandrogen, and in particular 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro [3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is used in combination with bilateral orchiectomy.

In some embodiments, the antiandrogen is 4-(3-(4-cyano-3(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide . In additional embodiments, 4-(3-(4-cyano-3-(tri(tormethyl)(enyl)-5,5-dimethyl-4-oxo-2thioxoimidazolin-1-yl)-2-fluoro-N-methylbenzamide orally administered to a male human at a dose of about 160 mg per day.

In some embodiments, the antiandrogen is 4-[7-[4-cyano-3(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro -N-methylbenzamide.

In some embodiments, the antiandrogen is N-{(2S)-1-[3-(3-chloro-4cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)- 1H-pyrazole-3-carboxamide (darolutamide). In further embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole -3-carboxamide is administered orally to a male human at a dose of 600 mg twice daily. In further embodiments, N-{(2S)-1-[3-(3-chloro-4cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole -3-carboxamide is administered orally to a male human at a dose of 600 mg twice daily with meals.

Also described herein are methods of treating metastatic castration-sensitive prostate cancer, comprising or substantially providing a therapeutically effective amount of an antiandrogen to a male subject with metastatic castration-sensitive prostate cancer, wherein the antiandrogen is one or more of the following: 4-[ 7-(6-cyano-5-tri(toromethylpyridintri(toromethylpyridin-3-yl)-8-oxo6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, 4 -(3-(4-cyano-3-(trifluoromethyl)phenyl)

- 2 046078

5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-Nmethylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6- thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-Nmethylbenzamide or N-{(2S)-1-[3-(3chloro-4-cyanophenyl)-1H-pyrazol-1- yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide.

Also described herein are methods of treating metastatic castration-sensitive prostate cancer in a male human, comprising: (a) determining the presence of metastatic castration-sensitive prostate cancer in a male human; and (b) administering to a male subject an antiandrogen in a therapeutically effective amount for the treatment of metastatic castration-sensitive prostate cancer, wherein the antiandrogen is: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo -6-thioxo5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-Nmethylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4 -oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-Nmethylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro [3.4]oct-5-yl]-2-fluoro-Nmethylbenzamide or N-{(2S)-1-[3-(3-chloro-4cyanophenyl)-III-pyrazol-1-yl]propan-2-yl }-5-(1-hydroxyethyl)-III-pyrazole-3-carboxamide.

Also described herein are methods of treating metastatic castration-sensitive prostate cancer, comprising administering an approved drug product containing apalutamide to a male subject with metastatic castration-sensitive prostate cancer in an amount as specified in the information provided with the drug product. In some embodiments, the authorized drug product containing apalutamide is an abbreviated marketing authorization application (ANDA) drug product, a supplemental marketing authorization application (ANDA) drug product, or a 505(b)(2) drug product. In some embodiments, the method is clinically proven safe and/or effective.

Also described herein are pharmaceutical products containing a clinically proven safe and clinically proven effective amount of apalutamide, wherein such pharmaceutical product is contained in a package, and wherein such package includes information accompanying the drug product that (a) apalutamide is identified as a chemical entity, approved by regulatory authorities, and (b) provides instructions for the use of apalutamide in the treatment of castration-sensitive prostate cancer.

In addition, described herein is a method of marketing an authorized drug product containing apalutamide, which method includes the sale of such drug product, and the information accompanying the comparator product for such drug product includes instructions for the treatment of castration-sensitive prostate cancer. This document further describes methods for marketing an authorized drug product containing apalutamide, which method includes marketing such drug product, wherein the information accompanying the comparator product for such drug product includes instructions for the treatment of castration-sensitive prostate cancer . In some embodiments, the drug product is a drug product with an ANDA, a drug product with a supplemental marketing authorization application, or a 505(b)(2) drug product.

Brief description of graphic materials

The summary of the invention as well as the following detailed description will be more clearly understood when taken in conjunction with the accompanying drawings. To illustrate the described methods, the figures show examples of the implementation of the methods; however, such methods are not limited to the specific embodiments described. The graphic materials show the following.

In fig. Figure 1 shows a flowchart of the phase III clinical trial design for apalutamide. ADT=androgen deprivation therapy.

In fig. 2A-2B show Kaplan-Meier estimates of radiographic progression-free survival (Fig. 2A) and a forest plot of radiographic progression-free survival by baseline patient characteristics (Fig. 2B). Analyzes were performed using the log-rank test with stratification by Gleason score at diagnosis (<7 or >7), by region (North America and European Union or all other countries) and prior docetaxel treatment (yes or no).

In fig. 3A-3B show Kaplan-Meier estimates of overall survival (Fig. 3A) and a forest plot of overall survival by baseline patient characteristics (Fig. 3B). Analyzes were performed using the log-rank test with stratification by Gleason score at diagnosis (<7 or >7), by region (North America and European Union or all other countries) and prior docetaxel treatment (yes or no).

In fig. Figure 4 shows the Kaplan-Meier estimate of time to cytotoxic chemotherapy. Analyzes were performed using the log-rank test with Gleason stratification at

- 3 046078 by diagnosis (<7 or >7), by region (North America and European Union or all other countries) and previous docetaxel treatment (yes or no).

In fig. Figure 5 shows the Kaplan-Meier estimate of time to PSA progression. Time to PSA progression was the time from the date of randomization to the date of PSA progression based on Prostate Cancer Working Group 2 criteria. Analyzes were performed using the log-rank test with stratification by Gleason score at diagnosis (<7 or >7), by region (North America and European Union or all other countries) and prior docetaxel treatment (yes or no).

In fig. Figure 6 shows the Kaplan-Meier estimate of time to second progression-free survival. Secondary progression-free survival was the time from the date of randomization until the first occurrence of investigator-defined disease progression (PSA progression, diagnostic imaging progression, or clinical progression) while the patient received the first subsequent therapy for prostate cancer, or until death from any cause. depending on what happens first. Analyzes were performed using the log-rank test with stratification by Gleason score at diagnosis (<7 or >7), by region (North America and European Union or all other countries) and prior docetaxel treatment (yes or no).

In fig. Figure 7 shows repeated measures mixed-effects analyzes for mean change from baseline in FACT-P total score. Error bars reflect the standard error of the mean. Raw FACT-P scores range from 0 to 156, with higher scores indicating more favorable health-related quality of life; a minimally significant difference would be a change in FACT-P total score from 6 to 10 points. However, this figure represents the average change in total scores from baseline, not the original total scores. FACT-P, Functional Assessment of Cancer Therapy - Prostate.

Detailed Description of Illustrative Embodiments

It should be understood that certain elements of the invention, which for clarity are described herein in the context of different embodiments, can also be used in combination in a single embodiment. That is, unless obviously inconsistent or specifically excluded, each individual embodiment is considered to be combined with any other embodiment(s), and such combination is considered to be another embodiment. On the other hand, various elements of the invention, which for brevity are described in the context of a single embodiment, may also be presented separately or in any subcombination. Finally, although an embodiment may be described in terms of a series of steps or part of a more general structure, each specified step may also be considered an independent embodiment that is combined with others.

The transitional terms containing, consisting essentially of, and consisting of are intended to designate them as substantially common patent meanings; that is, (i) the term containing, which is synonymous with including, including, or is characterized as being inclusive or non-limiting and does not exclude additional, unspecified elements or method steps; (ii) consisting of excludes any element, step or ingredient not specified in the claims; and (iii) consisting essentially of limiting the scope of the claims to specific materials or steps and to that which does not materially affect the essential and novel feature(s) of the claimed invention. More specifically, the basic and novel features relate to the ability of the method to provide at least one of the benefits described herein, including, without limitation, the ability to increase the survival rate of a group of male humans compared to the survival of a comparative group of male humans described elsewhere sections of this document.

Embodiments described with respect to the expression comprising (or its equivalent) provide the same meaning as embodiments described independently with respect to the expression consisting essentially of and consisting of.

When a value is stated as approximate using the characteristic about, it should be understood that the specific value constitutes another embodiment. In general, the use of the term about refers to approximations that may vary depending on the desired properties sought to be achieved by the subject matter described, and should be interpreted in the particular context in which the term is used based on its function. One skilled in the art will be able to interpret this in the normal manner. In some cases, one non-restrictive way to determine the value of a term about may be the number of significant figures used in a particular value. In other cases, gradations of a series of values can be used to determine the target range associated with the term about for each of the values. All ranges, when available, are inclusive and combinable. Thus, references to values specified in ranges include each

- 4 046078 value within this range.

Unless otherwise indicated, the term about means a variance of ±10% of the value associated therewith, but additional embodiments include instances in which the variance may be ±5%, ±15%, ±20%, ±25%, or ±50%.

It should be understood that certain elements of the invention, which for clarity are described herein in the context of different embodiments, may also be used in combination in a single embodiment. That is, unless obviously inconsistent or specifically excluded, each individual embodiment is considered to be combined with any other embodiment(s), and such combination is considered to be another embodiment. On the other hand, various elements of the invention, which for brevity are described in the context of a single embodiment, may also be presented separately or in any subcombination. Finally, although an embodiment may be described in terms of a series of steps or part of a more general structure, each specified step may also be considered an independent embodiment that is combined with others.

When presented as a list, unless otherwise indicated, it is understood that each individual element of the list and each combination of the list is a separate embodiment. For example, a list of embodiments represented by A, B, or C should be interpreted as a list including embodiments A, B, C, A or B, A or C, B or C, or A, B, or C.

The present invention will be better understood by reference to the following description in conjunction with the accompanying drawings and examples, each of which is part of the present description. It should be understood that the present invention is not limited to the specific products, methods, conditions or parameters described or shown herein, and that the terminology used herein is intended to describe specific embodiments by way of example only and is not intended to limit any claimed invention. Likewise, unless specifically stated otherwise, any description regarding a possible mechanism or mode of action or reason for an improvement is to be understood as illustrative only, and the invention described herein is not intended to be limited by the correctness or incorrectness of any such proposed mechanism or mode of action. or reasons for improvement. It is noted herein that the descriptions provided relate to various compounds, compositions, and methods of using said compounds and compositions. Thus, if the text describes or claims a particular feature or embodiment associated with a particular composition or method of using a composition, it should be understood that such description or claim is intended to expand on such features or embodiments in each from such contexts (i.e. compositions and methods of application).

The androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily. Within this broad family of proteins, only five vertebrate steroid receptors are known, which include the androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor, and mineralocorticoid receptor. AR is a soluble protein that functions as an intracellular transcription factor. AR function is regulated by androgen binding, which initiates sequential conformational changes of the receptor that influence receptor-protein interactions and receptor-DNA interactions.

AR is primarily expressed in androgen target tissues such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest levels of expression observed in the prostate, adrenal gland, and epididymis. AR can be activated by binding of endogenous androgens, including testosterone and 5-dihydrotestosterone (5a-DHT).

The androgen receptor (AR), located on Xql 1-12, is a 110 kDa nuclear receptor that, when activated by androgens, mediates the transcription of target genes that modulate the growth and differentiation of prostate epithelial cells. Similar to other steroid receptors, unbound AR is primarily localized in the cytoplasm and is associated with the heat shock protein (HSP) complex through interactions with the ligand-binding domain. Upon agonist binding, the AR undergoes a series of conformational changes: heat shock proteins dissociate from the AR, and the transformed AR undergoes dimerization, phosphorylation, and nuclear translocation mediated by a nuclear localization signal. Subsequently, the translocated receptor binds to the androgen response element (ARE), which is distinguished by the generic typical half-site sequence of six nucleotides 5′-TGTTCT-3′, separated by three random nucleotides, and is localized in the promoter or enhancer region of AR target genes. Recruitment of other transcriptional coregulators (including coactivators and corepressors) and the transcription machinery further mediate transactivation of AR-regulated gene expression. All these processes are initiated by ligand-induced

- 5 046078 conformational changes in the ligand-binding domain.

The AR signal is essential for the formation and maintenance of male reproductive organs, including the prostate, because genetic males carrying AR loss-of-function mutations and mice genetically engineered to have AR defects do not develop prostate glands or prostate cancer . This dependence of prostate cells on AR signaling persists even after neoplastic transformation. Androgen reduction (eg, with gonadotropin-releasing hormone (GnRH) agonists) continues to be the mainstay of prostate cancer treatment. However, androgen reduction is usually effective for a limited period of time, and prostate cancer regains its ability to grow despite low levels of androgens in the circulatory system.

Castration-resistant prostate cancer (CRPC) is a fatal clinical manifestation of the disease, and almost all patients die from such prostate cancer. Interestingly, while a minority of CRPCs bypass the requirement for AR signaling, the vast majority of CRPCs, although often called androgen-independent prostate cancer or hormone-resistant prostate cancer, retain their inherited dependence on AR signaling.

Prostate cancer is the second most common cause of cancer death among men in the United States, and approximately one in every six Americans will be diagnosed with the disease during their lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men who develop recurrent disease, usually first manifesting as an increase in plasma levels of prostate-specific antigen (PSA) followed by spread to distant sites. Because prostate cancer cell proliferation and survival are dependent on androgen receptors (AR), these men are treated with agents that block testosterone production (eg, GnRH agonists), alone or in combination with antiandrogens (eg, bicalutamide), which antagonize the action of any residual testosterone on AR. The approach appears to be effective, as evidenced by a drop in PSA levels and regression of visible tumor (if present) in some patients; however, this is followed by relapse in the form of castration-resistant prostate cancer (CRPC), which kills most patients. Recent studies on the molecular basis of CRPC have demonstrated that CRPC remains dependent on AR signaling and that the primary mechanism of acquired resistance is increased levels of AR protein (Nat. Med, 2004, 10, 33-39). AR-targeting agents with activity against castration-sensitive and castration-resistant prostate cancer have great potential in the treatment of this deadly disease.

The course of prostate cancer from diagnosis to death is best classified as a series of clinical conditions based on the extent of disease, hormonal status, and the presence or absence of detectable metastases: localized disease, elevated prostate-specific antigen (PSA) levels after radiation therapy or surgery without detectable metastases, and clinical metastases in the uncastrated or neutered state. Although surgery, radiation therapy, or a combination of both treatments may be curative in patients with localized disease, a significant proportion of these patients experience disease recurrence, as evidenced by rising PSA levels, which may lead to the development of metastases, especially in the high risk - transition to the manifestation of the fatal stage of the disease.

Androgen depletion is a standard treatment, with essentially the predicted outcome of a decline in PSA levels, a period of stability during which the tumor does not proliferate, followed by an increase in PSA levels and recurrence in the form of castration-resistant disease. Molecular profiling studies of castration-resistant prostate cancer typically show increased androgen receptor (AR) expression, which may occur through AR gene amplification or other mechanisms.

Antiandrogens are used to treat prostate cancer in its early stages. However, prostate cancer often progresses to a hormone-resistant state, in which the disease progresses in the presence of chronic androgen removal or antiandrogen therapy. In addition, there are cases of antiandrogen withdrawal syndrome after prolonged treatment with antiandrogens. Antiandrogen withdrawal syndrome is often observed in clinical settings and is defined based on tumor regression or symptomatic relief observed after cessation of antiandrogen therapy. This phenomenon may be at least partially due to mutations in the AR, which result in a lack of receptor selectivity and the ability of these antiandrogens to exhibit agonistic activity. For example, hydroxyflutamide and bicalutamide act as AR agonists in the AR mutants T877A and W741L/W741C, respectively.

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In prostate cancer cells that have become castration-resistant as a result of AR overexpression, certain antiandrogen compounds, such as bicalutamide, have been shown to have a mixed antagonist/agonist profile (Science, 2009 May 8;324(5928): 787-90) . This agonist activity helps explain the clinical observation called antiandrogen withdrawal syndrome, in which about 30% of men with successful use of AR antagonists experience a decrease in serum PSA after discontinuation of therapy (J Clin. Oncol, 1993. 11(8): p. 1566-72 ).

Stages of prostate cancer.

In the early stages of prostate cancer, the cancer is located in the prostate gland. In these early stages, treatment typically involves either surgical removal of the prostate, radiation therapy to the prostate, or observation alone without active interventional therapy in some patients. In the early stages, when prostate cancer is localized and requires intervention, surgery or radiation therapy provides treatment by eliminating cancer cells. About 30% of the time, these treatments fail and the prostate cancer continues to progress, usually indicated by rising PSA levels. In men whose prostate cancer progresses after these early treatment strategies, the prostate cancer is called advanced or recurrent.

Because prostate cancer cell proliferation and survival are dependent on androgen receptors (AR), men with advanced prostate cancer are treated with agents that block testosterone production (eg, GnRH agonists), alone or in combination with antiandrogens (eg, bicalutamide), which antagonize the actions of any residual testosterone on AR. These treatments lower testosterone levels to castration levels, which essentially slows the progression of the disease over a period of time. The approach is effective, as evidenced by a drop in PSA levels and regression of visible tumors in some patients. Eventually, however, this is followed by a resurgence of castration-resistant prostate cancer (CRPC), which kills most patients. Castration-resistant prostate cancer (CRPC) is classified as non-metastatic or metastatic depending on whether the prostate cancer has metastasized to other parts of the body.

Estimates obtained from specific European country registries indicate that approximately 15% to 30% of males diagnosed with prostate cancer had metastatic (M1) castration-sensitive prostate cancer (mCSPC). See, for example, Flamand V, et al., Prog Urol. 2008;18:53-59. Patients in the United States with mCSPC account for approximately 4% of all prostate cancer diagnoses. Cetin K, et al. Urology 2010;75:1396-1405. This discrepancy may be due to differences in the use of PSA screening in different geographic areas. Schroder FH, et al., Eur Urol. 2012;62:745-752. However, the percentage of males in the United States with mCSPC may increase as the use of PSA screening is now believed to be declining after the US Preventive Services Task Force (USPSTF) issued recommendations against PSA screening in 2012. Drazer MW, et al., J Clin. Oncol 2015;33:2416 2423; Lin K, et al. Agency for Healthcare Research and Quality, 2011;No. 12-05160-EF-1.

Because prostate cancer cell proliferation and survival are dependent on AR signaling, the standard treatment for patients with mCSPC disease is androgen deprivation therapy (ADT). The definition of androgen deprivation therapy includes medical castration (ie, gonadotropin-releasing analogue [GnRHa; agonist or antagonist] agonist or antagonist) or surgical castration (ie, bilateral orchiectomy). To prevent worsening clinical tumor manifestations in subjects with advanced metastases, a short period of treatment with a first-generation antiandrogen can be used to reduce the testosterone surge upon initiation of a GnRH agonist.

Antiandrogens.

As used herein, the term antiandrogen is used in its common sense and may refer to a group of hormone receptor antagonist compounds that are capable of preventing or inhibiting the biological effects of androgens on normally sensitive tissues of the body. In some embodiments, the antiandrogen is a small molecule. In some embodiments, the antiandrogen is an AR antagonist. In some embodiments, the antiandrogen is a full AR antagonist. In some embodiments, the antiandrogen is a first generation antiandrogen. In some embodiments, the antiandrogen is a second generation antiandrogen.

When used herein, the terms AR antagonist and AR inhibitor are used interchangeably herein to refer to an agent that inhibits or

- 7 046078 reducing at least one type of activity of the AR polypeptide. Examples of AR polypeptide activity types include, but are not limited to, coactivator binding, DNA binding, ligand binding, or intranuclear translocation.

As used herein, the term full antagonist refers to an antagonist that, at an effective concentration, substantially completely inhibits the activity of the AR polypeptide. As used herein, the term partial antagonist refers to an antagonist that is capable of partially inhibiting the activity of an AR polypeptide, but which, even at the highest concentration, is not a full antagonist. By essentially completely inhibiting the activity of the AR polypeptide by at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or more.

As used herein, the term first-generation antiandrogen refers to an agent that exhibits antagonistic activity against a wild-type AR polypeptide. However, first-generation antiandrogens differ from second-generation antiandrogens in that first-generation antiandrogens may potentially act as agonists in castration-resistant prostate cancer (CRPC). Examples of first generation antiandrogens include, but are not limited to, flutamide, nilutamide and bicalutamide.

As used herein, the term second-generation antiandrogen refers to an agent that exhibits complete antagonistic activity against a wild-type AR polypeptide. Second-generation antiandrogens differ from first-generation antiandrogens in that second-generation antiandrogens act as full antagonists in cells expressing elevated levels of AR, such as in castration-resistant prostate cancer (CRPC). Examples of second generation antiandrogens include 4-[7-(6-cyano-5-trifluoromethylpyridin3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-No. methylbenzamide (also known as apalutamide, ARN-509, or JNJ-56021927; CAS No. 956104-40-8); 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-Nmethylbenzamide (also known as MDV3100 or enzalutamide ; CAS number: 915087-33-1), 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro -Nmethylbenzamide (RD162; CAS No. 915087-27-3) and N-{(2S)-1[3-(3-chloro-4-cyanophenyl)-N-pyrazol-1-yl]propan-2-yl} -5-(1-hydroxyethyl)-III-pyrazole-3-carboxamide (also known as darolutamide). In some embodiments, the second generation antiandrogen binds to the AR polypeptide at or near a ligand binding site of the AR polypeptide.

4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoroN-methylbenzamide (apalutamide) .

4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N methylbenzamide (enzalutamide).

- 8 046078

4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N methylbenzamide (RD162).

H-{(^)-1-[3-(3-chloro-4-cyano(|)enyl)-1H-pyrazol-1-yl|propan-2-yl;-5-(1-hydroxyethyl)-1H -pyrazole-3-carboxamide (darolutamide). In some embodiments, the antiandrogen contemplated in the methods described herein inhibits nuclear translocation of AR, such as darolutamide, DNA binding to androgen response elements, and recruitment of coactivators. In some embodiments, the antiandrogen contemplated in the methods described herein does not exhibit agonistic activity in AR-overexpressing prostate cancer cells.

Apalutamide is a second-generation antiandrogen that binds directly to the ligand-binding domain of AR, disrupting nuclear translocation, AR DNA binding, and target gene modulation by AR, and thus inhibits tumor growth and promotes apoptosis. Apalutamide binds to AR with higher α((ity) than bicalutamide and induces partial or complete tumor regression in xenograft models of non-castration hormone-sensitive and bicalutamide-resistant human prostate cancer (Clegg et al. Cancer Res. March 15, 2012 72; 1494 Apalutamide lacks the partial agonist activity observed for bicalutamide under conditions of AR overexpression.

Darolutamide, BAY1841788 or ODM-201, is an AR antagonist that includes two diastereomers - ORM-16497 and ORM-16555. Chemical name - N{^)-1-[3-(3-chloro-4cyanophenyl)-III-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-III-pyrazol-3- carboxamide It has activity against known AR mutants that are resistant to other second-generation antiandrogens. Darolutamide binds to AR with high a((ity) and reduces subsequent androgen-induced AR nuclear translocation and AR target gene transcription. Matsubara, N., Mukai, H., Hosono, A. et al. Cancer Chemother Pharmacol (2017) 80: 1063 .

Certain terminology.

The terms used in this document have their generally accepted meaning, but for the avoidance of doubt, certain definitions are provided herein.

As used herein, the term cancer refers to the abnormal growth of cells that are prone to uncontrolled proliferation and, in some cases, metastasis (spread).

As used herein, the term prostate cancer refers to histologically or cytologically confirmed adenocarcinoma of the prostate.

The term androgen deprivation therapy (ADT) refers to the reduction of androgen levels in a patient with prostate cancer to post-castration testosterone levels (<50 ng/dL). Such treatments may include orchiectomy or the use of gonadotropin-releasing hormone agonists or antagonists. ADT therapy involves surgical castration (orchiectomy) and/or giving the person luteinizing hormone releasing hormone (LRF)/gonadotropin releasing hormone (GnRH) agonists or antagonists. Examples of a GnRH agonist or antagonist are or include leuprolide, buserelin, napherelin, histrelin, goserelin, deslorelin, degarelix, osarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109, or triptorelin. In certain embodiments, examples of GnRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin palmoate.

The term locally advanced prostate cancer refers to prostate cancer in which all active cancer cells are likely confined to the prostate gland and its associated organs or adjacent organs (eg, seminal vesicle, bladder neck, and rectal wall).

The term localized high-risk prostate cancer refers to locally advanced prostate cancer that is likely to develop metastases or recur after initial curative therapy. In some embodiments, high risk of developing metastases is defined as a prostate-specific antigen doubling time (PSADT) of <20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, < 12 months or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months or <1 month. In some embodiments, high risk of developing metastases is defined as a prostate-specific antigen doubling time (PSADT) of <10 months. In some embodiments

- 9 046078 a high risk of developing metastases is defined as a high Gleason score or a massive tumor.

For the avoidance of doubt, the terms castration-sensitive prostate cancer and hormone-sensitive prostate cancer are equivalent and are used interchangeably.

The terms castration-sensitive prostate cancer and hormone-sensitive prostate cancer refer to cancers that are sensitive to androgen deprivation therapy (ADT) in the form of localized disease, biochemical recurrence, or metastatic disease.

The terms metastatic castration-sensitive prostate cancer and metastatic hormone-sensitive prostate cancer refer to cancer that has spread (metastasized) to other areas of the body, such as the bones, lymph nodes, or other parts of the body in a man, and that is sensitive to androgen deprivation therapy (ADT). ).

The term non-metastatic castration-sensitive prostate cancer refers to cancer that has not spread (metastasized) in a male person and that is sensitive to androgen deprivation therapy (ADT). In some embodiments, non-metastatic castration-resistant prostate cancer is assessed using skeletal bone scans and computed tomography (CT) or magnetic resonance imaging (MRI) scans. [0089] As used herein, the term CRPC refers to castration-resistant prostate cancer. CPRC is prostate cancer that continues to grow despite the suppression of male hormones that stimulate the growth of prostate cancer cells.

The term metastatic castration-resistant prostate cancer refers to castration-resistant prostate cancer that has metastasized to other parts of a person's body.

Metastatic castration-sensitive prostate cancer (CSPC) refers to prostate cancer that continues to respond to testosterone suppression therapy.

The term NM-CRPC as used herein refers to non-metastatic castration-resistant prostate cancer. In some embodiments, NMCRPC is assessed using skeletal bone scans and computed tomography (CT) or magnetic resonance imaging (MRI) scans.

The term metastatic castration-resistant prostate cancer, chemotherapy-naïve, refers to metastatic castration-resistant prostate cancer that has not previously been treated with a chemotherapy agent.

The term metastatic castration-resistant prostate cancer after treatment with abiraterone acetate in combination with prednisolone refers to metastatic castration-resistant prostate cancer that has already been treated with abiraterone acetate.

The term high-risk NM-CRPC refers to the likelihood of a man with NM-CRPC developing metastases. In some embodiments, high risk of developing metastases is defined as a prostate-specific antigen doubling time (PSADT) of <20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, < 12 months or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months or <1 month. In some embodiments, high risk of developing metastases is defined as a prostate-specific antigen doubling time (PSADT) of <10 months. In some embodiments, a high risk of developing metastases is defined as the presence of locoregional recurrence (eg, primary tumor bed, bladder neck, anastomotic site, pelvic lymph nodes).

The terms co-administration or the like as used herein include the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same route or by different routes of administration or at the same or different times. .

The term pharmaceutical combination as used herein means a preparation obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term fixed combination means that the active ingredients, eg, apalutamide and the co-administered agent, are administered to the patient at the same time in a single dosage unit or dosage unit. The term "unfixed combination" means that the active ingredients, e.g., apalutamide and the coadministered agent, are administered to a patient in separate dosage units or separate dosage forms simultaneously, concurrently, or sequentially without specific time restrictions between administrations, such administration providing safe and effective levels of the two active ingredients in the body of a male person. The latter also applies to mixture therapy, for example the administration of three or more active

- 10 046078 ingredients.

The term FDGT-PET refers to 18F-16P-(|)Top-5adihydrotestosterone positron emission tomography and is a technique that uses a dihydrotestosterone-based radiotracer to visually assess androgen receptor ligand binding in a patient. It can be used to evaluate the pharmacodynamics of androgen receptor-targeted therapies.

The term continuous daily dosing regimen refers to the administration of a specific therapeutic agent without any omissions of the specific therapeutic agent. In some embodiments, a continuous daily dosing regimen of a particular therapeutic agent includes daily administration of the particular therapeutic agent at approximately the same time every day.

The terms treat and treat refer to the treatment of a patient suffering from a pathological condition and refer to an effect that reduces the condition by destroying cancer cells, as well as an effect that results in inhibition of the progression of the condition and includes reducing the rate of progression, stopping the progression, weakening the condition and cure for the condition. This also includes treatment as a preventative measure (ie prophylaxis). Unless otherwise indicated, the terms treat and treat refer to the totality of the described effects, but in other embodiments such terms may also refer to any one of the described effects or solely to at least one effect.

The term metastasis-free survival, or MFS, refers to the percentage of study subjects who survive without cancer spreading for a specified period of time or until death. MFS is usually reported as the time from the start of study enrollment, randomization, or treatment in a study. MFS is presented for an individual patient or study population. In the context of antiandrogen treatment for CRPC, the increase in metastasis-free survival represents the additional time spent free of cancer spread or death, whichever occurs first, compared with placebo treatment. In some embodiments, the increase in metastasis-free survival is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months or more than 20 months. In some embodiments, administration of a safe and effective amount of an antiandrogen provides an increase in metastasis-free survival in a male subject, wherein the increase in metastasis-free survival is optionally measured relative to the average survival rate in a group of male subjects with non-metastatic castration-resistant prostate cancer, wherein said a group of patients were treated with placebo. In some embodiments, metastasis-free survival refers to the period of time from randomization until the first sign of BICR-confirmed bone or soft tissue metastases or until death, whichever occurs first.

The term time to metastasis is the period of time from randomization until the scan demonstrates the first signs of BICR-confirmed radiologically detectable bone or soft tissue metastases. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved antitumor activity as measured by time to metastasis (TTM).

The term radiographic progression-free survival reflects the time from randomization to the first diagnostic imaging documentation of disease progression or death, whichever occurred first. A subject is considered to have radiographic progressive disease if the subject has either a progression of soft tissue lesions on a computed tomography or magnetic resonance imaging scan or a new lesion on a bone scan.

The term progression-free survival is based on RECIST v1.1 and is defined as follows: In subjects with at least one measurable lesion, progressive disease is defined as an increase in the sum of target lesion diameters of at least 20%, using the smallest sum in the study as the reference ( including the amount at baseline if it represents the smallest value in the study). In addition to the relative increase of 20%, the amount must also reflect an absolute increase of at least 5 mm. Moreover, the appearance of one or more new lesions is also considered progression. In subjects with only non-measurable disease seen on CT or MRI scans, progression was defined as clear progression (representing an overall change in disease stage) or the appearance of one or more new lesions. In relation to new foci of bone tissue lesions detected during a skeletal bone scan,

- 11 046078 Imaging by other means (eg CT or MRI) was necessary to confirm progression. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved antitumor activity as measured by progression-free survival rate.

Prostate cancer survival is defined as the time from randomization until death, if attributable to prostate cancer.

The term PFS2 refers to the time from initial study randomization to 2 disease progression or death from any cause.

The term time to symptom progression is defined as the time from randomization to the recording of any of the following (whichever occurs first) on the Individual Recording Record (IRR): (1) occurrence of a skeletal-related event (SRE): pathological fracture, spinal compression brain or the need for surgery or radiation therapy to the bone; (2) progression of pain or worsening of disease-related symptoms requiring initiation of new systemic anticancer therapy; or (3) development of clinically significant symptoms due to locoregional tumor progression requiring surgery or radiation therapy. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved antitumor activity as measured by time to symptom progression.

The term time to pain progression is defined as the time from randomization to pain progression (mean increase of 2 points from baseline on the Brief Pain Inventory-Short Form [BPI-SF] of the greatest pain intensity observed on two consecutive assessments separated by >3 weeks, with a mean worst pain score >4 in patients who did not taper their opioid dose or initiate chronic opioid use, whichever occurs first). The BPI-SF most severe pain (item 3) is used to determine the time to end point of pain progression. Scores range from 0 to 10, with lower scores representing lower levels of pain intensity; the minimum significant difference was a change of 2.

The term time to skeletal-related event (SRE) is defined as the time from the date of randomization to the date of first observation of the SRE (symptomatic pathological fracture, spinal cord compression, bone radiotherapy, or bone surgery).

The term time to chronic opioid use is defined as the time from the date of randomization to the first date of documented chronic opioid use. Chronic opioid use was defined as use of opioid analgesics for >3 weeks for oral formulations or >7 days for non-oral formulations. For patients who were already receiving opioids at the time of study enrollment, chronic opioid use was defined as a >30% increase in the total daily dose of opioid analgesics for >3 weeks for oral formulations or >7 days for non-oral formulations. Administration of opioid analgesics as needed (eg, without a fixed or prescribed dosage schedule) or chronic use of opioids for forms of treatment other than the patient's prostate cancer did not require discontinuation of study treatment.

The term time to progression of local symptoms is defined as the time from the date of randomization to the date of progression of local symptoms, whichever occurs first. Examples of progression of local symptoms include, but are not limited to, urethral obstruction or bladder outlet obstruction.

The term time to ECOG PS grade worsening is defined as the time from the date of randomization to the first date of ECOG PS grade worsening (defined as a worsening of ECOG PS grade by at least 1 point).

Overall survival is defined as the time from randomization to death from any cause. Survival data for subjects who were alive at the time of analysis had to be censored at the last known date on which the subjects were alive. In addition, for subjects for whom survival information was missing after study entry, data had to be censored at the date of randomization; for subjects who did not return for follow-up or who withdrew their consent, data were censored at the last known date the subjects were alive. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved antitumor activity as measured by overall survival.

The term time to cytotoxic chemotherapy is defined as the time from randomization to documentation of a new cytotoxic chemotherapy.

Term progression-free survival with first subsequent therapy (PFS2)

- 12 046078 is defined as the period of time from randomization until the investigator's assessment of disease progression (PSA, radiographic assessment, symptomatic assessment, or any combination thereof) during the first subsequent anticancer therapy or until death (from any cause) before the start of the second subsequent anticancer therapy, depending from what happens first.

The term time to PSA progression is defined as the time from the date of randomization to the date of PSA progression based on the Prostate Cancer Working Group 2 criteria. Scher HI, et al. J Clin Oncol 2008;26:1148-1159.

The term time to second progression-free survival is defined as the time from the date of randomization until the first occurrence of investigator-defined disease progression (PSA progression, diagnostic imaging progression, or clinical progression) while the patient received the first subsequent therapy for prostate cancer, or until death according to for any reason, whichever comes first.

Progression data for subjects without documented progression after subsequent therapy are censored at the last date of progression-free or date of death. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved antitumor activity as measured by progression-free survival rate with first subsequent therapy.

Prostate-specific antigen response and time to PSA progression are assessed at the time of the initial MFS analysis according to Prostate Cancer Working Group (PCWG2) criteria. Time to PSA progression is calculated as the time from randomization to meeting PCWG2 criteria for PSA progression.

The term placebo as used herein means the administration of a pharmaceutical composition that does not include a second generation antiandrogen. In the context of treatment of metastatic castration-sensitive prostate cancer, male subjects treated with an antiandrogen or placebo should continue to maintain castrate testosterone levels either by coadministration of a GnRH agonist/antagonist or by orchiectomy.

The term survival benefit as used herein means an increase in a patient's survival from the time of randomization in the study of the administered drug until 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 more than 100 months.

The term arrest of symptoms associated with disease progression as used herein means an increase in the time to onset of symptoms such as pain, urinary tract obstruction, and an improvement in quality of life from the time of randomization in the study of the administered drug.

The term randomization in relation to a clinical trial refers to the point at which a patient is deemed eligible to participate in a clinical trial and is assigned to a treatment group.

The terms kit and finished product are used interchangeably.

The terms subject and patient and person are used interchangeably.

Methods of administration and pharmaceutical compositions.

The therapeutic agents described herein are administered by any suitable route or in any suitable formulation. Acceptable routes of administration of therapeutic agents include, but are not limited to, oral and parenteral (eg, intravenous, subcutaneous, intramuscular). All formulations are in dosage forms suitable for administration to humans. A summary of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference to such description.

Safety studies also look for and identify any potential unwanted effects that may be caused by the drug. Efficacy is often measured by determining whether an active pharmaceutical ingredient provides a treatment effect compared to a placebo or other intervention when tested in an appropriate setting, such as a tightly controlled clinical trial.

Unless otherwise specified, as used herein, the terms effective amount or therapeutically effective amount refer to the amount of antiandrogen administered that treats the underlying disease or condition, including stopping or slowing

- 13 046078 progression of the disease or condition.

As used herein, the term acceptable in relation to a formulation, composition or ingredient means that the beneficial effect of such formulation, composition or ingredient on the general health of a male subject receiving treatment substantially outweighs its harmful effects to the maximum extent possible.

In some embodiments, the antiandrogen is a solid dosage form for oral administration. In some embodiments, the antiandrogen is formulated in an oral dosage form, an oral dosage unit, or a solid dosage form (eg, a capsule, tablet, or pill). In some embodiments, for example, the antiandrogen is formulated as a tablet. In some embodiments, the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro -N-methylbenzamide. In some embodiments, the antiandrogen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide. In some embodiments, the antiandrogen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]-2-fluoro- N-methylbenzamide. In some embodiments, the antiandrogen is N{^)-1-[3-(3-chloro-4-cyanophenyl)-III-pyrazol-1-yl]propan-2-yl}-5-(1hydroxyethyl)-III- pyrazole-3-carboxamide. The compositions may also contain two or more of these materials in combinations. Solid oral dosage forms containing the antiandrogen may be provided in the form of soft gelatin capsules, as described in applications WO2014113260 and CN104857157, each of which is incorporated herein by reference, or in tablet form, as described in applications WO2016090098, WO2016090101, WO2016090105 and WO2014043208, each of which is incorporated herein by reference. Methods suitable for preparing solid oral dosage forms of the present invention are described in Remington's Pharmaceutical Sciences, 18th edition, edited by AR. Gennaro, 1990, chapter 89, and in Remington - Science and Practice of Pharmacy, 21st edition, 2005, chapter 45.

In certain embodiments, the antiandrogen is present in a solid dosage unit form and in a solid dosage unit form suitable for oral administration. A unit dosage form may contain about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220 or 240 mg of antiandrogen per unit dosage form or an amount within a range of two of these values.

To prepare the pharmaceutical compositions of the present invention, the active pharmaceutical ingredient is thoroughly mixed with a pharmaceutical carrier in accordance with standard pharmaceutical mixing techniques, and the carrier can take many different forms depending on the form of preparation required for the route of administration (eg, oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

In solid formulations for oral administration, such as, for example, dry powders for reconstitution or inhalation, granules, capsules, caplets, gelatin capsules, pills and tablets (each of which includes immediate-release, delayed-release and sustained-release formulations), acceptable carriers and additives include, but are not limited to, diluents, granulating agents, lubricants, binders, lubricants, disintegrating agents, and the like. Due to their ease of administration, tablets and capsules are the oral dosage unit form with the greatest advantages, in which case they obviously use solid pharmaceutical carriers. If necessary, tablets can be sugar-coated, gelatin-coated, film-coated or enteric-coated using standard techniques.

Preferably, these compositions are in unit dosage forms such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered-dose aerosol or liquid sprays, drops or suppositories for oral, intranasal, sublingual, intraocular , transdermal, rectal, vaginal administration and administration by inhalation or dry powder insufflation.

These formulations are prepared using traditional formulation techniques. To prepare solid pharmaceutical compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example conventional tabletting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, release agents and flow control agents. Acceptable diluents include, but are not limited to, starch (i.e., corn, wheat, or potato starch that can be hydrolyzed), lactose (granulated, spray-dried, or anhydrous), sucrose, sucrose-based diluents (confectioners' sugar; sucrose plus about 7 -10 wt.% invert

- 14 046078 sugar; sucrose plus about 3 wt.% modified dextrins; sucrose plus invert sugar, about 4 wt.% invert sugar, about 0.1-0.2 wt.% corn starch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (for example, AVICEL microcrystalline cellulose manufactured by FMC Corp. .), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate, etc. Suitable binders and adhesives include, but are not limited to, gum arabic, guar gum, gum tragacanth, sucrose, gelatin, glucose, starch, and cellulose derivatives (eg, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, etc.), dispersible or water-soluble binders (for example, alginic acid and its salts, magnesium aluminum silicate, hydroxyethylcellulose [for example, TYLOSE from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch), etc. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), cellulose derivatives (such as cross-linked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (for example, corn starch, etc.), gums (for example, agar, guar, locust bean, karaya, pectin and tragacanth gums), cross-linked polyvinylpyrrolidone, etc. Suitable lubricants and release agents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc, waxes, stearowet, boric acid, sodium chloride, DL-leucine, Carbowax 4000, Carbowax 6000, sodium oleate , sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, etc. Suitable flow control agents include, but are not limited to, talc, corn starch, silica (i.e., CAB-O-SIL silica from Cabot, SYLOID silica from W.R. Grace/Davison, and AEROSIL silica from Degussa), and the like. Sweeteners and flavoring agents may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. In addition, solid dosage forms may be colored or coated to facilitate drug identification or for aesthetic purposes. These carriers are used in admixture with the active pharmaceutical ingredient to precisely provide the appropriate dose of the active pharmaceutical ingredient and drug release profile.

An aspect of the invention is a solid dispersion containing an antiandrogen. There are various techniques for preparing the solid dispersions of the invention, including melt extrusion (eg, hot melt extrusion), spray drying and solution evaporation, in particular hot melt extrusion and spray drying, with spray drying being preferred. An aspect of the invention is a particle consisting of a solid dispersion described herein. In an aspect of the invention, the particles described herein can be obtained, in particular they are obtained by spray drying a mixture containing essentially an antiandrogen, and in particular ARN-509 and HPMCAS, in a suitable solvent. In an aspect, the particles can be produced, in particular produced, by melt extrusion.

HPMCAS, or hydroxypropyl methylcellulose acetate succinate, or hypromellose acetate succinate (CAS No. 71138-97-1), is a mixture of esters of acetic acid and monosuccinic acid with hydroxypropyl methylcellulose (IUPAC name: cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate ). Various grades are available and are differentiated based on the degree/ratio of substitution (acetyl content, succinoyl content) and particle size (micronized and granular). In an aspect of the invention, the HPMCAS dispersion with ARN-509 is HPMCAS LG (granular) or HPMCAS LF (micronized) (Shin-Etsu Chemical Co., Ltd), in particular HPMCAS LG.

Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starches, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose), polyvinyl-1-pyrrolidone, and the same. mixtures.

Examples of excipients suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof.

The binder or excipient in pharmaceutical compositions is typically present in an amount of from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Disintegrants can be used in compositions to produce tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate during storage, while tablets that contain too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Thus, for education

- 15 046078 solid dosage forms for oral administration, a sufficient amount of disintegrant should be used which is neither too much nor too little and therefore does not adversely affect the release of the active ingredients. The amount of disintegrant used depends on the type of composition and is well known to those skilled in the art. Typical pharmaceutical compositions contain from about 0.5 to about 15 wt.% disintegrant, in particular from about 1 to about 5 wt.% disintegrant. Disintegrants that may be used in the pharmaceutical compositions provided herein include, without limitation, croscarmellose sodium, crospovidone, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate , talc, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl ureate, agar, and mixtures thereof. Lubricants are generally used in amounts of less than about 1% by weight of the pharmaceutical compositions or dosage forms in which they are included.

Compressed tablet formulations may optionally be film-coated to provide color, light protection and/or taste masking. Tablets may also be coated to modulate the onset and/or rate of release in the gastrointestinal tract to optimize or maximize the biological effect of the API on the patient.

Formulations such as hard capsules can be formed by filling the mixture or granulate of apalutamide or enzalutamide into shells consisting of, for example, gelatin or hypromellose.

Formulations such as soft gelatin capsules can be formed.

Pharmaceutical compositions intended for oral administration can be prepared from the solid dispersions and mixed materials described above in accordance with the methods described herein and other methods known in the art for preparing pharmaceutical compositions. Such compositions may further contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colors and preservatives to provide pharmaceutically acceptable and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients may be, for example, inert diluents, granulating and disintegrating agents, binding agents, glidants, lubricants and antioxidants, for example propyl gallate, butylated hydroxyanisole and butylated hydroxytoluene. Tablets may be uncoated, or may be film-coated to alter their appearance, or may be functionally coated to retard disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period of time.

Compositions for oral administration may also be presented in the form of capsules (eg, hard gelatin) in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or starch, or in the form of soft gelatin capsules in which the active ingredient is mixed with liquids or semi-liquids such as peanut oil, paraffin oil, fractionated glycerides, surfactants or olive oil. Aqueous suspensions contain the active substances in mixture with excipients suitable for preparing aqueous suspensions. Dispersible powders and granules, suitable for preparing an aqueous suspension by the addition of water, provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. In certain embodiments of the invention, the pharmaceutical compositions of the invention include a diluent system, a disintegrant, a salt, a lubricant, a glidant, and a film coating in concentrations of about 3 wt.% to about 58 wt.%, from about 4 wt.% to about 20 wt. %, from about 4 wt.% to about 20 wt.%, from about 0.5 wt.% to about 4 wt.%, from about 0 wt.% to about 2 wt.% and from about 1 wt.% to about 5 wt.%, respectively, or from about 18 wt.% to about 40 wt.%, from about 7 wt.% to about 15 wt.%, from about 7 wt.% to about 18 wt.%, from about l, 0 wt% to about 3.0 wt%, about 0.1 wt% to about 1.0 wt%, and about 2.0 wt% to about 4.0 wt%, respectively. In certain embodiments, the solid dispersions are mixed with a diluent, one or more disintegration agents, lubricants, and glidants. An example of a mixed composition or oral dosage form includes mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

- 16 046078

The disintegrant may be present in a concentration of from about 4 wt.% to about 20 wt.% or from about 7 wt.% to about 15 wt.%. In addition, a salt may be present, which may be sodium chloride, potassium chloride, or a combination thereof. The combination of salts and disintegrant is present in a concentration of from about 5 wt.% to about 35 wt.% of the final pharmaceutical composition.

In certain embodiments, the inactive tablet core ingredients are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. In other embodiments, the tablets are processed by applying a film coating consisting of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

In other embodiments, a unit dosage form of the pharmaceutical composition contains or consists of or essentially consists of about 60 mg of apalutamide. In some embodiments, a human is administered multiple doses of a single dosage form of a pharmaceutical composition containing, consisting of, or substantially consisting of about 60 mg of apalutamide, such as 4 multiple or single dosage forms. The total daily dose of apalutamide may be approximately 240 mg per day.

In some embodiments, the unit dosage form of the pharmaceutical composition contains, consists of, or essentially consists of about 40 mg of enzalutamide. In some embodiments, a human is administered multiple doses of a single dosage form of a pharmaceutical composition comprising, consisting of, or substantially consisting of about 40 mg of enzalutamide, such as 4 multiple or single dosage forms. The total daily dose of enzalutamide can be approximately 160 mg per day.

In additional other embodiments, the unit dosage form of the pharmaceutical composition contains, consists of, or essentially consists of about 300 mg of darolutamide. In some embodiments, a human is administered multiple doses of a single dosage form of a pharmaceutical composition comprising, consisting of, or substantially consisting of about 300 mg of darolutamide, such as 2 multiple or single dosage forms. The total daily dose of darolutamide may be about 600 mg twice daily. The total daily dose of darolutamide can be approximately 1200 mg per day.

All formulations for oral administration are in dosage forms suitable for such administration.

Dosage methods and treatment regimens.

In one aspect, described herein are methods of treating metastatic castration-sensitive prostate cancer in a male human, comprising, comprising, or substantially comprising administering a therapeutically effective amount of an antiandrogen to a male human with metastatic castration-sensitive prostate cancer, wherein the antiandrogen is at least one of the following: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]2-fluoro -N-methylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or No. {^)-1-[3-(3-chloro-4-cyanophenyl)-III-pyrazol-1yl]propan-2-yl}-5-(1-hydroxyethyl)-III-pyrazol-3-carboxamide. In the following description, methods of treating metastatic castration-sensitive prostate cancer may in an alternative embodiment be referred to as methods of treating a male subject suffering from metastatic castration-sensitive prostate cancer. For the sake of brevity, each possible alternative is not analyzed, but each is treated separately as if it were fully described.

Also described herein are methods of treating metastatic castration-sensitive prostate cancer comprising or substantially providing a therapeutically effective amount of an antiandrogen to a male subject with metastatic castration-sensitive prostate cancer, wherein the antiandrogen is one or more of the following: 4-[7-( 6-cyano-5-trifluoromethylpyridinetrifluoromethylpyridin-3-yl)-8-oxo6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, 4-(3-(4- cyano-3-(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl )phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or N-{(2S)-1-[3-(3chloro- 4-cyanophenyl)-III-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-III-pyrazol-3-carboxamide.

In another aspect described herein, administration of an antiandrogen provides an increase in the overall survival of a male subject relative to the overall survival of a comparative group of male subjects with metastatic castration-sensitive prostate cancer, wherein the comparative group was administered placebo in combination with

- 17 046078 androgen deprivation therapy, wherein said placebo was administered before or during the administration of the antiandrogen. In other embodiments, the comparison group received no treatment. In another aspect described herein, administration of an antiandrogen provides an increase in the overall survival of a male subject relative to the overall survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, which comparison group was receiving androgen deprivation therapy. In certain embodiments, administration of the antiandrogen provides an increase in the overall survival of a male subject relative to the overall survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, wherein the comparison group did not receive any treatment. In certain embodiments, administration of an antiandrogen provides an increase in overall survival of a male subject relative to the overall survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, wherein the comparison group was administered a first generation antiandrogen with or without androgen deprivation therapy. In some embodiments, the antiandrogen-administered group and the comparison group have previously been treated with the same or similar prior treatment regimen.

In additional embodiments, administration of an antiandrogen provides an increase in progression-free survival in a male subject relative to progression-free survival in a comparison group of male subjects with metastatic castration-sensitive prostate cancer, wherein the comparison group was administered placebo in combination with androgen deprivation therapy. In another aspect described herein, administration of an antiandrogen provides an increase in progression-free survival of a male subject relative to progression-free survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, the comparison group having previously received androgen deprivation therapy. In certain embodiments, administration of an antiandrogen provides an increase in progression-free survival of a male subject relative to progression-free survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, which comparison group has not previously received any treatment. In certain embodiments, administration of an antiandrogen provides an increase in progression-free survival of a male subject relative to progression-free survival of a comparison group of male subjects with metastatic castration-sensitive prostate cancer, which comparison group had previously been administered a first generation antiandrogen in combination with androgen deprivation therapy, or without her. Again, in preferred embodiments, the antiandrogen-administered group and the comparison group were previously treated according to the same or similar prior treatment regimen.

In one aspect, methods of treating metastatic castration-sensitive prostate cancer are described herein, comprising, comprising, or substantially providing for the administration of a therapeutically effective amount of an antiandrogen to a male subject with metastatic castration-sensitive prostate cancer, wherein the antiandrogen is administered orally. In some embodiments, the antiandrogen is administered daily. In some embodiments, the antiandrogen is administered twice daily. In some embodiments, the antiandrogen is administered three times daily. In some embodiments, the antiandrogen is administered four times daily. In some embodiments, the antiandrogen is administered every other day. In some embodiments, the antiandrogen is administered once per week. In some embodiments, the antiandrogen is administered twice per week. In some embodiments, the antiandrogen is administered every other week. In some embodiments, the antiandrogen is administered orally in a continuous daily dosing regimen.

In one embodiment, the desired dose is conveniently presented as a single dose or divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as two, three, four or more portions per day. In some embodiments, the antiandrogen is conveniently presented in divided doses that are administered simultaneously (or over a short period of time) once daily. In some embodiments, the antiandrogen is conveniently presented in divided doses that are administered in equal parts twice daily. In some embodiments, the antiandrogen is conveniently presented in divided doses that are administered in equal parts three times daily. In some embodiments, the antiandrogen is conveniently presented in divided doses that are administered in equal parts four times daily.

In certain embodiments, the required dose may be delivered as 1, 2, 3, 4, 5, 6,

- 18 046078

7, 8, 9 or 10 divided unit doses throughout the day so that the total amount of antiandrogens delivered in divided unit doses throughout the day provides the total daily doses.

In additional embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide is administered to a male human daily. In additional embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide is administered orally to a male subject. In some embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide is administered orally to a male subject in a continuous daily dosing regimen.

In further embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolin-1-yl)-2-fluoro-N-methylbenzamide is administered to a male subject daily. In other further embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolin-1-yl)-2-fluoro-N-methylbenzamide is orally administered to a human male. In some embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2thioxoimidazolin-1-yl)-2-fluoro-N-methylbenzamide is orally administered to a human male floor on a continuous daily dosing schedule.

In additional embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide administered to a male human daily. In other additional embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H β-methylbenzamide is administered orally to a male human. In some embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide administered orally to a male subject on a continuous daily dosing schedule.

In further embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1yl]propan-2-yl}-5-(1-hydroxyethyl)-N-pyrazole -3-carboxamide is administered to a male human daily. In other additional embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1Hpyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-III- pyrazole-3-carboxamide is administered orally to a male subject. In some embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol1-yl]propan-2-yl}-5-(1-hydroxyethyl)-N-pyrazole -3-carboxamide is administered orally to a male subject on a continuous daily dosing schedule.

In some embodiments, the antiandrogen is a second generation antiandrogen. In certain embodiments, the antiandrogen is enzalutamide, apalutamide, RD-162, or darolutamide. In some embodiments, the antiandrogen is apalutamide. In some embodiments, the antiandrogen is enzalutamide. In some embodiments, the antiandrogen is RD-162. In some embodiments, the antiandrogen is darolutamide.

In general, antiandrogen doses used to treat the diseases or conditions described herein in humans are typically in the range of 10 mg to 1000 mg per day. In some embodiments, the antiandrogen is administered orally to a human at a dose of from about 30 mg per day to about 1200 mg per day. In some embodiments, the antiandrogen is administered orally to a human at a dose of from about 30 mg per day to about 600 mg per day. In some embodiments, the antiandrogen is administered orally to a human at a dose of about 30 mg per day, about 60 mg per day, about 90 mg per day, about 120 mg per day, about 160 mg per day, about 180 mg per day, about 240 mg per day day, about 300 mg per day, about 390 mg per day, about 480 mg per day, about 600 mg per day, about 780 mg per day, about 960 mg per day or about 1200 mg per day.

In certain embodiments, doses of the antiandrogen used to treat the diseases or conditions described herein in humans may range from 30 to 40 mg/day, 40 to 50 mg/day, 50 to 60 mg/day, 60 to 70 mg/day, 70 to 80 mg/day, 80 to 90 mg/day, 90 to 100 mg/day, 100 to 120 mg/day, 120 to 140 mg/day, 140 up to 160 mg/day, from 160 to 180 mg/day, from 180 to 200 mg/day, from 200 to 220 mg/day, from 220 to 240 mg/day, from 240 to 260 mg/day, from 260 to 280 mg/day, 280 to 300 mg/day, 300 to 320 mg/day, 320 to 340 mg/day, 340 to 360 mg/day, 360 to 380 mg/day, 380 to 400 mg/day day, 400 to 420 mg/day, 420 to 440 mg/day, 440 to 460 mg/day, 460 to 480 mg/day, or any range defined by two or more of these ranges, or any single value , lying in these ranges.

In some embodiments, doses of the antiandrogen used to treat the diseases or conditions described herein in humans may range from 0.3 to 0.4 mg/kg/day, 0.4 to 0.5 mg/kg /day, from 0.5 to 0.6 mg/kg/day, from 0.6 to 0.7 mg/kg/day, from 0.7 to 0.8 mg/kg/day, from 0.8 to 0.9 mg/kg/day, 0.9 to 1 mg/kg/day, 1 to 1.2 mg/kg/day, 1.2 to

1.4 mg/kg/day, 1.4 to 1.6 mg/kg/day, 1.6 to 1.8 mg/kg/day, 1.8 to 2 mg/kg/day, 2 to

2.2 mg/kg/day, 2.2 to 2.4 mg/kg/day, 2.4 to 2.6 mg/kg/day, 2.6 to 2.8 mg/kg/day , from 2.8 to

3.0 mg/kg/day, 3.0 to 3.2 mg/kg/day, 3.2 to 3.4 mg/kg/day, 3.4 to 3.6 mg/kg/day , from 3.6 to

3.8 mg/kg/day, 3.8 to 4.0 mg/kg/day, 4.0 to 4.2 mg/kg/day, 4.2 to 4.4 mg/kg/day , from 4.4 to

- 19 046078

4.6 mg/kg/day, 4.6 to 4.8 mg/kg/day, or any range defined by two or more of these ranges, or any single value within those ranges.

In additional embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide is administered orally to a male human at a dose of about 30 mg per day to about 480 mg per day. In other additional embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5yl]-2-fluoro-H β-methylbenzamide is administered orally to a male human at a dose of about 180 mg per day to about 480 mg per day. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro- N-methylbenzamide is administered orally to a male human in the following doses: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In some embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro- Nmethylbenzamide is administered orally to a male human at a dose of about 240 mg per day.

In some embodiments, the dosage of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H -methylbenzamide is reduced to 180 mg per day if a male subject experiences grade 3 or higher toxicity. In an alternative or additional embodiment, the initial dose can be maintained until symptoms of a toxic reaction reach a toxic reaction level of grade 1 or less; subsequently, the dosage may be reduced as noted herein, or the original dosage may be resumed with close monitoring. In some embodiments, the dosage of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoroN -methylbenzamide is reduced to 180 mg per day if an intolerable side effect is observed in a male person. In some embodiments, a dose of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H -methylbenzamide is reduced to 120 mg per day if a male subject suffers from toxicity equal to grade 3 or greater. In an alternative or additional embodiment, the initial dose can be maintained until symptoms of a toxic reaction reach a toxic reaction level of grade 1 or less; subsequently, the dosage may be reduced as noted herein, or the original dosage may be resumed with close monitoring. In some embodiments, a dose of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro -N-methylbenzamide is reduced to 120 mg per day if an intolerable side effect is observed in a male person.

In some embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo2-thioxoimidazolin-1-yl)-2-fluoro-N-methylbenzamide is administered orally at a dose of about 160 mg per day. In some embodiments, more than 160 mg of enzalutamide is administered per day.

In some embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide administered orally to a male human at a dose of about 30 mg per day to about 480 mg per day. In other additional embodiments, 44-[7-[4cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide is administered orally to a male human at a dose of about 180 mg per day to about 480 mg per day. In certain embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide administered orally to a male subject in the following doses: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In some embodiments, 44-[7-[4-cyano-3(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- Methylbenzamide is administered orally to a male human at a dose of about 240 mg per day.

In some embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-nurazol-1-yl]nropan2-yl}-5-(1-hydroxyethyl)-N-pyrazole -3-carboxamide is administered orally to a male human at a dose of about 1200 mg per day. In some embodiments, more than 1200 mg of N-{(2S)-1-[3-(3chloro-4-cyanophenyl)-N-pyrazol-1-yl]propan-2-yl}-5-(1- hydroxyethyl)-III-pyrazole-3-carboxamide.

In certain embodiments, in which there is no positive trend in the disease or condition in a person, the daily dose of the antiandrogen is increased. In some embodiments, the once daily dosing regimen is changed to a twice daily dosing regimen. In some embodiments, a three times daily dosing regimen is used to increase the amount of antiandrogen administered.

In some embodiments, the amount of antiandrogen that is administered to a person varies depending on factors such as, without limitation, the condition and severity of the disease or condition and characteristics (eg, weight) of the person, as well as the specific additional therapeutic agents administered (if applicable).

In some embodiments, the male subject has received at least one prior therapy for treating cancer, wherein the prior therapy for treating cancer is radiation, surgery, or docetaxel therapy. In some

- 20 046078 embodiments, the male subject has not previously received any treatment.

In some embodiments, the antiandrogen is administered in combination with androgen deprivation therapy. In additional embodiments, the antiandrogen is administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist. In other additional embodiments, the at least one GnRH agonist or antagonist is or contains leuprolide, buserelin, napherelin, histrelin, goserelin, deslorelin, degarelix, osarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100 , KLH-2109 or triptorelin.

Doctors may prescribe GnRH agonists according to instructions, guidelines, and practice. In some embodiments, the gonadotropin releasing hormone agonist or antagonist is leuprolide. In some embodiments, leuprolide is administered as a depot injection at a dose of about 7.5 mg every 4 weeks, or 22.5 mg every 3 months, or about 30 mg every 4 months, or about 45 mg every 6 months. In some embodiments, leuprolide is administered in an amount of 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. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is buserelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is napherelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is histrelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is histrelin acetate. In some embodiments, the hysterelin acetate is administered in an amount of about 50 mg of histrelin acetate over a 12-month period of histrelin acetate dosing, or about 50 μg of histrelin acetate per day. In some embodiments, the GnRH agonist or antagonist is goserelin. In some embodiments, goserelin is administered as a subcutaneous implant at a dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 weeks. In some embodiments, goserelin is administered in an amount of from about 0.01 mg to about 20 mg of goserelin over a period of about 28 days to about 3 months, preferably from about 3.6 mg to about 10.8 mg of goserelin over a period of about 28 days up to about 3 months. In some embodiments, the GnRH agonist or antagonist is deslorelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is degarelix. In some embodiments, degarelix is administered as a subcutaneous injection at a dose of about 240 mg, followed by about 80 mg every 4 weeks. In some embodiments, the GnRH agonist or antagonist is osarelix. In some embodiments, the GnRH agonist or antagonist is osarelix. In some embodiments, the GnRH agonist or antagonist is ABT-620 (elagolix). In some embodiments, the GnRH agonist or antagonist is TAK-385 (relugolix). In some embodiments, the GnRH agonist or antagonist is EP-100. In some embodiments, the GnRH agonist or antagonist is KLH-2109. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is triptorelin. In some embodiments, triptorelin is administered in an amount of from about 0.01 mg to about 20 mg triptorelin over a period of about 1 month, preferably about 3.75 mg triptorelin over a period of about 1 month.

In certain embodiments, the antiandrogen is administered in combination with bilateral orchiectomy. In certain embodiments, the antiandrogen is administered following bilateral orchiectomy.

In other additional embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro- N-methylbenzamide should not be administered concomitantly with: (a) a medicinal product that is an active inhibitor of CYP2C8 or CYP3A4; (b) a drug that is primarily metabolized by CYP3A4, CYP2C19 or CYP2C9; (c) a drug that is a UDP-glucuronosyltransferase (UGT) substrate; or (d) a drug that is a substrate of P-glycoprotein, BCRP or OATP1B1. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- Methylbenzamide is not administered in combination with a drug that is an active inhibitor of CYP2C8 or CYP3A4. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- Methylbenzamide is not administered in combination with a drug that is primarily metabolized by CYP3A4, CYP2C19, or CYP2C9. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide is not administered in combination with a drug that is a UDP-glucuronosyltransferase (UGT) substrate; or (d) a drug that is a substrate of P-glycoprotein, BCRP or OATP1B1.

- 21 046078

A non-limiting example of active CYP2C8 inhibitors is gemfibrozil.

Non-limiting examples of strong CYP3A4 inhibitors include boceprevir, aprepitant, clarithromycin, conivaptan, grapefruit juice, indinavir, lopinavir, itraconazole, mibefradil, ketoconazole, nefazodone, ritonavir, posaconazole, nelfinavir, saquinavir, conivaptan, telaprevir, boceprevir, telithromycin, Clari thromycin, voriconazole, clotrimazole , diltiazem, erythromycin, fluconazole, verapamil and troleandomycin.

Non-limiting examples of moderate to strong CYP3A4 inducers include avasimib, St. John's wort, carbamazepine, efavirenz, phenytoin, etravirine, bosentan, nafcillin, rifampin, modafinil, rifabutin and barbiturates.

A non-limiting example of a drug that is primarily metabolized by CYP3A4 is midazolam. A non-limiting example of a drug that is primarily metabolized by CYP2C19 is omeprazole. A non-limiting example of a drug that is primarily metabolized by CYP2C9 is S-warfarin.

A non-limiting example of a drug that is a P-glycoprotein substrate is fexofenadine.

A non-limiting example of a drug that is a BCRP substrate is rosuvastatin.

A non-limiting example of a drug that is a substrate of OATP1B1 is rosuvastatin.

In another aspect, provided herein are methods of treating metastatic castration-sensitive prostate cancer in a male human, comprising, comprising, or comprising: (a) determining the presence of metastatic castration-sensitive prostate cancer in a male human; and (b) administering an antiandrogen to a male human subject in a therapeutically effective amount for the treatment of metastatic castration-sensitive prostate cancer, wherein the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-Nmethylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8oxo-6-thioxo-5,7-diazaspiro[3.4 ]oct-5-yl]-2-fluoro-N-methylbenzamide or N-{(2S)-1-|3-(3-x.top-4cyanophenyl)-III-pyrazol-1-yl]propan-2- yl}-5-(1-hydroxyethyl)-III-pyrazol-3-carboxamide.

Methods of treatment using an approved drug.

Also provided herein are methods of treating metastatic castration-sensitive prostate cancer in a human male, comprising administering an approved drug product containing apalutamide to a male human with metastatic castration-sensitive prostate cancer in an amount as specified in the information accompanying the drug product. In some embodiments, the authorized drug product containing apalutamide is an abbreviated marketing authorization application (ANDA) drug product, an additional marketing authorization application (ANDA) drug product, or a 505(b)(2) drug product. In certain embodiments, the method is clinically proven safe and/or effective. In certain embodiments, the method is clinically proven to be safe. In certain embodiments, the method is clinically proven effective.

The term drug product or approved drug product refers to a drug that contains an active pharmaceutical ingredient that has been approved for marketing by at least one regulatory authority, such as the US Food and Drug Administration (FDA) or similar authority in other countries.

Similarly, the term drug package information refers to information provided to the patient that provides important information about the drug. Such information includes, without limitation, one or more of the drug description, clinical pharmacology, indications (uses of the drug), contraindications (who should not take the drug), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and geriatric patients, route of drug delivery, patient safety information, or any combination thereof. In certain embodiments, the information accompanying the drug product includes instructions for use in a patient with metastatic castration-sensitive prostate cancer. In additional embodiments, the implementation included with

- 22 046078 drug information identifies apalutamide as a chemical compound approved by regulatory authorities. In other embodiments, the information provided with the drug product contains data on superior efficacy for improving radiographic progression-free survival or overall survival compared with placebo. In other additional embodiments, the information provided with the drug product includes instructions for the patient or physician to administer apalutamide if the patient has metastatic castration-sensitive prostate cancer.

The term reference listed drug (RLD) refers to the drug to which new synonyms (generic forms) of the drug are compared to demonstrate their bioequivalence. See 21 CFR 314.3(b)). It also denotes a medicinal product that has already received marketing authorization in one of the Member States of the European Union or from the Commission based on the examination of the prepared dossier, i.e. with the provision of quality data, preclinical and clinical trial results in accordance with Chapters 8(3), 10a, 10b or 10c of Directive 2001/83/EC, and to which the application for marketing authorization for a synonym/hybrid medicinal product refers by demonstrating bioequivalence, usually by submitting the results of an appropriate bioavailability study.

In the US, a company seeking marketing authorization for a synonymous product is required to list the RLD in its Abbreviated New Drug Application (ANDA). For example, an ANDA applicant relies on an FDA finding that a previously approved drug, such as an RLD, is safe and effective and is required to demonstrate, among other things, that the proposed synonym drug is in some way similar to the comparator RLD. More 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 forms , dosage and (with certain acceptable differences) labeling as the comparator RLD. An RLD is a scheduled drug for which the ANDA applicant must demonstrate similarity in terms of active ingredient(s), dosage forms, routes of administration, dosage, labeling and conditions of use, among other characteristics. In the electronic version of the List of registered medicinal products with therapeutic equivalence assessments, there is a column for RLD and a column for reference drugs. In the printed version of the List of registered medicinal products with therapeutic equivalence assessments, RLDs and reference drugs are indicated with special symbols. For an ANDA based on an approved petition of compliance (ANDA with petition), the scheduled comparator is essentially the scheduled drug to which the comparison is made in the approved petition of compliance.

A reference drug is a drug product selected by the FDA that the ANDA applicant must use to conduct the in vivo bioequivalence study required for approval. The FDA essentially selects one reference drug that ANDA applicants must use for in vivo bioequivalence studies. Typically, the FDA will select a listed comparator drug as the reference drug. However, in some cases (for example, if a scheduled comparator drug is withdrawn from the market and the FDA determines that it has not been withdrawn for reasons of safety or effectiveness and the FDA selects an ANDA as the reference drug), the scheduled comparator drug and the reference drug may be different.

The FDA selects comparator drugs from the lists of prescription drugs, over-the-counter drugs, and discontinued drugs. Scheduled medicinal products selected as comparator scheduled medicinal products are those medicinal products on which the applicant may rely when submitting an ANDA. The FDA plans to periodically update the comparator drug listings prescribed under the Prescription Drug, Over-the-Counter, and Discontinued Drug Lists.

The FDA also selects reference drugs from the prescription drug and over-the-counter drug lists. Scheduled drugs selected as reference drugs represent the most appropriate comparator drug at that time, in FDA's opinion, to conduct any in vivo bioequivalence studies required for approval.

In some cases where the FDA has not designated a scheduled drug as a comparator drug, the scheduled drug may be protected from generic competition. If the FDA has not designated a comparator for the drug that the applicant intends to duplicate, the potential applicant may request the FDA to designate a comparator for that drug.

The FDA may, in its sole discretion, select a new reference drug when it

- 23 046078 will help facilitate the submission and evaluation of generic drug applications, for example where the scheduled drug currently selected as the reference drug has been withdrawn from the market for reasons other than safety and effectiveness.

In Europe, applicants indicate in the application form for a synonym/hybrid drug product, which is similar to the drug product under ANDA or supplementary NDA (sNDA), a reference medicinal product (name of drug, dosage, pharmaceutical form, marketing authorization holder for the drug, date of first issue marketing authorization, Member State/EU), which is synonymous with RLD, in the following form.

1. A medicinal product which is or has been authorized in the EEA, used as the basis for demonstrating that the data protection period defined in the European Pharmaceutical Legislation has expired. The reference medicinal product used to determine the expiration of the data protection period may have a different dosage, pharmaceutical form, route of administration or release form than the synonym/hybrid medicinal product.

2. A medicinal product, the dossier of which is cross-referenced in the application for a synonym/hybrid medicinal product (name of the drug, dosage, pharmaceutical form, holder of the registration certificate for the drug, registration number). This reference medicinal product may have received registration under independent procedures and under a different name than the reference medicinal product indicated for determining the expiration of the data protection period. The drug information for a given reference medicinal product will, in principle, serve as the basis for the drug information claimed for the synonym/hybrid product.

3. The medicinal product (name of drug, strength, pharmaceutical form, marketing authorization holder for the drug, Member State of origin of the drug) used in the bioequivalence study(s) (if applicable).

The various shortcuts to drug approval under the Food, Drug, and Cosmetic Act (FD&C) include the shortcuts described in section 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 23 355(b)(2), respectively).

In accordance with FDA guidance (https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM579 751.pdf), the contents of which are incorporated herein by reference, registration applications (NDAs) and abbreviated registration applications (ANDA) can be divided into the following four categories:

(1) A standalone NDA is an application filed pursuant to section 505(b)(1) and approved pursuant to section 505(c) of the FD&C Act that contains complete reports of safety and effectiveness studies that have been conducted by the applicant or on his behalf, or to which the applicant has the right to refer or which he has the right to use.

(2) A 505(b)(2) application is an NDA filed pursuant to section 505(b)(1) and approved pursuant to section 505(c) of the FD&C Act that contains complete reports of safety and effectiveness studies. , but in which at least some of the information required for the claim is derived from research that was not conducted by or on behalf of the applicant and to which the applicant has not obtained the right to refer to or use.

(3) An ANDA is an application to duplicate a previously approved drug product that has been submitted and approved pursuant to section 505(j) of the FD&C Act. The ANDA is based on the FDA's finding that a previously approved drug, i.e. reference listed drug (RLD), is safe and effective. The ANDA must substantially contain information showing that the proposed generic drug^) is similar to the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, dosage and labeling (with certain acceptable differences), and ( b) is bioequivalent to RLD. An ANDA cannot be submitted if studies are required to establish the safety and effectiveness of the proposed drug.

(4) A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD with respect to dosage form, routes of administration, dosage, or active ingredient (in a product with multiple active ingredients), and for which FDA has determined, in response to the petition, filed pursuant to section 505(j)(2)(C) of the FD&C Act (petition for compliance) that studies are not required to establish the safety and effectiveness of the proposed drug product.

The scientific premise underlying the Hatch-Waxman amendments is that a drug product approved under an ANDA under section 505(j) of the FD&C Act is considered therapeutically equivalent to its RLD. Drugs classified as therapeutically equivalent may be replaced with full confidence that the replaced drug will be

- 24 046078 provide a similar clinical efficacy and safety profile as the prescribed drug when administered to patients under the conditions specified on the package insert. Unlike an ANDA, a 505(b)(2) application has more flexibility regarding the characteristics of the proposed drug. A drug product receiving approval under a 505(b)(2) application does not necessarily need to be evaluated as therapeutically equivalent to the scheduled drug product to which it is being compared at the time of approval.

The term therapeutically equivalent to a listed comparator means that the drug is a generic equivalent, i.e. pharmaceutical equivalent of the listed comparator drug, and is thus assessed by the FDA to be therapeutically equivalent to the AB listed comparator drug, and actual or potential bioequivalence issues have been resolved by sufficient in vivo and/or in vitro evidence to support bioequivalence.

Pharmaceutical equivalents are medicinal products in identical dosage forms and with identical route(s) of administration that contain identical amounts of the identical active ingredient of the medicinal product compared to the listed comparator drug.

The FDA classifies as therapeutically equivalent those drugs that meet the following general criteria: (1) they are approved as safe and effective; (2) they are pharmaceutical equivalents in the sense that (a) they contain identical quantities of the same active drug ingredient in a similar dosage form and route of administration, and (b) they comply with pharmacopoeial or other applicable dosage standards, quality, purity and identity; (3) they are bioequivalent in the sense that (a) they have no known or potential problems associated with bioequivalence and meet an acceptable in vitro standard, or (b) if they have such a known or potential problem, they are shown to meet the applicable bioequivalence standard; (4) they are properly labeled; and (5) they are obtained in accordance with applicable principles of good manufacturing practice.

The term bioequivalent or bioequivalence means that there is no significant difference in the rate and extent of the active ingredient or active functional group in pharmaceutical equivalents or pharmaceutical alternatives at the site of action of the drug when administered at the same molar dose under similar conditions in an appropriately designed study. Section 505(j)(8)(B) of the FD&C Act describes one set of conditions under which the investigational drug and the reference drug must be considered bioequivalent: the rate and extent of absorption of the [investigational] drug are not significantly different from the rate and extent of absorption of the [reference drug]. ] a medicinal product when administered single or multiple times in the same molar dose of the therapeutic ingredient under similar experimental conditions; or the extent of absorption of the [test] medicinal product is not significantly different from the extent of absorption of the [reference] medicinal product when administered single or multiple times at the same molar dose of the therapeutic ingredient under similar experimental conditions, and differs from the [reference] medicinal product with respect to the rate of absorption of the medicinal product is intentional, is reflected on the proposed package insert, does not affect the achievement of effective concentrations of the drug in the body during chronic use, and is considered not to be medically significant for the drug.

If the above methods are not applicable (for example, for drugs that are not intended to be absorbed into the bloodstream), other evidence-based in vivo or in vitro testing methods to demonstrate bioequivalence may be appropriate.

For example, bioequivalence in some cases may be demonstrated using an in vitro bioequivalence standard, especially when such an in vitro test correlates with human bioavailability data obtained in vivo. In other situations, bioequivalence can sometimes be demonstrated through comparative clinical studies or pharmacodynamic studies.

Also provided herein are pharmaceutical products containing a clinically proven safe and clinically proven effective amount of apalutamide, wherein the pharmaceutical product is contained in a package, and wherein the package includes information accompanying the drug product that (a) apalutamide is identified as a regulatory approved chemical entity organs, and (b) provides instructions for the use of apalutamide in the treatment of metastatic castration-sensitive prostate cancer. In certain embodiments, the information provided with the drug product contains data on improved radiographic progression-free survival or overall survival compared with placebo. In certain embodiments, the information provided with the drug product lists the adverse reactions as

- 25 046078 ischemic cardiovascular events, fractures, falls and seizures. In certain embodiments, the information provided with the drug product includes data indicating an increase in the incidence of ischemic cardiovascular events, fractures, falls, or seizures compared to standard clinical practice. In certain embodiments, standard clinical practice is to administer androgen deprivation therapy.

As used herein, unless otherwise specified, the term safe means the absence of undesirable side effects (such as toxicity, irritation or allergic reaction), consistent with an acceptable benefit/risk ratio when used in the method of the present invention. Likewise, unless otherwise indicated, the term effective means that the treatment has been demonstrated to be effective in treating patients with metastatic castration-sensitive prostate cancer when administered at a therapeutically effective dose. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In additional embodiments, the methods described herein are safe and effective. In some other embodiments, a therapeutically effective amount of apalutamide is safe. In other further embodiments, a therapeutically effective amount of apalutamide is effective. In other embodiments, a therapeutically effective amount of apalutamide is safe and effective.

As used herein, unless otherwise noted, the term clinically proven (used independently or in addition to the terms safe and/or effective) means that such confirmation has been demonstrated by a phase III or IV clinical trial sufficient to meet FDA approval standards. food and drug control or similar examination for entry into the EMEA market. To clinically confirm the effects of apalutamide, a randomized, placebo-controlled, double-blind study of adequate size is preferably used. To clinically confirm the effects of apalutamide for the treatment of metastatic castration-sensitive prostate cancer, a randomized, placebo-controlled, double-blind study of apalutamide with androgen deprivation therapy versus androgen deprivation therapy, assessing patient status by radiographic progression-free survival or overall survival, would be preferable. survivability. For example, confirmation may be obtained from the clinical trial described in Example 1.

As used herein, unless otherwise stated, the term clinically proven effective means that the effectiveness of the treatment has been demonstrated to be statistically significant in a phase III or IV clinical trial, i.e. the results of the clinical study are unlikely to have been obtained by chance with a significance level of less than 0.05, or the clinical efficacy results are sufficient to meet the standards for approval by the US Food and Drug Administration or a similar study for marketing authorization in the EMEA. For example, apalutamide has been clinically demonstrated to be effective in the treatment of patients with metastatic castration-sensitive prostate cancer when administered orally at a therapeutically effective dose of 240 mg and when administered concomitantly with androgen deprivation therapy to improve radiographic progression-free survival and overall survival compared with patients receiving placebo along with androgen deprivation therapy, and as specifically presented in the examples.

In the context of this document, unless otherwise noted, the term clinically proven safe means that the safety of the treatment has been demonstrated in a phase III or IV clinical trial through analysis of study data and results to establish that the treatment is free of unwanted side effects and corresponds to statistically significant clinical significance. benefits (e.g., effectiveness) sufficient to meet US Food and Drug Administration approval standards or similar studies for market authorization in Europe, the Middle East and Africa (EMEA). For example, apalutamide has been clinically demonstrated to be safe for the treatment of patients with metastatic castration-sensitive prostate cancer when administered orally at a therapeutically effective dose of 240 mg and when administered concomitantly with androgen deprivation therapy, and as particularly presented in the Examples.

Sales methods.

Proposed herein are methods of marketing an authorized drug product containing apalutamide, wherein said method includes, involves, or substantially involves the sale of such drug product, wherein the information accompanying the comparator product listing for such drug product includes instructions for

- 26 046078 treatment of metastatic castration-sensitive prostate cancer. In certain embodiments, the drug product is a drug product with an ANDA, a drug product with a supplemental marketing authorization application, or a 505(b)(2) drug product.

The terms sell or sell refer to the transfer of a drug product, such as a pharmaceutical composition or oral dosage form, from a seller to a buyer.

Further provided herein are methods for marketing an authorized drug product containing apalutamide, wherein said method includes, provides for, or substantially provides for the process for marketing such drug product, wherein the information accompanying the comparator listing for such drug product includes instructions for the treatment of metastatic castration-sensitive prostate cancer. In certain embodiments, the drug product is a drug product with an ANDA, a drug product with a supplemental marketing authorization application, or a 505(b)(2) drug product.

The term offering for sale means an offer for sale of a drug product, such as a pharmaceutical composition or oral dosage form, from a seller to a buyer.

In another aspect, described herein are methods of marketing apalutamide, wherein said method comprises, involves, and/or substantially involves commercializing apalutamide, wherein said apalutamide includes a label that contains instructions for the safe and effective treatment of metastatic castration-sensitive prostate cancer glands using apalutamide.

In a number of additional aspects, described herein are methods of marketing apalutamide, wherein said method includes, involves, or substantially involves presenting apalutamide for commercialization, wherein said apalutamide includes a label that contains instructions for the safe and effective treatment of metastatic castration-disease. sensitive prostate cancer using apalutamide.

Examples

These examples are presented for illustrative purposes only and do not limit the scope of the claims presented herein.

Example 1: Randomized, placebo-controlled, double-blind, phase 3 study of apalutamide in combination with androgen deprivation therapy (ADT) versus ADT for the treatment of subjects with metastatic hormone-sensitive prostate cancer (mCSPC).

Goals.

The main objective.

To determine whether the addition of apalutamide to androgen deprivation therapy (ADT) provides greater efficacy in improving radiographic progression-free survival (rPFS) or overall survival (OS) for subjects with mCSPC.

Secondary goals.

To evaluate clinically meaningful improvements with the addition of apalutamide to ADT, including delayed progression in prostate cancer pain and opioid use, skeletal-related events, and requirement for cytotoxic chemotherapy.

To determine the safety of adding apalutamide to ADT for subjects with mCSPC.

Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of apalutamide for the cohort.

To assess leuprolide concentrations and assess the effect of leuprolide PD on testosterone concentrations when used as monotherapy or in combination with apalutamide.

To evaluate treatment efficacy when adding apalutamide to ADT for subgroups of subjects with mCSPC at low volume versus high volume.

Other goals.

To evaluate exploratory biomarkers predicting treatment response and resistance.

Assess meaningful patient outcomes, including symptoms (ie, pain, fatigue, urination) and function (ie, physical, emotional, social), and health-related quality of life.

To evaluate improvements in other clinically relevant endpoints for apalutamide with ADT compared with ADT alone.

Collect medical resource utilization (MRU) data that can be used in future economic modeling.

Research plan.

The study described in Example 1 has been at least partially completed in accordance with the criteria described herein and is ongoing. It represented

- 27 046078 randomized, double-blind, placebo-controlled, international, multicenter, phase 3 study designed to identify possible benefits for subjects with mCSPC when adding apalutamide to ADT. The data in this document are provided in connection with the subject research and reflect the status of the subject research at the time of filing this application. The study was conducted at 260 centers in 23 countries. The Institutional Review Boards of all participating institutions approved the study, which was conducted in accordance with current International Conference on Harmonization guidelines for good clinical practice and in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent. The sponsor engaged an independent data monitoring committee to monitor safety and efficacy prior to disclosure and recommendations for the study. Staff transferred data at each site from source documents to sponsor-prepared electronic individual record cards. Randomization codes were masked to investigators, patients, study site personnel, and the sponsor's study team until completion of the study, recommendations of the independent data monitoring committee, or medical necessity for a particular patient.

Approximately 1000 subjects were planned for this study. Subjects who met all inclusion criteria and none of the exclusion criteria were stratified by Gleason score at diagnosis (<7 or >7), region (North America [NA] and European Union [EU] or other countries), and prior use of docetaxel (Yes or no).

In addition to continuous ADT, patients were randomized 1:1 to receive apalutamide (240 mg) or matching placebo administered orally once daily. Patients were stratified by Gleason score at diagnosis (<7 or >7), region (North America and European Union or other countries), and prior docetaxel therapy (yes or no). To confirm eligibility for study participation, a screening phase was performed up to 28 days before randomization. Subjects will receive/receive treatment in 28-day cycles during the treatment phase until disease progression, or the occurrence of a treatment-related unacceptable toxicity, or the sponsor causes the study to be discontinued. If the subject is/has radiographic progression without clinical progression and alternative therapy is not/has not been started, treatment may be continued until clinical progression is observed; subjects must discontinue study drug upon documented clinical progression based on the criteria specified in the protocol. Upon discontinuation of study drug, subjects will be invited to an end-of-treatment visit within 30 days of the last dose of study drug. During the follow-up phase, data collection (every 4 months) will include survival, additional data on secondary endpoints, date and form of disease progression (radiographic data, PSA, clinical indicators, or a combination of these) for first subsequent prostate cancer therapy and subsequent therapy prostate cancer. Follow-up data collection will continue until the subject's death, consent is withdrawn, follow-up is unavailable, or the study is terminated by the sponsor. Scores on the Brief Pain Inventory - Abbreviated (BPI SF), Brief Fatigue Questionnaire (BFI), and EQ-5D-5L Patient Reported Outcome (PRO) questionnaire will continue to be collected during the follow-up phase up to 12 months. after stopping treatment. If the study is positive at both the interim analyzes and the endline analysis, all subjects in the treatment phase will have the opportunity to participate in an open-label extension phase, allowing subjects to receive the active drug (apalutamide) for approximately 3 years.

Subjects were/will be monitored for safety from the time of signing the informed consent until 30 days after the last dose of study drug. Adverse events (AEs), including laboratory AEs, will be classified and summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE); version 4.03). Dose adjustments will be/were made in accordance with the dose adjustment rules described in the protocol.

A diagram of the study plan is shown in Fig. 1.

Study population.

Each potential subject met all of the following criteria for inclusion in the study:

Review of patient eligibility criteria.

- 28 046078

Eligible patients must have a documented diagnosis of prostate adenocarcinoma and disease with distant metastases documented by >1 lesion on bone scan, with or without visceral or lymph node extension. All patients had an Eastern Cooperative Oncology Group performance status (5-point scale, with higher scores indicating greater disability) of 0 or 1. Patients were castration sensitive (i.e., patients who did not receive ADT during progression) . Previous treatment for prostate cancer was limited to prior docetaxel therapy (maximum of six cycles, with no evidence of progression during treatment or before randomization), ADT for <6 months for metastatic castration-sensitive prostate cancer, or a total duration of <3 years for localized prostate cancer , one course of radiation or surgery for symptoms associated with metastatic disease, and other localized treatments (eg, radiation therapy, prostatectomy) completed >1 year before randomization. Patients receiving a gonadotropin-releasing hormone agonist <28 days before randomization were required to receive a first-generation antiandrogen (eg, biclutamide, flutamide, or nilutamide) for >14 days before randomization. The antiandrogen should have been discontinued before randomization. Patients with severe angina pectoris, myocardial infarction, congestive heart failure, arterial/venous thromboembolic events, a history of or predisposition to seizures, or recent ventricular arrhythmias were excluded from the study.

Inclusion criteria.

The subject must be a male person >18 years of age (or of legal age to consent in the jurisdiction where the study is being conducted).

Diagnosis of prostate adenocarcinoma confirmed by the investigator.

Disease with distant metastases documented by >1 bone lesion(s) on a technetium-99m (99mTc) bone scan, with or without extension to visceral tissue or lymph node. In subjects with a single bone lesion, bone metastasis should be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI).

All patients had an Eastern Cooperative Oncology Group (ECOG) PS grade of 0 or 1.

Androgen deprivation therapy (ie, medical or surgical castration) should be started >14 days before randomization. Subjects starting a GnRH agonist <28 days before randomization are required to take a first-generation antiandrogen for >14 days before randomization. The antiandrogen should be discontinued before randomization.

Subjects were castration sensitive, and subjects who received docetaxel treatment must meet the following criteria:

a. Received a maximum of 6 cycles of docetaxel therapy for mCSPC.

b. Received the last dose of docetaxel <2 months before randomization.

c. Investigator-assessed diagnostic imaging and pre-randomization PSA maintained response to docetaxel to stable disease or better.

Able to swallow study drug tablets whole.

To avoid drug exposure through ejaculate (even in post-vasectomized male subjects), subjects should use a condom during sexual activity while taking study drug and for 3 months after the last dose of study drug. Sperm donation is not permitted while you are taking the study drug and for 3 months after the last dose of the study drug.

Each subject must sign an informed consent form (ICF) indicating that they understand the purposes and procedures required for the study and are voluntarily participating in the study. The subject must be willing and able to comply with the prohibitions and restrictions specified in this protocol.

Other approved forms of prior treatment for mCSPC:

a. Maximum of 1 course of radiation therapy or surgery for metastatic disease and other localized forms of treatment completed >1 year before randomization; Radiation therapy for metastatic lesions should be completed before randomization.

b. <6 months of ADT therapy before randomization for mCSPC or <3 years total duration for localized prostate.

Allowed prior forms of treatment for localized prostate cancer (all forms of treatment must have been completed >1 year before randomization).

- 29 046078

A. Total <3 years ADT.

b. All other forms of prior therapy, including radiation therapy, prostatectomy, lymph node dissection, and forms of systemic therapy.

Exclusion criteria.

Any potential subject who met any one of the following criteria was excluded from participation in the study.

Pathologic observations consistent with small cell, ductal, or neuroendocrine carcinoma of the prostate.

Established brain metastases.

Lymph nodes as the only localization of metastases.

Visceral (i.e. liver or lung) metastases as the only location of metastases.

Any previous malignancy (exceptions: appropriately treated basal or squamous cell skin cancer, superficial bladder cancer, or any other in situ cancer currently in complete remission) <5 years before randomization.

Clinical laboratory parameters during the screening phase:

a. hemoglobin <9.0 g/dl;

b. neutrophils <1.5*109/l;

With. platelets <100*109/l;

d. total bilirubin >1.5 x upper limit of normal (ULN) [Note: in subjects with Gilbert's syndrome, if total bilirubin is >1.5 x ULN, measure direct or free bilirubin, and if direct bilirubin is <1.5 x ULN, the subject may be considered eligible];

e. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x ULN;

f. serum creatinine >2.0 x ULN;

g. serum albumin <3.0 g/dL.

Previous treatment with other next-generation antiandrogens (eg, enzalutamide), CYP17 inhibitors (eg, abiraterone acetate), immunotherapy (eg, sipuleucel-T), radiopharmaceutical agents, or other forms of treatment for prostate cancer other than those listed in the inclusion criteria.

Initiation of bisphosphonate or denosumab treatment for bone metastases <28 days before randomization.

Medicines known to lower the seizure threshold should be discontinued or changed >28 days before randomization.

Administration of other investigational therapeutic agents, blood product support, growth factor support, or an invasive surgical procedure (other than surgical castration) <28 days before randomization or enrollment in an ongoing pilot study.

Ongoing or previous therapy with antiepileptic drugs for the treatment of seizures. History of seizures or conditions that may predispose to seizures (including, but not limited to, previous cerebrovascular accident, transient ischemic attack, or loss of consciousness within 1 year before randomization; cerebral arteriovenous malformation; or intracranial neoplasms such as schwannoma or meningioma causing swelling or mass impact).

Existing data on any of the following:

a. Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant arterial or venous thromboembolic events (eg, pulmonary embolism), or clinically significant ventricular arrhythmias <6 months before randomization.

b. Gastrointestinal disorders affecting absorption.

c. Active infection requiring systemic therapy, such as that associated with human immunodeficiency virus (HIV).

d. Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding due to liver dysfunction.

The subject has a known allergy, hypersensitivity, or intolerance to apalutamide or its excipients.

Any condition or situation that, in the opinion of the investigator, would prevent participation in this study.

Prescription of treatment.

Stratification and randomization procedures.

Subjects were stratified by Gleason score at diagnosis (<7 or >7), region (North America [NA] and European Union [EU] or other countries), and prior docetaxel use (yes or no). Subjects were randomly assigned to the active group or control group in a 1:1 ratio. Randomization was balanced by using random

- 30 046078 permutations of blocks. The Interactive Web Reporting System (IWRS) assigned a unique treatment code that identified treatment assignment and the corresponding set of study drugs for the subject. The requester used its own user identification number and personal identification number when contacting IWRS and subsequently provided relevant subject information to uniquely identify the subject.

Dose and route of administration.

Administration of apalutamide.

Apalutamide was administered continuously, but for planning study assessments and treatment compliance, the treatment cycle was set to 28 days. Subjects were randomly assigned in a 1:1 ratio to receive either apalutamide or a matching placebo:

apalutamide 240 mg (4 tablets x 60 mg); taken orally once a day, regardless of food intake, or placebo (4 tablets); taken orally once a day, regardless of food intake.

If a dose of apalutamide (or placebo) was missed, it was omitted and not made up or taken with the next dose the next day.

Introduction to ADT.

All subjects who did not undergo surgical castration received ADT and remained on a constant ADT regimen. The choice of GnRHa (agonist or antagonist) was at the discretion of the investigator. Dosing (dose and frequency of administration) was carried out in accordance with the prescribing information for the drug.

Control of toxic reactions and allergic rashes.

Table 1 summarizes apalutamide/placebo dose changes for drug-related toxicities. Dosage adjustments may also be made for drug-related allergic rash. After a dose reduction due to a drug-related toxic reaction, a repeat dose increase was discussed with the sponsor.

Table 1

Apalutamide/placebo dose adjustments

Heaviness Number of apalutamide/placebo tablets 1st or 2nd degree No change or save until return to original level >3rd degree Maintain to grade 1 or baseline, resume at full dose Recurrence >3rd degree Maintain to grade 1 or baseline. 2 dose reductions are allowed for recurrent treatment-related toxicity (180 mg [3 tablets]) and 120 mg [2 tablets]). Discontinue if toxicity persists after 2 dose reductions. First appearance of seizures of any grade or grade 4 neurotoxicity Stop Note. Adverse events are classified according to NCI-CTCAE version 4.03

If any signs of desquamation, mucosal lesions, or pustules are present with the skin rash, discontinue the apalutamide/placebo dose, the subject is/will be referred to a dermatologist for evaluation, and a skin biopsy is recommended (in addition to dose changes). For grade 3 skin rashes or higher, the subject may be asked to consent to documentation by photographic evidence followed by evaluation by a dermatologist.

Previous and concomitant therapy.

Permitted maintenance forms of therapy.

The use of maintenance medications is allowed in accordance with the recommendations adopted in the institution. The following forms of maintenance therapy are allowed during the study:

For pain relief, periodic short courses of opioid analgesics are allowed.

Surgeries and procedures such as transurethral resection of the prostate (TURP) and placement of ureteral stents to treat complications caused by local progression.

Bisphosphonates and denosumab for the treatment of bone metastases should be used in accordance with their approved marketing information provided with the medicinal product. Subjects must receive a constant dose of such medications for >28 days prior to randomization or agree not to initiate such therapy until radiographic progression is documented. The use of bisphosphonates and

- 31 046078 denosumab in doses for the prevention of osteoporosis.

Traditional multivitamins, selenium and soy dietary supplements.

Blood transfusion and hematopoietic growth factors in accordance with institutional practice guidelines (note that blood product support and growth factor support are not permitted <28 days before randomization).

Immune globulin therapy for non-cancer treatment according to institutional practice guidelines.

Not approved forms of concomitant therapy.

Consistent with the class effect, AR antagonists were associated with seizures due to an off-target mechanism of action (gamma-aminobutyric acid [GABAA] chloride channel inhibition). Medicines known to lower the seizure threshold or cause seizures should not be taken, and a representative list of them is given below:

Atypical antipsychotics (eg, clozapine, olanzapine, risperidone, ziprasidone);

bupropion;

lithium;

meperidine (pethidine);

phenothiazine antipsychotic drugs (eg, chlorpromazine, mesoridazine, thioridazine);

tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine);

amino fillin/theo fillin.

Other prohibited forms of therapy include the following:

Investigational agents;

abiraterone acetate or other CYP17 inhibitor;

other hormonal agents for the treatment of prostate cancer;

other antineoplastic agents;

radiation therapy for new painful lesions of metastatic prostate cancer that were absent on diagnostic imaging at baseline;

5-a-reductase inhibitors;

chemotherapy;

immunotherapy or vaccine therapy to treat cancer;

other antiandrogens (eg, bicalutamide, nilutamide, flutamide, cyproterone acetate, enzalutamide).

Bisphosphonates or denosumab for the treatment of bone metastases, unless such therapy was initiated >28 days before randomization and subjects were on a stable dose. The use of a bisphosphonate or denosumab in doses for the prevention of osteoporosis is allowed;

systemic use of ketoconazole (or other azole drugs such as fluconazole or itraconazole);

diethylstilbestrol (DES) or similar drug;

other drugs, such as pomegranates or pomegranate juice, or saw palmetto, which are thought to have endocrine effects on prostate cancer;

radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm), or similar analogues such as radium-223 (223Ra);

spironolactone.

Restrictions on the simultaneous use of drugs.

The most important drug interactions are listed below.

Active inducers of CYP3A4: The potential for drug-drug interactions for apalutamide has not been clinically studied. Active CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort) should be avoided to the maximum extent possible;

apalutamide may also induce CYP3A4; therefore, use cautiously with CYP3A4 substrates with a narrow therapeutic index;

Active CYP2C8 inhibitors (for example, gemfibrozil) should be used concurrently with apalutamide with caution;

During the study, long-term use of systemically administered corticosteroids was not allowed. Short-term use (<4 weeks, including tapering) and topical use of steroids (eg, inhaled, topical, ophthalmic, and intra-articular) are acceptable when clinically indicated.

Performance assessments/outcomes.

- 32 046078

Radiographic progression was/will be assessed by soft tissue damage on computed tomography (CT)/magnetic resonance imaging (MRI) according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or bone progression on scans bone tissue. Survival data were/will be collected throughout the treatment phase and during the follow-up phase.

Ratings.

Efficacy in patients was assessed according to the modified Objective Response Evaluation Criteria in Solid Tumors version 1.1 using computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis at screening (<6 weeks before randomization) and Working Group 2 criteria. prostate cancer based on bone scans during cycles 3 and 5 and every fourth cycle thereafter. Progression events were assessed by the investigator. Scan data from ~60% of patients was randomly selected for independent central assessment. Adverse events were assessed monthly and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.3. FACT-P scores were collected on day 1 of cycles 2–7, every other cycle thereafter, at the time of treatment completion, and every 4 months for up to 1 year after treatment cessation. BPI-SF scores were collected 6 days before cycle 1, every other cycle thereafter, at the time of treatment completion, and every 4 months for up to 1 year after treatment cessation.

More specifically, performance assessments include the following:

tumor measurements (CT or MRI [abdomen, chest and pelvis], 99mTc bone scan). The same diagnostic imaging modalities should be used during all evaluations for an individual subject. Unroutine tumor evaluations and appropriate diagnostic imaging should be considered if signs or symptoms indicate disease progression, including increasing pain from another cause, worsening ECOG PS functional status, or based on physical examination findings consistent with disease progression.

Scan data from approximately 60% of patients was randomly selected for independent central assessment.

Serum PSA assessments (performed in a central laboratory).

A skeletal-related event (SRE) is defined as the occurrence of a symptomatic pathologic fracture, spinal cord compression, bone radiation therapy, or bone surgery.

Progression in pain was defined as a 2-point increase in worst pain intensity from baseline on the BPI-SF (item 3) observed at 2 consecutive assessments >4 weeks apart; for mean worst pain scores >4 in subjects without opioid reduction or initiation of chronic opioid use, whichever occurs first.

Results obtained from patients.

Patient-reported outcomes include the use of a variety of questionnaires, including the Brief Pain Inventory-Short Form (BPI-SF), analgesic use record, Brief Fatigue Inventory (BFI), Functional Assessment of Treatment for Prostate Cancer (FACT-P), and EQ-5 D-5 L (a standardized measure of health status developed by the EuroQoL Group to provide a simple general measure of health status for clinical and economic evaluation (EuroQoL Group, 1990)). Patient outcome questionnaire data were/will be collected throughout the study, as well as during the follow-up phase (up to 12 months after treatment cessation) and during the open-label extension phase.

Tumor response criteria.

Tumor response to treatment was assessed using diagnostic imaging measurements as defined in the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In the present study, RECIST was modified based on the Prostate Cancer Working Group 2 (PCWG2) criteria, which are specific to this patient population. Prostate-specific antigen measurements were assessed according to PCWG2 criteria. The rPFS was assessed by the investigator.

Efficacy for patients in the personalized study was assessed according to the modified Prostate Cancer Working Group 2 Objective Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Working Group 2.2 The following Prostate Cancer Working Group 2 progression criteria were used:

PSA: first increase >25% relative to baseline and >2 ng/ml above the low

- 33 046078 level (confirmed by a second value received after 3 weeks or more).

Soft tissue lesions: in accordance with the criteria for assessing the objective response in solid tumors with reservations.

Diagnostic imaging should, at a minimum, include computed tomography or magnetic resonance imaging scans; centers with appropriate capabilities should use endorectal magnetic resonance imaging or transrectal ultrasound.

Report lymph node changes only if lymph node diameter was >2 cm at baseline.

Record changes in the localization of nodal and visceral soft tissues separately.

Register the complete elimination of the disease in any localization separately.

Confirm favorable change on second scan.

Log changes to the waterfall chart.

Progression at the first assessment should be confirmed by a second scan >6 weeks later.

Bone: appearance of >2 new lesions, and for first reassessment only, confirmatory scan performed >6 weeks indicating at least >2 new lesions.

Final indicators.

Dual primary endpoints.

The dual primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS).

Secondary endpoints.

Secondary outcome measures were time to cytotoxic chemotherapy, time to pain progression assessed by the Brief Pain Inventory-Short Form (BPI-SF; worst pain intensity [item 3] was used as the endpoint for time to pain progression; item range from 0 to 10, with lower scores representing lower pain intensity levels; a change of 2 was a minimally significant difference), time to chronic opioid use, and time to skeletal-related event. Prespecified subgroup analyzes based on patient data were planned with low- or high-volume metastatic castration-sensitive prostate cancer, and evaluation of treatment outcome in these groups was a secondary objective. The definition of high-volume disease was adapted from Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373:737-46 as follows: 1) visceral metastases and >1 bone lesions, or 2) >4 bone lesions, with >1 outside the axial skeleton. Low-volume disease was defined as the presence of bone lesions that did not meet the definition of high-volume disease.

Search outcome measures.

Exploratory endpoints included time to prostate-specific antigen (PSA) progression, second progression-free survival, and time to local symptom progression. Time to second progression-free survival was defined as the time from the date of randomization until the first occurrence of investigator-defined disease progression (PSA progression, diagnostic imaging progression, or clinical progression) while the patient received the first subsequent therapy for prostate cancer, or until death due to any reason, whichever happens first. Patient-reported health-related quality of life outcomes were assessed using the Functional Assessment of Treatment for Prostate Cancer Questionnaire (FACT-P). Raw FACT-P scores range from 0 to 156, with higher scores indicating more favorable health-related quality of life. A minimally significant difference is a change in the FACT-P total score from 6 to 10 points.

Group pharmacokinetic assessments.

Residual samples for PK have been/will be collected. Pre-dose blood samples for analysis of concentrations of apalutamide and active metabolite (JNJ-56142060) were/will be collected on day 1 of cycles 2, 3, 4, 5 and 6.

Additional study of the PK of leuprolide.

Optional PK samples were/will be collected from at least 60 consenting subjects (in sample countries) who were or will be receiving leuprolide acetate as GnRHa at the time of randomization. Samples were/will be collected on day 1 of cycles 1, 3, 4, 5 and 6 for analysis of leuprolide and testosterone concentrations.

- 34 046078

Biomarker assessments.

Plasma circulating DNA levels have been/will be used to assess the presence of the androgen receptor (AR) F876L mutation, and whole blood or plasma DNA to assess other markers that may be associated with apalutamide resistance. Formalin-fixed paraffin-embedded (FFPE) tumor blocks or tumor slides have been/will be collected to assess mRNA expression for AR signaling genes, to compare the biological basis of high- and low-volume disease with outcomes, and to assess the expression of immune markers. such as OX40, GITR and FOXP3.

Safety assessments.

Safety assessments include AEs, vital sign measurements (blood pressure), physical examinations, ECOG PS, and clinical laboratory tests including, but not limited to, complete blood count, complete blood chemistry panel, liver function test, and fasting lipid profile. In case of additional safety monitoring, unscheduled laboratory evaluations have been/will be performed as needed. Vital signs and performance status according to the Eastern Cooperative Oncology Group score were assessed at screening and at each scheduled visit during treatment. Safety was assessed continuously, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.3. FACT-P scores were collected on day 1 of cycles 1 to 7, every other cycle thereafter, at the time of treatment completion, and every 4 months for up to 1 year after treatment cessation.

Electrocardiogram (ECG).

Electrocardiograms (ECG) (12 leads) were recorded at screening.

Vital signs.

During screening, body temperature, heart rate, respiratory rate and blood pressure were recorded. At all other visits, only blood pressure will be measured.

Physical examination.

Physical examinations at screening included, at a minimum, the subject's general appearance, height, weight, skin, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. A limited symptom-driven physical examination and weight assessment were required during the treatment phase and at the end-of-treatment visit.

Eastern Cooperative Oncology Group (ECOG) PS grade.

When scheduled, ECOG PS was assessed before any other procedures scheduled for the same day, as with PRO questionnaires.

Completion/discontinuation of study participation by subject.

End of participation.

A subject will be considered to have completed the study if the subject dies before the end of the study, is not lost to follow-up, or consent is not withdrawn before the end of the study.

Discontinue apalutamide.

If a subject needs to stop taking the study drug before disease progression, this will not automatically remove the subject from the study. If a subject progresses radiographically without clinical progression and alternative therapy is not initiated, treatment may be continued until clinical progression is observed; Every effort should be made to document radiographic progression even in subjects for whom evidence of clinical progression has been obtained.

However, the subject's investigational treatment should be discontinued in the following cases:

Clinical progression is defined as:

Deterioration of ECOG PS grade to 3 or higher (associated with progression of prostate cancer).

It becomes necessary to initiate any of the following due to tumor progression (even in the absence of radiographic evidence of disease).

Subsequent anticancer therapy for metastatic prostate cancer is planned.

Radiation therapy for lesion(s) due to metastatic prostate cancer (palliative irradiation of lesions observed at baseline will not be considered clinical progression).

Surgical interventions for complications due to progression of metastatic prostate cancer.

The need for continuous use of opioid analgesics: for subjects beginning

- 35 046078 Opioid Free Study, Chronic opioid use is defined as administration of opioid analgesics continuing for >3 weeks for oral formulations or >7 days for non-oral formulations. For subjects entering the study who are already taking opioids, chronic opioid use is defined as a >30% increase in the total daily dose of opioid analgesics for >3 weeks for oral formulations or >7 days for non-oral formulations.

More than 2 dose reductions due to treatment-related grade 3 or higher AEs (Table 1).

Seizures of any degree or neurotoxic reaction of the 4th degree.

Subjects for whom treatment assignment information was disclosed for any reason other than IDMC's recommendation to disclose study information.

The investigator believes that for safety reasons (eg, AEs), it is in the subject's best interest to discontinue study treatment.

Every effort should be made to assess radiographic progression at the time of discontinuation of treatment or the end of treatment visit. Study drug was/will be continued for subjects with increasing PSA values in the absence of radiographic progression or clinical progression. Although serial PSA measurements were performed in the present study, progression or change in PSA values was not used as the sole indicator of disease progression or treatment discontinuation. If a subject stops taking the study drug but does not withdraw consent to follow-up, routine assessments should continue according to the follow-up phase of the activity schedule.

Statistical methods.

Review.

The clinical study cited herein as an example was designed to enroll »1000 patients. First, radiographic progression-free survival was examined. If it was statistically significant, the resulting alpha value was used to calculate overall survival by reversion method. The Type I error was assumed to be 5% overall. To achieve at least 85% power to capture a hazard ratio of 0.67 with a two-sided significance level of 0.005, 368 progression-free survival events on diagnostic imaging were required. For the final analysis of overall survival, 410 deaths were required to provide »80% power to record a hazard ratio of 0.75 with a two-sided significance level of 0.045. The overall survival analysis involved sequential group organization with a cost alpha function, which was calculated as Wang-Ziatis power-law bounds with a shape parameter of 0.2. For overall survival, two interim analyzes were planned. The evaluation indicated that the first interim analysis would include »50% of the total required events for overall survival at the time of the primary analysis of radiographic progression-free survival. The alpha level for the interim analysis of overall survival was 0.009, with an overall two-sided significance level of 0.045. Subgroup analyzes were determined a priori to assess the stability of the treatment effect. If the dual primary endpoints were statistically significant, assessment of the secondary endpoints was performed in the following hierarchical order in each case with an overall two-sided significance level of α=0.05: 1) time to cytotoxic chemotherapy, 2) time to pain progression, 3) time to chronic opioid use, 4) time to skeletal-related event. Patient information and baseline characteristics were summarized using descriptive statistics. The primary statistical method for comparing outcome measures by time to event was the stratified log-rank test according to stratification factors. The Kaplan-Meier multiplier estimation method and the Cox proportional hazards model were used to estimate time-to-event variables and determine hazard ratios and associated confidence intervals.

Group analysis.

The primary group analysis uses the intention-to-treat (ITT) arm, which includes all randomized subjects. The ITT group was used to analyze subject allocation and performance. The safety population included all subjects who received at least 1 dose of study drug during treatment.

Determining sample size.

For this study, a Type I error was assumed to be 5% overall. The present study uses the combined primary endpoints of rPFS and OS with a significance level of 0.005 assigned to the rPFS endpoint and 0.045 for OS. A study is considered successful if at least one of the two combined primary endpoints is statistically significant.

- 36 046078

The reversion method was used to restore the alpha level for radiographic progression-free survival to overall survival if radiographic progression-free survival was statistically significant. It is estimated that »50% (205) of the total number of required events for overall survival analysis would have been observed in the primary analysis of radiographic progression-free survival. The alpha level for the interim analysis of overall survival was 0.009, with an overall two-sided significance level of 0.045. Additional subgroup analyzes of patients with high- or low-volume disease in the overall survival analysis were performed without the alpha cost function specified. If the dual primary endpoints of overall survival and radiographic progression-free survival were statistically significant, secondary endpoints were assessed in the following hierarchical order in each case with an overall two-sided significance level of α=0.05: 1) time to initiation of cytotoxic chemotherapy, 2 ) time to pain progression, 3) time to chronic opioid use, 4) time to skeletal-related event. Patient information and baseline characteristics were summarized using descriptive statistics. The Kaplan-Meier multiplier estimation method and the Cox proportional hazards model were used to estimate time-to-event variables and determine hazard ratios and associated confidence intervals. For analyzes without radiographic progression, patients without evidence of radiographic progression or death or patients withdrawn from the study or receiving new subsequent anticancer therapy without documented disease progression were censored at the date of last tumor evaluation, and patients without tumor evaluation after study entry tumors were censored at the date of randomization.

Estimated to provide at least 85% power to detect a hazard ratio (HR) of 0.67 (median rPFS at 20 months in the control group [ADT] versus 30 months in the apalutamide treatment group with ADT), at a two-sided significance level of 0.005, approximately 368 rPFS events were required. The study will also provide sufficient power (approximately 80%) to detect an HR of 0.75 in the composite primary endpoint of OS, assuming a median OS of 44 months for the control group (ADT). To capture an estimated HR at a two-sided significance level of 0.045 with a duration of participation of approximately 30 months (approximately 1000 subjects), approximately 410 deaths would be needed. For 410 deaths, the total study duration would be approximately 54 months.

Efficiency analysis.

The Kaplan-Meier multiplier estimation method and the Cox proportional hazards model will be used to estimate time-to-event variables and determine HRs within their confidence intervals.

Interim analysis.

For the composite primary endpoint of OS, 2 interim analyzes are planned for this study after approximately 60% (~246 events) and approximately 75% (~308 events) of the total required (410) events have been observed. The first interim OS analysis may occur at the same time as the primary rPFS analysis. However, this analysis may be performed at another time if the number of deaths required for a valid interim OS analysis would require a long delay in the analysis of the rPFS endpoint. No interim analysis is planned for the rPFS endpoint.

PK and PD analysis for groups.

Group PK analysis of apalutamide plasma concentration-time data will be performed using nonlinear mixed-effects modeling. If sufficient data are available, the relationship between exposure to apalutamide and the active metabolite (JNJ-56142060) can also be analyzed to evaluate efficacy and AEs.

PK analysis of leuprolide.

Descriptive statistics of PK data for leuprolide will be summarized by treatment group (apalutamide or placebo) and leuprolide acetate dose. Statistical analyzes will be performed to compare leuprolide concentrations when used alone or in combination with apalutamide. The percentage of subjects with testosterone levels <50 ng/dL will be summarized and described by treatment group.

Biomarker analysis.

Associations of biomarkers with clinical response or time-to-event endpoints can be assessed using appropriate statistical techniques (such as analysis of variance [ANOVA], categorical model, or survival model) depending on the endpoint.

- 37 046078

Security analysis.

The safety parameters assessed are the incidence and intensity of treatment-related AEs, clinically significant changes in the subject's physical examination findings, vital sign measurements, and clinical laboratory results. Data regarding study drug exposure and reasons for discontinuation of study treatment will be provided in the table.

Results.

Review.

Five hundred twenty-five (525) patients were randomized to receive apalutamide with ADT and 527 were randomized to receive placebo with ADT. The median age was 68 years; 8% had previously been treated for localized disease; 11% had received prior docetaxel therapy; 63% had high-volume and 37% had low-volume disease. At the first interim analysis, with a median follow-up of 22.7 months, apalutamide significantly increased radiographic progression-free survival (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.39 to 0.60 ; P<0.0001), with a 52% reduction in the risk of radiographic progression or death. Overall survival was also improved with apalutamide, with a 33% reduction in the risk of death (HR, 0.67; 95% CI, 0.51 to 0.89; P=0.0053). The rates of grade 3/4 adverse events were similar for the apalutamide and placebo groups. The independent data monitoring committee recommended disclosure to allow patients receiving placebo to switch to apalutamide. The addition of apalutamide to ADT significantly improved overall survival and radiographic progression-free survival for patients with metastatic castration-sensitive prostate cancer, and the side effect profile was no different from that of the placebo group with ADT.

Patients.

Five hundred twenty-five (525) patients were randomized to receive apalutamide and 527 to placebo (Figure 1). At the time of data cutoff for the first prespecified interim analysis and after 83 and 117 deaths in the apalutamide and placebo groups, respectively, the median follow-up time was 22.7 months. The median number of cycles completed was 23 for apalutamide and 19 for placebo (range, 1 to 37 in each group). The median treatment duration was 20.5 months for apalutamide and 18.3 months for placebo. 66% and 46% of patients in the apalutamide and placebo groups, respectively, remained at the clinical treatment end date. A total of 45 patients in all groups withdrew consent to study treatment. These patients were followed up for survival and secondary endpoints and their data were not excluded. A total of 39 patients were unable to continue follow-up or they withdrew consent for further data collection; this information is not otherwise reflected in FIG. 1.

Patient information and baseline disease characteristics were well balanced (Table 2). Patients had newly diagnosed metastatic castration-sensitive prostate cancer or recurrent metastatic disease after an initial diagnosis of localized disease; the majority had newly diagnosed metastatic disease. Previous forms of therapy for prostate cancer are listed in Table. 3.

Table 2 Patient information and baseline disease characteristics

Apalutamide (n=525) Placebo (n=527) Age, median - year (range) 69 (45-94) 68 (43-90) Age (years) - no. (%) 149 (28.4) 182 (34.5) <65 136 (25.9) 108 (20.5) from 65 to 69 107 (20.4) 124 (23.5) from 70 to 74 133 (25.3) 113 (21.4) >75 Race - number (%) 354 (67.4) 365 (69.3) Caucasians 119 (22.7) 110 (20.9) Asians 10 (1.9) 9 (1.7) Black or African American 6 (1.1) 13 (2.5) American Indians or Aboriginals 11 (2.1) 8 (1.5) Alaska 24 (4.6) 22 (4.2) Not reported 1 (0.2) 0

- 38 046078

Other Combined ECOG PS indicator - no. (%) n=525 n=527 0 328 (62.5) 348 (66.0) 1 197 (37.5) 178 (33.8) 2 0 1 (0.2) Gleason index at initial n=525 n=527 diagnosis - no. (%) 41 (7.8) 39 (7.4) <7 133 (25.3) 130 (24.7) 7 351 (66.9) 358 (67.9) >7 Tumor, lymph node, stage n=525 n=527 metastasis during initial 1 (0.2) 0 diagnosis - no. (%) 41 (7.8) 27 (5.1) T0 146 (27.8) 110 (20.9) T1 210 (40.0) 225 (42.7) T2 76 (14.5) 105 (19.9) T3 51 (9.7) 60 (11.4) T4 212 (40.4) 216 (41.0) TX 199 (37.9) 184 (34.9) N0 114 (21.7) 127 (24.1) N1 85 (16.2) 59 (11.2) NX 411 (78.3) 441 (83.7) M0 29 (5.5) 27 (5.1) M1 MX Disease volume - no. (%) 200 (38.1) 192 (36.4) Low High 325 (61.9) 335 (63.6) Degree of disease at registration 525 (100.0) 527 (100.0) research - no. (%) 289 (55.0) 269 (51.0) Bones 199 (37.9) 219 (41.6) Bone tissue only 56 (10.7) 72 (13.7) Lymph node 47 (9.0) 64 (12.1) Visceral and bone tissues 12 (2.3) 13 (2.5) Lung Liver Soft and bone tissue 22 (4.2) 27 (5.1) Median time from initial diagnosis to randomization (range) - 4.1 (0.5-222.9) 4.0 (0.7-341.4) months Previous therapy with docetaxel - 58 (11.0) 55 (10.4) number (%) Not really 467 (89.0) 472 (89.6) Median number of docetaxel cycles in patients with prior therapy 6 6 docetaxel Previous therapy 94 (17.9) 79 (15.0) localized prostate cancer 26 (5.0) 27 (5.1) glands - no. (%) 47 (9.0) 39 (7.4) Prostatectomy or radiotherapy Prostatectomy only Radiotherapy only Prostatectomy and radiotherapy 21 (4.0) 13 (2.5) Median PSA (range) - µg/L 5.97 (0-2682) 4.02 (0-2229) Median lactate dehydrogenase (LDH) level (range) - units/l 178 (88-1248) 179 (85-1514)

- 39 046078

Median alkaline phosphatase 98 (26-5193) (range) - units/l

Average baseline pain score 198 (37.7)

BPI-SFf - number (%) 195 (37.1) (no pain) 98 (18.7)

1-3 (mild pain) 12 (2.3)

4-7 (moderate pain)

8-10 (severe pain)__________________________________________

Median Baseline Total 113 FACT-PJ Score (32-3892)

200 (38.0)

207 (39.3) 95 (18.0) (2.1)

113

ECOG PS, Eastern Cooperative Oncology Group performance status; FACT-P, Functional Assessment of Treatment for Prostate Cancer; PSA, prostate-specific antigen.

*At diagnosis, 27 patients (46.6%) in the apalutamide group and 22 patients (40.0%) in the placebo group were N1.

{Items range from 0 to 10, with lower scores representing lower levels of pain intensity; the minimum significant difference was a change of 2. ¹ {Scores range from 0 to 156, with higher scores indicating more favorable health-related quality of life. The minimum significant difference is a change in the FACT-P total score from 6 to 10 points.

Previous forms of therapy for prostate cancer are listed in Table. 3.

Table 3

Previous therapy for prostate cancer

Apalutamide (n=525)

Placebo (n=527)

Prostatectomy or radiotherapy - no. (%) 94 (17.9) 79 (15.0) Prostatectomy only 26 (5.0) 27 (5.1) Radiotherapy only 47 (9.0) 39 (7.4) Prostatectomy and radiotherapy 21 (4.0) 13 (2.5) Hormone therapy - no. (%) 525 (100) 527 (100) First generation antiandrogen 352 (67.0) 361 (68.5) Gonadotropin-releasing hormone agonist 462 (88.2) 455 (86.3) Gonadotropin-releasing antagonist hormone 56 (10.7) 53 (10.1) Bilateral orchiectomy 33 (6.3) 40 (7.6) Docetaxel - no. (%) 58 (11.0) 55 (10.4) Vandetanib - no. (%) 1 (0.2) 0

Dual primary endpoints.

Radiographic progression-free survival and overall survival.

There were 365 radiographic progression events observed (134 in the apalutamide group, 231 in the placebo group). The event-free rate at 24 months was 68% in the apalutamide group and 48% in the placebo group. Treatment with apalutamide significantly increased radiographic progression-free survival (HR, 0.48; 95% CI, 0.39 to 0.60; P<0.0001), with a 52% reduction in the risk of radiographic progression or death ( Fig. 2A). At this final analysis, the median radiographic progression-free survival was not reached for apalutamide and 22.1 months for placebo. The effect of apalutamide on radiographic progression-free survival was consistent

- 40 046078 favorable for all subgroups analyzed (Fig. 2B), including prior docetaxel exposure and disease volume. An independent central review further confirmed the investigator's assessment of radiographic progression (agreement rate, 85%).

Treatment with apalutamide significantly increased overall survival (event-free rates at 24 months were 82% and 74% in the apalutamide and placebo groups, respectively; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.51-0. 89; P=0.0053), with a 33% reduction in the risk of death (Fig. 3A). The treatment effect on overall survival was consistently more favorable for apalutamide compared with placebo, and there was no difference in the effect of apalutamide on disease volume (Figure 3B).

Secondary endpoints.

Time to cytotoxic chemotherapy was significantly increased with apalutamide compared with placebo (Table 4, Fig. 4). Time to pain progression was examined based on a preplanned hierarchical test sequence, and because this measure did not reach statistical significance, formal tests for additional secondary endpoints were not performed.

Table 4 ___________Prespecified secondary and exploratory efficacy endpoints___________ P-value, Risk stratified ratio (95% CI) log-rank test

Secondary endpoints a A Apalutamide Placebo

Final indicator , (n=525) (n=527)

Median time to cytotoxic chemotherapy - months. BUT BUT 0.39 0.56) (0.27- <0.0001 Median time to pain progression* - months. BUT BUT 0.83 1.05) (0.65- 0.1173} Median time to constant opioid use - months. BUT BUT 0.77 1.11) (0.54- - Median time to skeletal-related events} - months. BUT BUT 0.80 1.15) (0.56- - Other clinically relevant endpoints Median time to progression of symptoms is months. BUT BUT 1.20 2.02) (0.71- Median time to PSA progression months. BUT 12.91 0.26 0.32) (0.21- Median second progression-free survival - months. BUT BUT 0.66 0.87) (0.50-

N/A, not subject to assessment.

^Pain progression was determined by the patient's report of the greatest pain intensity on the BPI-SF (item 3). Items range from 0 to 10, with lower scores representing lower levels of pain intensity; the minimum significant difference was a change of 2.

^Secondary endpoints were tested in a preplanned hierarchical sequence. If time to pain progression was not found to be significantly improved by apalutamide, additional secondary endpoints were not formally tested.

{Skeleton-related events (SRE) are defined as the occurrence of a symptomatic pathological fracture, spinal cord compression, radiation therapy to bone, or bone surgery.

Other clinically relevant endpoints.

Median time to PSA progression was more favorable with apalutamide

- 41 046078 compared with placebo (Fig. 5, Table 4), and PSA reached undetectable levels (PSA <0.2 ng per ml) in 68% and 29% of patients in the apalutamide and placebo groups, respectively. 87 and 190 patients in the apalutamide and placebo groups, respectively, received subsequent treatment for prostate cancer (the first forms of therapy described in Table 5). Median second progression-free survival was improved with apalutamide compared with placebo (Table 4; Fig. 6). There were a small number of events, and there were no differences between groups in time to progression of local symptoms (Table 4). Analysis of change in FACT-P from baseline using a mixed-effects repeated measures model showed maintenance of health-related quality of life and no differences between groups (Figure 7).

Table 5

First subsequent systemic therapy for prostate cancer

Apalutamide (n=525) Placebo (n=527) Patients who discontinued treatment for any reason* and survived (the denominator for the calculation of the first subsequent therapy is given below) - no. 170 (%) 271 (%) Patients who stopped treatment due to progression of the disease - no. (%) 99 (18.9) 227 (43.1) Patients with adverse events as the main reason for discontinuation of treatment - no. (%) 39 (7.4) 17 (3.2) Patients with adverse events leading to discontinuation of use - no. (%) 42 (8.0) 28 (5.3) Patients with life-prolonging follow-up therapy for prostate cancer} - no. (%) 87 (63) 190 (78) Patients receiving subsequent systemic therapy for prostate cancer at the time of data cutoff} - no. (%) 87 (51.2%) 190 (70.1%) First follow-up therapy Hormone therapy - no. (%) 44 (25.9) 98 (36.2) Abiraterone acetate and prednisone 21 (12.4) 45 (16.6) Bicalutamide 16 (9.4) 31 (11.4) Enzalutamide 3 (1.8) 17 (6.3) Other} 4 (2.4) 5 (1.8) Chemotherapy - no. (%) 35 (20.6) 73 (26.9) Docetaxel 29 (17.1) 67 (24.7) Cabazitaxel 1 (0.6) 2 (0.7) Other§ 5 (2.9) 4 (1.5) Other therapy - number. (%) 8 (4.7) 19 (7.0) Radium-223 2 (1.2) 4 (1.5) Sipuleucel-T 2 (1.2) 5 (1.8) Other** 4 (2.4) 10 (3.7)

*Possible reasons for discontinuation of treatment were disease progression,

- 42 046078 adverse event, patient refusal, death, physician decision and protocol violation.

{Including docetaxel, abiraterone acetate and prednisone, enzalutamide, cabazitaxel, radium-223 and sipuleucel-T.

{Data from some patients were disclosed after study termination and before the start of the first follow-up therapy for inclusion in a subsequent clinical trial.

§Including diethylstilbestrol, flutamide and cyproterone.

**Including etoposide, paclitaxel, estramustine, carboplatin and cisplatin.

***Including zoledronic acid, clodronate, prednisolone and prednisone.

Safety.

Table 6 shows the most common treatment-related adverse events. The rates of grade 3 and 4 events (42.2% in the apalutamide group; 40.8% in the placebo group) and serious adverse events (19.8% in the apalutamide group; 20.3% in the placebo group) were not differed between groups. Most treatment discontinuations were the result of progressive disease (99 [19%] apalutamide; 227 [43%] placebo; Table 5). adverse events led to treatment discontinuation (42 (8.0%) patients in the apalutamide group and 28 (5.3%) in the placebo group (Table 7). Ten (1.9%) and 16 (3.0%) patients in the apalutamide and placebo groups, respectively, died due to an adverse event (Table 8).Rash of any grade was more common among patients receiving apalutamide than placebo (27.1% and 8.5%, respectively; Table 6), and the most common The event considered to be associated with apalutamide was rash of any type (6.3%), hypothyroidism was reported in 6.5% and 1.1% of each group, respectively (Table 6), all events were classified as grade 1 or Grade 2: Coronary artery disease occurred in 4.4% and 1.5% of patients in the apalutamide and placebo groups, respectively, and ischemic events were fatal in two patients in each group.

Table 6

Treatment-related adverse events

Adverse event Apalutamide (n=524) Placebo (n=527) Any adverse event 507 (96.8) 509 (96.6) Grade 3 or 4 adverse event 221 (42.2) 215 (40.8) Any serious adverse event 104 (19.8) 107 (20.3) Any adverse event leading to cessation 42 (8.0) 28 (5.3) treatment Undesirable phenomenon leading to death 10 (1.9) 16 (3.0) Treatment-related adverse events phenomena recorded in patients, or >grade 3 in >10% >10 All degrees .о ·· „ _{Ω Ω} All >3rd degree degree >3rd degree patients in any group Tides 119 (22.7) 0 86 (16.3) 0 Fatigue 103 (19.7) 8 (1.5) 88 (16.7) 6 (1.1) Hypertension 93 (17.7) 44 (8.4) 82 (15.6) 48 (9.1) Backache 91 (17.4) 12 (2.3) 102 (19.4) 14 (2.7) Joint pain 91 (17.4) 2 (0.4) 78 (14.8) 5 (0.9) Pain in limb 64 (12.2) 3 (0.6) 67 (12.7) 5 (0.9) Itching 56 (10.7) 1 (0.2) 24 (4.6) 1 (0.2)

- 43 046078

Increased weight 54 (10.3) 6 (1.1) 89 (16.9) 10 (1.9) Anemia 48 (9.2) 9 (1.7) 71 (13.5) 17 (3.2) Constipation 47 (9.0) 0 57 (10.8) 0 Asthenia 37 (7.1) 10 (1.9) 44 (8.3) 3 (0.6) Bone pain 34 (6.5) 6 (1.1) 53 (10.1) 9 (1.7) Generalized rash 34 (6.5) 14 (2.7) 5 (0.9) 2 (0.4) Elevated levels of phosphatase in the blood alkaline 16 (3.1) 2 (0.4) 28 (5.3) 13 (2.5) Urinary retention 13 (2.5) 0 19 (3.6) 10 (1.9) Adverse events of special interest All degrees >3rd degree All degrees >3rd degree Rash* 142 (27.1) 33 (6.3) 45 (8.5) 3 (0.6) A fall 39 (7.4) 4 (0.8) 37 (7.0) 4 (0.8) Fracture^ 33 (6.3) 7 (1.3) 24 (4.6) 4 (0.8) Hypothyroidism:: 34 (6.5) 0 6 (1.1) 0 Seizures§ 3 (0.6) 1 (0.2) 2 (0.4) 0

Values are given in numerical form. (%).

*Rash was defined according to a group term including rash, butterfly rash, erythematous rash, scaling rash, follicular rash, generalized rash, macular rash, maculopapular rash, papules, papular rash, pruritic rash, pustular rash, genital rash, blisters , exfoliation skin, exfoliative dermatitis, skin reaction, systemic lupus erythematosus, toxicoderma, ulcerative stomatitis, drug dermatitis, conjunctivitis, erythema multiforme, stomatitis and urticaria.

{Fracture was defined according to a group term including acetabular fracture, ankle fracture, clavicle fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, forearm fracture, fracture, ischium fracture, fracture pain, fracture hands, fracture of the femoral neck, fracture of the lower limb, fracture of the patella, fracture of the radius, fracture of the rib, fracture of the skull, compression fracture of the spine, fracture of the spine, fracture of the sternum, fracture of the thoracic vertebra, fracture of the tibia, traumatic fracture, fracture of the ulna, fracture of the upper limbs and wrist fracture.

{Hypothyroidism was defined according to a group term including autoimmune thyroiditis, elevated thyroid-stimulating hormone and hypothyroidism.

§Seizure was defined according to a group term including seizures and tongue biting.

Table 7

Treatment-related adverse events leading to discontinuation of treatment, dose reduction, and ___________________________________dose interruption__________________________________

Apalutamide (n=524) Placebo (n=527) All degrees >3rd degree All degrees >3rd degree

- 44 046078

Stopping treatment Patients with treatment-related adverse events leading to discontinuation - no. (%) 42 (8.0) 26 (5.0) 28 (5.3) 22 (4.2) Rash* 12 (2.3) 7 (1.3) 1 (0.2) 1 (0.2) New cancerous growth} 7 (1.3) 5 (1.0) 5 (0.9) 3 (0.6) Infections} 1 (0.2) 1 (0.2) 3 (0.6) 0 Fatigue 4 (0.8) 1 (0.2) 0 0 Ischemic cardiac events§ 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) Convulsive attack 2 (0.4) 1 (0.2) 1 (0.2) 0 Pulmonary embolism 1 (0.2) 1 (0.2) 2 (0.4) 1 (0.2) Sudden death 0 0 2 (0.4) 2 (0.4) Cerebrovascular disorders 1 (0.2) 1 (0.2) 0 0 Parkinson's disease 1 (0.2) 1 (0.2) 0 0 Radiculopathy 1 (0.2) 1 (0.2) 0 0 Cognitive disorder 0 0 1 (0.2) 0 Intracranial hemorrhage 0 0 1 (0.2) 1 (0.2) Loss of consciousness 0 0 1 (0.2) 1 (0.2) Atrial fibrillation 1 (0.2) 1 (0.2) 0 0 Cardiopulmonary arrest 1 (0.2) 1 (0.2) 0 0 Cardiogenic shock 1 (0.2) 1 (0.2) 0 0 Heart failure 0 0 1 (0.2) 1 (0.2) Sudden cardiac death 1 (0.2) 1 (0.2) 0 0 Hypothermia 0 0 1 (0.2) 1 (0.2) Anxiety 1 (0.2) 0 0 0 Euphoric mood 1 (0.2) 0 0 0 Suicide 0 0 1 (0.2) 1 (0.2) Perforation of colon ulcer 1 (0.2) 1 (0.2) 0 0 Swelling of the lips 1 (0.2) 0 0 0 Dyspnea 0 0 1 (0.2) 0 Pleural effusion 0 0 1 (0.2) 1 (0.2) Pulmonary edema 0 0 1 (0.2) 1 (0.2) Respiratory failure 0 0 1 (0.2) 1 (0.2)

- 45 046078

Dehydration 1 (0.2) 0 0 0 Tides 1 (0.2) 0 0 0 Subdural hemorrhage 0 0 1 (0.2) 1 (0.2) Increased alanine aminotransferase 0 0 1 (0.2) 1 (0.2) Dose reduction Patients with treatment-related adverse events leading to dose reduction - no. (%) 37 (7.1) 19 (3.6) 11 (2.1) 1 (0.2) Rash* 28 (5.3) 11 (2.1) 4 (0.8) 1 (0.2) Increased level aspartate aminotransferase or alanine aminotransferase 0 0 4 (0.8) 0 Fatigue 2 (0.4) 2 (0.4) 0 0 Headache 1 (0.2) 0 1 (0.2) 0 Hypertension 1 (0.2) 1 (0.2) 1 (0.2) 0 Neutropenia 2 (0.4) 2 (0.4) 0 0 Cognitive disorder 1 (0.2) 1 (0.2) 0 0 General deterioration in physical condition 1 (0.2) 1 (0.2) 0 0 Tides 1 (0.2) 0 0 0 Asthenia 0 0 1 (0.2) 0 Dehydration 1 (0.2) 0 0 0 Lethargy 0 0 1 (0.2) 0 Pain** 1 (0.2) 0 0 0 Deterioration of general condition 0 0 1 (0.2) 0 Vertigo 1 (0.2) 1 (0.2) 0 0 Weight loss 1 (0.2) 1 (0.2) 0 0 Suspension of a dose Patients with phenomena arising during treatment leading to dose interruption - no. (%) 104 (19.8) 68 (13.0) 63 (12.0) 43 (8.2) Rash* 44 (8.4) 20 (3.8) 5 (0.9) 2 (0.4) Increased level aspartate aminotransferase or alanine aminotransferase 7 (1.3) 4 (0.8) 12 (2.3) 7 (1.3) Pain** 9 (1.7) 4 (0.8) 7 (1.3) 3 (0.6) Infections} 6 (1.1) 4 (0.8) 9 (1.7) 3 (0.6) Hypertension 6 (1.1) 6 (1.1) 6 (1.1) 6 (1.1)

- 46 046078

Fatigue 6 (1.1) 1 (0.2) 2 (0.4) 1 (0.2) Vomit 3 (0.6) 0 4 (0.8) 0 Anemia 2 (0.4) 0 3 (0.6) 2 (0.4) Asthenia 3 (0.6) 3 (0.6) 2 (0.4) 1 (0.2) Decreased appetite 2 (0.4) 1 (0.2) 3 (0.6) 1 (0.2) New cancerous tumor^ 3 (0.6) 1 (0.2) 1 (0.2) 1 (0.2) Diarrhea 1 (0.2) 0 3 (0.6) 0 Chronic obstructive pulmonary disease 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) G hyperthermia 3 (0.6) 0 1 (0.2) 0 Urinary retention 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) Joint pain 2 (0.4) 0 1 (0.2) 0 Insomnia 3 (0.6) 0 0 0 Acute kidney injury 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Anxiety 2 (0.4) 0 0 0 Cerebrovascular accident 1 (0.2) 1 (0.2) 1 (0.2) 0 Dizziness 1 (0.2) 0 1 (0.2) 0 Dyspnea 1 (0.2) 0 1 (0.2) 1 (0.2) A fall 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Headache 1 (0.2) 0 1 (0.2) 1 (0.2) Hematuria 2 (0.4) 2 (0.4) 0 0 Tides 1 (0.2) 0 1 (0.2) 0 Hypersensitivity 1 (0.2) 0 1 (0.2) 0 Hypertriglyceridemia 2 (0.4) 2 (0.4) 0 0 Hyponatremia 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Muscle weakness 1 (0.2) 0 1 (0.2) 1 (0.2) Nausea 1 (0.2) 0 1 (0.2) 0 Neutropenia 2 (0.4) 2 (0.4) 0 0 Spinal cord compression 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Acute respiratory failure 1 (0.2) 1 (0.2) 0 0 Allergy to chemicals 1 (0.2) 1 (0.2) 0 0 Unstable angina 0 0 1 (0.2) 1 (0.2) Atrial fibrillation 1 (0.2) 1 (0.2) 0 0

- 47 046078

Bile duct obstruction 0 0 1 (0.2) 1 (0.2) Elevated levels of alkaline phosphatase in the blood 1 (0.2) 1 (0.2) 0 0 Cardiac amyloidosis 0 0 1 (0.2) 1 (0.2) Heart disorders 0 0 1 (0.2) 1 (0.2) Heart failure 0 0 1 (0.2) 0 Congestive heart failure 1 (0.2) 1 (0.2) 0 0 Cheilitis 1 (0.2) 0 0 0 Chronic hepatitis 1 (0.2) 0 0 0 Cognitive disorder 1 (0.2) 1 (0.2) 0 0 Confusion 1 (0.2) 1 (0.2) 0 0 Constipation 1 (0.2) 0 0 0 Dehydration 0 0 1 (0.2) 0 Depression 1 (0.2) 0 0 0 Diabetes 1 (0.2) 1 (0.2) 0 0 Diplegia 0 0 1 (0.2) 1 (0.2) Dysuria 1 (0.2) 1 (0.2) 0 0 Edema 1 (0.2) 0 0 0 Swelling of the eyelid 1 (0.2) 0 0 0 Facial swelling 1 (0.2) 0 0 0 Febrile neutropenia 1 (0.2) 1 (0.2) 0 0 Elevated gamma glutamyl transferase 1 (0.2) 1 (0.2) 0 0 Perforation of gastric ulcer 1 (0.2) 1 (0.2) 0 0 G astritis 0 0 1 (0.2) 1 (0.2) General deterioration in physical condition 1 (0.2) 1 (0.2) 0 0 Hallucinations 1 (0.2) 0 0 0 Hematoma 1 (0.2) 1 (0.2) 0 0 Hemorrhagic erosive gastritis 1 (0.2) 1 (0.2) 0 0 Intracranial hemorrhage 1 (0.2) 1 (0.2) 0 0 Cirrhosis of the liver 1 (0.2) 0 0 0 Liver failure 0 0 1 (0.2) 1 (0.2) Femoral neck fracture 1 (0.2) 1 (0.2) 0 0 Hypokalemia 1 (0.2) 1 (0.2) 0 0

- 48 046078

Hydronephrosis 0 0 1 (0.2) 1 (0.2) Hyperbilirubinemia 1 (0.2) 1 (0.2) 0 0 Flu-like illness 1 (0.2) 0 0 0 Perforation of colon ulcer 1 (0.2) 1 (0.2) 0 0 Change in mental state 1 (0.2) 0 0 0 Musculoskeletal stiffness 0 0 1 (0.2) 0 Ischemic cardiac events§ 1 (0.2) 1 (0.2) 0 0 Osteoarthritis 0 0 1 (0.2) 1 (0.2) Osteoporosis 1 (0.2) 0 0 0 Pathological fracture 0 0 1 (0.2) 1 (0.2) Peripheral edema 1 (0.2) 0 0 0 Peripheral swelling 0 0 1 (0.2) 1 (0.2) Proctalgia 1 (0.2) 0 0 0 Kidney damage 0 0 1 (0.2) 0 Rheumatoid arthritis 1 (0.2) 1 (0.2) 0 0 Convulsive attack 1 (0.2) 0 0 0 Stomatitis 1 (0.2) 0 0 0 Subarachnoid hematoma 1 (0.2) 1 (0.2) 0 0 Subarachnoid hemorrhage 1 (0.2) 0 0 0 Subdural hemorrhage 0 0 1 (0.2) 1 (0.2) Fainting 1 (0.2) 1 (0.2) 0 0 Thrombocytopenia 1 (0.2) 0 0 0 Ulcerative glossitis 1 (0.2) 0 0 0 Urinary incontinence 1 (0.2) 0 0 0 Urinary tract obstruction 1 (0.2) 1 (0.2) 0 0 Urethral stenosis 0 0 1 (0.2) 0 Vertigo 1 (0.2) 1 (0.2) 0 0 Increased weight 0 0 1 (0.2) 0

*Rash was defined according to a group term including eczema, nummular eczema, rash exfoliating, generalized rash, rash, dermatitis, exfoliating dermatitis, psoriasis, hyperhidrosis, maculopapular rash, macular rash, drug dermatitis, erythema multiforme, lichenoid keratosis, pruritis, pruritus rash, skin peeling, skin lesions, skin reaction and toxic dermatitis.

{New cancers (benign, malignant and undefined [including cysts and polyps]) were defined according to a group term including lung malignancy, colon adenoma, colon neoplasm, leiomyosarcoma,

- 49 046078 oropharyngeal cancer, papilloma, rectal adenocarcinoma, small cell carcinoma, gastric adenocarcinoma, colon adenocarcinoma, bladder cancer and non-small cell lung cancer.

{Infections were defined according to a group term including urinary tract infection, Klebsiella infection, sepsis, urosepsis, fungal infection, localized infection, pulmonary infection, pneumonia, fungal respiratory tract infection, acarodermatitis, cellulitis, bacterial bronchitis, influenza, necrotizing fasciitis, and viral upper respiratory tract infection.

§Ischemic cardiac events were defined according to a group term including myocardial infarction, acute myocardial infarction, and acute coronary syndrome.

**Pain was defined according to a group term including limb pain, back pain, bone pain, upper abdominal pain, lower abdominal pain, musculoskeletal pain, neck pain, and noncardiac pain.

Table 8

Causes of death reported by the investigator during the study in the safety group

Apalutamide (n=524) Placebo (n=527) All deaths within 30 days after last dose - no. (%) 18 (3.4) 23 (4.4) Death due to prostate cancer 8 (1.5) 7 (1.3) Death due to an adverse event 10 (1.9) 16 (3.0) Adverse event leading to death - no. (%) Respiratory failure 1 (0.2) 2 (0.4) Acute kidney injury 2 (0.4) 0 Acute myocardial infarction 1 (0.2) 1 (0.2) Sudden death 0 2 (0.4) Acute coronary syndrome 0 1 (0.2) Heart failure 0 1 (0.2) Cardiopulmonary arrest 1 (0.2) 0 Cardiogenic shock 1 (0.2) 0 Cerebrovascular accident 1 (0.2) 0 Death 0 1 (0.2) Hypothermia 0 1 (0.2) Intracranial hemorrhage 0 1 (0.2) Perforation of colon ulcer 1 (0.2) 0 Myocardial infarction 1 (0.2) 0 Pulmonary embolism 0 1 (0.2) Sepsis 0 1 (0.2) Subdural hemorrhage 0 1 (0.2) Sudden cardiac death 1 (0.2) 0 Suicide 0 1 (0.2)

- 50 046078

Urosepsis 0 1 (0.2) Vascular rupture 0 1 (0.2)

Post hoc analysis taking into account the concurrent risk of death was performed based on the Fine and Gray model (Table 9). Fine JP, Gray RJ. J Am Stat Assoc 1999;94:496-509. Estimates of the secondary distribution of hazard ratios in the apalutamide group compared with the placebo group are presented, as well as the corresponding 95% confidence interval limits and Wald chi-square P values. The results of these post hoc analyzes were consistent with and supported the results of the preplanned analyses.

Table 9

Secondary distribution estimates of the hazard ratio of the apalutamide group relative to the placebo group

P-Value Risk ratio Risk interval limits 95% confidence level for the relationship Time to cytotoxic chemotherapy <0.0001 0.408 0.286 0.581 Time to pain progression 0.1540 0.843 0.667 1,066 Time to permanent opioid use 0.2004 0.789 0.549 1.134 Time before the skeleton 0.2759 0.818 0.570 1.174

events

Treatment of allergic rash.

Skin rash associated with apalutamide was most often described as a generalized or maculopapular rash. Treatment-emergent skin rash occurred in 27.1% of patients in the apalutamide group and 8.5% in the placebo group. Grade 3 rashes were observed with apalutamide (6.3%) and placebo (0.6%). No cases of Stevens-Johnson syndrome or toxicodermal necrolysis were recorded. Skin rash led to treatment discontinuation, dose reduction, and dose interruption in 12 (2.3%), 28 (5.3%), and 44 (8.4%) patients, respectively, in the apalutamide group and in 1 (0.2% ), 4 (0.8%) and 5 (0.9%) patients, respectively, in the placebo group. Rash >Grade 3 led to treatment discontinuation in 7 (1.3%) and 1 (0.2%) patients in the apalutamide and placebo groups, respectively (Table 7). For patients with skin rash, treatment included topical corticosteroids, oral antihistamines, systemic corticosteroids, medication interruption, and dose reduction. The median time to rash onset was 81 days in the apalutamide group and 141 days in the placebo group.

Discussion.

In this phase 3 study in male men with metastatic castration-sensitive prostate cancer (mCSPC), apalutamide plus ADT significantly improved overall survival and radiographic progression-free survival compared with placebo plus ADT. The reduced risk of death did not differ by disease volume, and there was a consistent benefit in radiographic progression-free survival across all subgroups analyzed, including patients with prior docetaxel therapy. Longer survival with apalutamide was observed even though a higher proportion of patients in the placebo group who discontinued treatment received life-prolonging prostate cancer follow-up therapy (64 of 170 patients [38%] and 165 of 271 patients [61]. %] in the apalutamide and placebo groups, respectively; Table 5). Based on the results of this first planned interim analysis, the independent data monitoring committee recommended disclosure to ensure that patients receiving placebo were switched to apalutamide.

Secondary and exploratory endpoints also indicated benefit from apalutamide treatment, including time to cytotoxic chemotherapy and time to second progression-free survival. Apalutamide in combination with ADT also resulted in an increased proportion of patients achieving undetectable PSA levels and prolongation of time to PSA progression compared with placebo in combination with ADT. In this example study, initial treatment

- 51 046078 apalutamide in patients with metastatic castration-sensitive prostate cancer led to improved clinical outcomes.

The aim of the study was to enroll a broad group of patients with metastatic castration-sensitive prostate cancer, resulting in the limitation of relatively small subgroup sizes of certain patients. For example, although all patients confirmed a survival benefit with docetaxel during the informed consent process, only 11% had received prior docetaxel therapy before enrollment. This likely reflects patients' perceived suitability of docetaxel and differences in patient choice or treatment approaches. However, it is encouraging that the clinical benefits of apalutamide were consistent across all subgroups.

The incidence of high-grade and serious adverse events did not differ between the apalutamide and placebo groups; Treatment discontinuation rates due to adverse events were low in both groups. Adverse events were substantially consistent with the known safety profile of apalutamide. Rash associated with apalutamide treatment was widespread and was typically treated with topical antihistamines and glucocorticoids, dose interruption, and dose reduction. Hypothyroidism was mild to moderate, controlled by thyroid-stimulating hormone, and treated with levothyroxine. In addition, health-related quality of life was maintained, with no differences between groups, confirming the tolerability of apalutamide in combination with ADT.

In conclusion, in the example of the present study, patients with metastatic castration-sensitive prostate cancer, including patients with high-volume and low-volume disease, prior docetaxel therapy, prior treatment for localized disease, and patients with previously diagnosed disease or newly diagnosed disease the addition of apalutamide to ADT significantly improved overall survival and slowed disease progression, with a safety profile no different from placebo plus ADT and health-related quality of life was maintained.

Composition of apalutamide.

The apalutamide tablet supplied for this study contains 60 mg of apalutamide. The sponsor was responsible for its receipt and delivery.

The placebo was matched in composition to the inactive ingredients of the tablet and will be matched in size, color and shape to maintain blinding of the study.

Package.

Apalutamide 60 mg tablets were packaged in 120 high density polyethylene (HDPE) bottles with a volume of 160 cc. cm with child-resistant lids.

Example 2: Final information accompanying an FDA-approved drug product.

On September 2019, the FDA approved the following information accompanying the drug product ERLEADA™ (apalutamide), which is the comparator product for apalutamide.

EXTRACTS FROM INSTRUCTIONS FOR USE OF THE MEDICINE

These extracts do not include all the information necessary for the safe and effective use of ERLEADA.

See complete instructions for use of ERLEADA.

ERLEADA® (apalutamide), oral tablets

Initial US Approval - 2018 RECENT MAJOR CHANGES Indications and Use (1) September 2019

Warnings and Precautions (5) September 2019

INDICATIONS FOR USE

ERLEADA is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-sensitive

WARNINGS AND PRECAUTIONS

Ischemic cardiovascular events have been reported in patients receiving ERLEADA. Monitoring for signs and symptoms of coronary artery disease is required. Reduce risk factors for cardiovascular disease as much as possible. (5.1)

Fractures have been reported in patients taking ERLEADA. Patients should be assessed for fracture risk and treated with bone-targeting drugs in accordance with current guidelines. (5.2)

In patients receiving ERLEADA, falls have been reported with an increased incidence in older adults. Assess patients for fall risk. (5.3)

Seizures occurred in 0.4% of patients taking ERLEADA. Patients who developed seizures during treatment

- 52 046078 prostate cancer (1) non-metastatic castration-resistant prostate cancer. (1)

DOSE AND METHOD OF ADMINISTRATION

ERLEADA 240 mg (four 60 mg tablets) is taken orally once daily.

The tablets should be swallowed whole. ERLEADA can be taken without regard to meals (2.1)

Patients should also receive a concomitant gonadotropin-releasing hormone (GnRH) analogue or undergo a bilateral orchiectomy. (2.1)

DOSAGE FORMS AND DOSAGES

Tablets: 60 mg (3)

CONTRAINDICATIONS

None.

attacks, you must completely stop taking ERLEADA and not restart it in the future. (5.4)

Embryofetal toxicity: ERLEADA may cause harm to the fetus. Men with female partners of reproductive potential are advised to use effective contraception. (5.5, 8.1, 8.3) ADVERSE REACTIONS

The most common adverse reactions (>10%) are fatigue, joint pain, rash, decreased appetite, falls, weight loss, hypertension, hot flashes, diarrhea, and fracture. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-5267736 (1-800-JANSSEN) or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Concomitant use of drugs that are sensitive substrates of CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 may result in loss of activity of these drugs. (7.2)

See 17 PATIENT INFORMATION and FDA-approved patient information provided with the drug.

Reviewed: September 2019

FULL INSTRUCTIONS FOR USE OF THE MEDICINE. CONTENT*

1. INDICATIONS FOR USE AND APPLICATION

2. DOSE AND METHOD OF ADMINISTRATION

2.1. Recommended dose

2.2. Dose adjustment

3. DOSAGE FORMS AND DOSAGES

4. CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1. Ischemic cardiovascular events

5.2. Fractures

5.3. Falls

5.4. Convulsive attack

5.5. Embryofetal toxicity

6. ADVERSE REACTIONS

6.1. Clinical Research Practice

7. DRUG INTERACTIONS

7.1. Effect of other drugs on ERLEADA

7.2. Effect of ERLEADA on other drugs

8. USE IN SPECIAL POPULATIONS

8.1. Pregnancy

8.2. Lactation

8.3. Women and men of childbearing potential

8.4. Use in pediatrics

8.5. Application in geriatrics

10. OVERDOSE

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of action

12.2. Pharmacodynamics

12.3. Pharmacokinetics

13. PRECLINICAL TOXICOLOGY

13.1. Carcinogenesis, mutagenesis, reproductive dysfunction

14. CLINICAL STUDIES

16. FORM OF RELEASE/STORAGE AND HANDLING

17. INFORMATION FOR THE PATIENT *The list does not include sections or subsections that are not included in the complete instructions for use of the drug.

Complete instructions for use of the drug.

1. Indications for use.

ERLEADA is indicated for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC);

- 53 046078 non-metastatic castration-resistant prostate cancer (nmCRPC).

2. Dose and route of administration.

2.1. Recommended dose.

The recommended dose of ERLEADA is 240 mg (four 60 mg tablets) and is taken orally once daily. The tablets should be swallowed whole. ERLEADA can be taken with or without food.

Patients should also receive concomitant gonadotropin-releasing hormone (GnRH) analogue therapy or undergo bilateral orchiectomy.

2.2. Dose adjustment.

If a patient experiences a grade 3 or higher toxic reaction or an intolerable side effect, withhold the drug until symptoms improve to grade 1 or lower or to baseline, then resume treatment at the same or reduced dose if necessary (180 mg or 120 mg).

3. Dosage forms and dosages.

Tablets (60 mg): slightly yellowish or greyish-green oblong, film-coated tablets embossed with AR 60 on one side.

4. Contraindications. None.

5. Warnings and precautions.

5.1. Ischemic cardiovascular events.

Ischemic cardiovascular events, including events leading to death, have been observed in patients taking ERLEADA.

Monitoring for signs and symptoms of coronary artery disease is required. Optimize treatment of cardiovascular risk factors such as hypertension, diabetes mellitus, or dyslipidemia. Consider discontinuing ERLEADA for grade 3 and 4 events.

In a randomized trial (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events were observed in 4% of patients receiving ERLEADA and 3% of patients receiving placebo. In a randomized trial (TITAN) of patients with mCSPC, ischemic cardiovascular events were observed in 4% of patients receiving ERLEADA and 2% of patients receiving placebo. During the SPARTAN and TITAN studies, 6 patients (0.5%) receiving ERLEADA and 2 patients (0.2%) receiving placebo died from an ischemic cardiovascular event.

Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within six months of randomization were excluded from the SPARTAN and TITAN studies.

5.2. Fractures.

Fractures have been reported in patients taking ERLEADA. Assess patients' risk of fractures. Monitor and treat patients at risk of fracture according to established treatment protocols and consider the use of bone-targeting agents.

In a randomized trial (SPARTAN) of patients with non-metastatic castration-resistant prostate cancer, fractures occurred in 12% of patients receiving ERLEADA and 7% of patients receiving placebo.

Grade 3 and 4 fractures occurred in 3% of patients receiving ERLEADA and 1% of patients receiving placebo. The median time to fracture was 314 days (range: 20 to 953 days) in patients receiving ERLEADA. Routine assessment of bone density and treatment of osteoporosis with bone-targeting agents were not performed in the SPARTAN study.

In a randomized trial (TITAN) of patients with metastatic castration-sensitive prostate cancer, fractures occurred in 9% of patients receiving ERLEADA and 6% of patients receiving placebo.

Grade 3-4 fractures were similar in both groups and accounted for 2%. The median time to fracture was 56 days (range: 2 to 111 days) in patients receiving ERLEADA. Routine assessment of bone density and treatment of osteoporosis with bone-targeting agents were not performed in the TITAN study.

5.3. Falls.

An increased incidence of falls in older adults has been reported among patients receiving ERLEADA [see Use in special populations (8.5)]. Assess patients for fall risk.

In a randomized trial (SPARTAN), falls occurred in 16% of patients treated with ERLEADA, compared with 9% of patients treated with placebo. The falls were not associated with loss of consciousness or seizure.

- 54 046078

5.4. Convulsive attack.

Seizures have occurred in patients taking ERLEADA. Patients who develop seizures during treatment should completely stop taking ERLEADA and not restart it in the future.

It is not known whether antiepileptic drugs can prevent seizures when treated with ERLEADA. Tell the patient about the risk of developing a seizure while taking ERLEADA and the risk associated with participating in any activity in which the patient could harm himself or others if he suddenly loses consciousness.

In two randomized studies (SPARTAN and TITAN), five patients (0.4%) receiving ERLEADA and one patient receiving placebo (0.1%) experienced a seizure. Seizures occurred from days 159 to 650 after initiation of ERLEADA. Patients with a history of seizures, seizure predisposing factors, or taking medications known to lower the seizure threshold or induce seizures were excluded. There is no clinical experience with reintroducing ERLEADA to patients who have had a seizure.

5.5. Embryofetal toxicity.

The safety and effectiveness of ERLEADA in women have not been established. Based on its mechanism of action, ERLEADA may cause fetal harm and cause miscarriage when administered to a pregnant woman [see Clinical pharmacology (12.1)].

Men with female partners of childbearing potential are advised to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see. Use in special populations (8.1, 8.3)].

6. Adverse reactions.

The following questions are presented in more detail in other sections of the package insert: sections.

Ischemic cardiovascular events [see. Warnings and precautions (5.1)].

Fractures [see Warnings and precautions (5.2)].

Falls [see Warnings and precautions (5.3)].

Convulsive attacks [see Warnings and precautions (5.4)].

6.1. Clinical research practice.

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions in clinical trials of one drug cannot be directly compared with the incidence in clinical trials of another drug and may not reflect the incidence observed in practice.

The most common adverse reactions (>10%) that occurred more frequently in ERLEADA-treated patients (>2% compared with placebo) from randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, joint pain, rash, decreased appetite , weight loss, hypertension, hot flashes, diarrhea and fracture.

Metastatic castration-sensitive prostate cancer (mCSPC).

TITANA, a randomized (1:1), double-blind, placebo-controlled, multicenter clinical trial included patients with mCSPC. In this study, patients received either ERLEADA 240 mg daily or placebo. All patients in the TITAN study were concurrently receiving a gonadotropin-releasing hormone (GnRH) analogue or had previously undergone bilateral orchiectomy. The median duration of exposure was 20 months (range: 0 to 34 months) in patients receiving ERLEADA and 18 months (range: 0.1 to 34 months) in patients receiving placebo.

Ten patients (2%) receiving ERLEADA died from adverse reactions. Causes of death were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardiopulmonary arrest (n=1), sudden cardiac death (n=1), respiratory failure (n=1) , cerebrovascular accident (n=1) and perforation of a colon ulcer (n=1).

ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly due to rash (2%). Adverse reactions leading to dose interruption or dose reduction of ERLEADA were observed in 23% of patients: the most common (>1%) were rash, fatigue and hypertension. Serious adverse reactions occurred in 20% of patients receiving ERLEADA and 20% of patients receiving placebo.

Table 1 shows adverse reactions occurring at a frequency of >10% in the ERLEADA arm of the TITAN study, which occurred with a >2% absolute increase in frequency compared with placebo.

Table 2 shows laboratory abnormalities that occurred in >15% of patients and occurred at a higher rate (>5%) in the ERLEADA group compared to the placebo group.

- 55 046078

Table 1

Adverse reactions during TITAN (mCSPC)

System organ class Adverse reaction ERLEADA N=524 All degrees, % 3-4 degree, % Placebo N=527 All degrees, % 3-4 degree, % General disorders and conditions at the injection site Fatigue ^1.3 26 3 25 2 Musculoskeletal and connective tissue disorders Pain in _______3 joints Pain in joints ³ 17 0.4 15 0.9 Skin and subcutaneous tissue disorders Rash ² 28 6 9 0.6 Itching eleven < 1 5 < 1 Blood vessel disorders Hot flashes 23 0 16 0 Hypertension 18 8 16 9

¹ Including fatigue and asthenia.

² Including rash, maculopapular rash, generalized rash, urticaria, pruritic rash, macular rash, conjunctivitis, erythema multiforme, papular rash, skin peeling, genital rash, erythematous rash, stomatitis, drug rash, ulcerative stomatitis, pustular rash , blisters, papules, pemphigus, skin erosions, dermatitis and vesicular rash.

³ According to the Common Terminology Criteria for Adverse Events (CTCAE), the highest severity for these events was grade 3.

Additional adverse reactions of interest, occurring in 2% but less than 10% of patients receiving ERLEADA, included diarrhea (9% versus 6% in the placebo group), muscle spasm (3% versus 2% in the placebo group) , dysgeusia (3% versus 1% in the placebo group), and hypothyroidism (4% versus 1% in the placebo group).

table 2

Laboratory abnormalities occurring in >15% of patients treated with ERLEADA, and at a higher rate than in the placebo group (differences between groups >5% for all grades), in the TITAN study (mCSPC)

Laboratory anomaly ERLEADA N=524 Placebo N=527 All degrees, % 3-4 degree, % All degrees, % 3-4% degree, Hematology Reduction in the number of leukocytes 27 0.4 19 0.6 com Chemical composition Hypertriglyceridemia ¹ 17 3 12 2

¹ Does not reflect fasting values.

Non-metastatic castration-resistant prostate cancer (nmCRPC).

SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multicenter clinical trial included patients with nmCRPC. In this study, patients received either ERLEADA 240 mg daily or placebo. All patients in the SPARTAN study were additionally treated with a gonadotropin-releasing hormone (GnRH) analogue or had a bilateral orchiectomy. The median duration of exposure was 16.9 months (range: 0.1 to 42 months) in patients receiving ERLEADA and 11.2 months (range: 0.1 to 37 months) in patients receiving placebo.

Eight patients (1%) receiving ERLEADA died from adverse reactions. Causes of death were infections (n=4), myocardial infarction (n=3) and cerebral hemorrhage (n=1). One patient (0.3%) receiving placebo died from an adverse cardiac arrest reaction (n=1), and ERLEADA was discontinued due to adverse reactions in 11% of patients, most commonly due to rash (3%). Adverse reactions leading to dose interruption or dose reduction of ERLEADA were observed in 33% of patients: the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension and hematuria. Serious adverse reactions occurred in 25% of patients receiving ERLEADA and 23% of patients receiving placebo. Most common

- 56 046078 serious adverse reactions (>2%) were fractures (3%) in the ERLEADA group and urinary retention (4%) in the placebo group.

Table 3 shows adverse reactions occurring at a frequency of >10% in the ERLEADA arm of the SPARTAN study, which occurred at a 2% absolute increase in frequency compared with placebo. Table 4 shows laboratory abnormalities that occurred in >15% of patients and occurred at a higher frequency (>5%) in the ERLEADA group compared to the placebo group.

Table 3

Adverse reactions in the SPARTAN study (nmCRPC) System organ class Adverse reaction ERLEADA N=803 All degrees, % 3-4 degree, % Placebo N=398 All degrees, % 3-4% degree, General disorders and conditions at the injection site Fatigue ^1.4 39 1 28 0.3 Musculoskeletal and connective tissue disorders Joint pain ⁴ 16 0 8 0 Skin and subcutaneous tissue disorders Rash ² 25 5 6 0.3 Metabolic and nutritional disorders Decreased appetite ⁵ 12 0.1 9 0 Peripheral edema ⁶ eleven 0 9 0 Injuries, poisonings and complications of procedures Fall ⁴ 16 2 9 0.8 Fracture ³ 12 3 7 0.8 Laboratory research Weight loss ⁴ 16 1 6 0.3 Circulatory disorders vascular hypertension 25 14 20 12 Tides 14 0 9 0 Gastrointestinal disorders intestinal tract Diarrhea 20 1 15 0.5 Nausea 18 0 16 0 ¹ Including fatigue and asthenia. ² Including rash, maculopapular rash, generalized rash, urticaria, rash itchy, macular rash, conjunctivitis, erythema multiforme, papular rash, skin peeling, rash in genital areas, erythematous rash, stomatitis, medicinal rash, ulcerative stomatitis, rash

pustular, blisters, papules, pemphigus, skin erosions, dermatitis and vesicular rash.

³ Including rib fracture, lumbar vertebra fracture, vertebral compression fracture, vertebral fracture, foot fracture, hip fracture, shoulder fracture, thoracic vertebra fracture, upper limb fracture, sacrum fracture, arm fracture, pubic bone fracture, acetabulum fracture, ankle fracture, compression fracture, fracture of the cartilaginous part of the rib, fracture of the facial bones, fracture of the lower limb, osteoporotic fracture, fracture of the wrist, avulsion fracture, fracture of the fibula, fracture of the coccyx, fracture of the pelvis, fracture of the radius, fracture of the sternum, stress fracture, traumatic fracture, fracture of the cervical vertebra, fracture of the femoral neck and fracture of the tibia.

⁴ For the Common Terminology Criteria for Adverse Events (CTCAE), the highest severity of these events is grade 3.

⁵ Including appetite loss, decreased appetite, early satiety and hypophagia.

⁶ Including peripheral edema, generalized edema, edema, genital edema, penile edema, peripheral edema, scrotal edema, lymphedema, swelling and localized edema.

Additional clinically significant adverse reactions occurring in 2% or more of patients receiving ERLEADA included hypothyroidism (8.1% versus 2% in the placebo group),

- 57 046078 pruritus (6.2% compared with 2% in the placebo group) and heart failure (2.2% compared with 1% in the placebo group).

Table 4

Laboratory abnormalities occurring in >15% of patients treated with ERLEADA, and at a higher rate than in the placebo group (differences between groups >5% for all severity grades), in the _________________________ SPARTAN (nmCRPC) Study_________________________

Laboratory anomaly ERLEADA N=803 Placebo N=398 All degrees, % 3-4 degree, % All degrees, % 3-4 degree, % Hematology Anemia 70 0.4 64 0.5 Leukopenia 47 0.3 29 0 Lymphopenia 41 2 21 2 Chemical composition Hypercholesterolemia ¹ 76 0.1 46 0 Hyperglycemia ¹ 70 2 59 1 Hypertriglyceridemia ¹ 67 2 49 0.8 Hyperkalemia 32 2 22 0.5

¹ Does not reflect fasting values. Rash.

In pooled data from two randomized, placebo-controlled clinical trials, rash associated with ERLEADA was most often described as macular or maculopapular. Adverse reactions in the form of rash were recorded in 26% of patients receiving ERLEADA and in 8% of patients receiving placebo. Grade 3 rash (defined as covering >30% body surface area [BSA]) was reported with ERLEADA treatment (6%) compared with placebo (0.5%).

The median onset of rash was 83 days after initiation of ERLEADA treatment. The rash resolved in 78% of patients within a median period of 78 days from rash onset. The rash is usually treated with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. For 14% and 28% of patients, respectively, a dose reduction or dose interruption was performed. Of patients for whom dosing was withheld, 59% experienced recurrence of rash after re-administration of ERLEADA.

Hypothyroidism.

In pooled data from two randomized, placebo-controlled clinical trials, hypothyroidism was reported in 8% of patients receiving ERLEADA and 2% of patients receiving placebo based on thyroid-stimulating hormone (TSH) assessments every 4 months. Elevations in TSH occurred in 25% of patients receiving ERLEADA and in 7% of patients receiving placebo. The median start time was the time of the first scheduled assessment. There were no grade 3 or 4 adverse reactions. Thyroid hormone replacement therapy was initiated in 5% of patients receiving ERLEADA. Thyroid hormone replacement therapy should be initiated or adjusted if clinically indicated [see. Interactions between drugs (7.2)].

7. Interactions between drugs.

7.1. Effect of other drugs on ERLEADA.

Strong inhibitors of CYP2C8 or CYP3A4.

Coadministration of a strong inhibitor of CYP2C8 or CYP3A4 is predicted to increase steady-state exposure to active functional groups (sum of unbound apalutamide plus activity-adjusted unbound N-desmethylapalutamide). No initial dose adjustment is necessary, but the ERLEADA dose should be reduced based on tolerability [see. Dose and route of administration (2.2)]. Weak or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect the effects of apalutamide.

7.2. Effect of ERLEADA on other drugs.

Substrates of CYP3A4, CYP2C9, CYP2C19 and UGT.

ERLEADA is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with drugs that are predominantly metabolized by CYP3A4, CYP2C19, or CYP2C9 may result in decreased exposure to these drugs. If possible, it is recommended to replace these medications or evaluate for decreased activity if they are continued. Concomitant administration of ERLEADA with drugs that are UDP-glucuronosyltransfer substrates

- 58 046078 times (UGT), may result in reduced exposure. Use caution if LIGT substrates must be coadministered with ERLEADA and evaluate for decreased activity [see Clinical pharmacology (12.3)].

Substrates P-gp, BCRP or OATP1B1.

Apalutamide has been clinically shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATPIB1). At steady state, apalutamide decreased the plasma levels of fexofenadine (P-gp substrate) and rosuvastatin (BCRP/OATPIB1 substrate). Concomitant use of ERLEADA with drugs that are substrates of P-gp, BCRP, or OATP1B1 may result in decreased exposure to these drugs. Use caution if P-gp, BCRP, or OATPIB1 substrates must be coadministered with ERLEADA, and evaluate for decreased activity if the drug is continued [see Clinical pharmacology (12.3)].

8. Use in special populations.

8.1. Pregnancy.

Risk Summary.

The safety and effectiveness of ERLEADA in women have not been established. Based on its mechanism of action, ERLEADA may cause harm to the fetus and may result in termination of pregnancy [see. Clinical pharmacology (12.1)]. There are no data on the use of ERLEADA in pregnant women. ERLEADA is not indicated for use in women, and embryofetal toxicity studies of apalutamide have not been conducted in animals.

8.2. Lactation.

Risk Summary.

The safety and effectiveness of ERLEADA in women have not been established. There are no data on the presence of apalutamide or its metabolites in breast milk, the effect on the infant, or the effect on milk production.

8.3. Women and men with childbearing potential.

Contraception.

Men.

Based on the mechanism of action and results of animal reproductive studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see. Use in special populations (8.1)].

Infertility.

Men.

Based on animal studies, it can be concluded that ERLEADA may affect reproductive function in men of reproductive potential [see Preclinical toxicology (13.1)].

8.4. Application in pediatrics.

The safety and effectiveness of ERLEADA in pediatric patients has not been established.

8.5. Application in geriatrics.

Of the 1,327 patients treated with ERLEADA in clinical studies, 19% of patients were younger than 65 years, 41% of patients were aged 65 to 74 years, and 40% were aged 75 years or older.

There were no overall differences in effectiveness between older and younger patients.

In patients receiving ERLEADA (n=1073), grade 3-4 adverse reactions were observed in 39% of patients under 65 years of age, 41% of patients aged 65-74 years, and 49% of patients aged 75 years or older. The incidence of falls in patients receiving ERLEADA with androgen deprivation therapy was increased in older adults, occurring in 8% of patients under 65 years of age. 10% of patients aged 65-74 years and 19% of patients aged 75 years or older.

10. Overdose.

A specific antidote for apalutamide overdose is unknown. If overdose occurs, discontinue ERLEADA and take general supportive measures until clinical signs of toxicity decrease or resolve.

11. Description.

Apalutamide, the active ingredient in ERLEADA, is an androgen receptor inhibitor. Chemical name: (4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-H- methylbenzamide). Apalutamide is a white or slightly yellow powder. Apalutamide is practically insoluble in aqueous media over a wide range of pH values.

- 59 046078

The molecular weight is 477.44 and the molecular formula is C21H ₁₅ F ₄ N ₅ O2S. Structural formula:

ERLEADA (apalutamide) is supplied as an oral film-coated tablet containing 60 mg of apalutamide. The inactive ingredients of the tablet core are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose and siliconized microcrystalline cellulose.

The tablets are treated by applying a commercially available film coating containing the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

12. Clinical pharmacology.

12.1. Mechanism of action.

Apalutamide is an androgen receptor (AR) inhibitor that directly binds to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and interferes with AR-mediated transcription. The major metabolite Ndesmethylapalutamide is a less active AR inhibitor and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Administration of apalutamide caused a decrease in tumor cell proliferation and an increase in apoptosis, leading to a decrease in tumor volume in xenograft mouse models of prostate cancer.

12.2. Pharmacodynamics.

Electrophysiology of the heart.

The effect of apalutamide 240 mg once daily on the QTc interval was assessed in an open-label, single-arm, multicenter, single-arm QT trial in 45 patients with CRPC. The maximum mean change in QTcF from baseline was 12.4 ms (two-sided upper 90% CI: 16.0 ms). Analysis of QT as a function of exposure showed a concentration-dependent increase in QTcF for apalutamide and its active metabolite.

12.3. Pharmacokinetics.

Pharmacokinetic parameters of apalutamide are presented as mean [standard deviation (SD)] unless otherwise stated. The _Cmax and area under the concentration curve (AUC) of apalutamide increased proportionally after repeated dosing from 30 to 480 mg once daily (a difference of 0.125 to 2 times the recommended dose). After administration of the recommended dose, steady-state apalutamide was achieved after 4 weeks, and the average accumulation rate increased approximately 5-fold. The _Cmax of apalutamide was 6.0 μg/ml (1.7) and the AUC was 100 μg-h/ml (32) at steady state. Daily variations in plasma apalutamide concentrations were low, with a peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeated dosing, likely due to induction of apalutamide's intrinsic metabolism. The autoinduction effect was likely greatest at the recommended dose because the effects of apalutamide over the dose range of 30 to 480 mg were dose proportional.

The _Cmax of the major active metabolite N-desmethylapalutamide was 5.9 μg/mL (1.0) and the AUC was 124 μg-h/mL (23) at steady state after the recommended dose. Ndesmethylapalutamide exhibited a flat steady-state concentration-time profile with an average peak-to-valley ratio of 1.27. The mean metabolite/parent drug AUC ratio for N-desmethylapalutamide after repeat dosing was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, it can be concluded that N-desmethylapalutamide likely contributed to the clinical activity of apalutamide.

Absorption.

The mean absolute oral bioavailability was approximately 100%. The median time to peak plasma concentration (max) was 2 hours (range: 1 to 5 hours).

The influence of food.

Administration of apalutamide to healthy subjects under fasted conditions and with a high-fat meal (approximately 500-600 calories of fat, 250 calories of carbohydrate and 150 calories of protein) is not recommended.

- 60 046078 led to clinically significant changes in Cm _ax and AUC. The median time to reach _tmax increased by approximately 2 hours after meals.

Distribution.

The average apparent volume of distribution at steady state for apalutamide was approximately 276 L.

Apalutamide was 96% and N-desmethylapalutamide was 95% bound to plasma proteins regardless of concentration.

Excretion.

The CL/F of apalutamide was 1.3 L/h after a single dose and increased to 2.0 L/h at steady state after once-daily dosing, likely due to autoinduction of CYP3A4. The mean effective half-life for apalutamide in patients was approximately 3 days at steady state.

Metabolism.

Metabolism is the main route of elimination of apalutamide. Apalutamide is metabolized primarily by CYP2CS and CYP3A4 to form the active metabolite N-desmethylapalutamide. The participation of CYP2CS and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% after a single dose, but changes to 40% and 37%, respectively, at steady state.

Apalutamide accounted for 45% and N-desmethylapalutamide accounted for 44% of the total AUC following a single 240 mg oral dose of radiolabeled apalutamide.

Excretion.

Up to 70 days after a single oral administration of radiolabeled apalutamide, 65% of the dose was excreted in the urine (1.2% of the dose as unchanged apalutamide and 2.7% as Ndesmethylapalutamide) and 24% was excreted in the feces (1.5% of the dose as unchanged apalutamide and 2% as N-desmethylapalutamide).

Special groups of patients.

There were no clinically significant differences in the pharmacokinetics of apalutamide or Ndesmethylapalutamide based on age (18-94 years), race (African American, Asian (except Japanese), Japanese), mild to moderate renal impairment (eGFR 30- 89 ml/min, 1.73 m, as assessed by Modified Dietary Dietary Disease Equation [MDRD]) or mild (Child-Pugh A) to moderate (Child-Pugh B) liver dysfunction.

The effect of severe or end-stage renal disease (eGFR <29 mL/min/1.73 m2, MDRD) or severe hepatic impairment (ChildPugh class C) on the pharmacokinetics of apalutamide is unknown.

Interactions between drugs.

Effect of other drugs on ERLEADA.

Active inhibitors of CYP2C8.

The _Cmax of apalutamide decreased by 21% and the AUC increased by 68% after coadministration of ERLEADA as a single 240 mg dose with gemfibrozil (an active CYP2C8 inhibitor). Gemfibrozil is predicted to increase the steady-state _Cmax of apalutamide by 32% and the AUC by 44%. For active functional groups (sum of unbound apalutamide plus activity-corrected unbound N-desmethylapalutamide), the estimated steady-state C _max increased by 19% and AUC increased by 23%.

Strong CYP3A4 inhibitors.

The _Cmax of apalutamide decreased by 22% and the AUC did not change after coadministration of ERLEADA as a single 240 mg dose with itraconazole (a strong CYP3A4 inhibitor). Ketoconazole (an active CYP3A4 inhibitor) is expected to increase the AUC of apalutamide single dose by 24%, but the AUC is not expected to affect _Cmax . Ketoconazole is predicted to increase the steady-state _Cmax of apalutamide by 38% and the AUC by 51%. For active functional groups, the estimated steady state _Cmax increased by 23% and AUC by 28%.

Inducers of CYP3A4/CYP2C8.

Rifampin (a strong inducer of CYP3A4 and a moderate inducer of CYP2C8) is predicted to reduce the steady-state _Cmax of apalutamide by 25% and the AUC by 34%. For active functional groups, the estimated steady state _Cmax was reduced by 15% and AUC by 19%.

Acidity reducing agents.

Apalutamide is not ionizable at the appropriate physiological pH, so acid-decreasing agents (eg, proton pump inhibitor, H2 receptor antagonist, antacid) do not affect the solubility and bioavailability of apalutamide.

Drugs that affect transporters.

In vitro, apalutamide and N-desmethylapalutamide are substrates for P-gp, but not

- 61 046078

BCRP, OATPIB1 and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide, and therefore inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.

Effect of ERLEADA on other drugs.

CYP substrates.

In vitro studies have shown that apalutamide and N-desmethylapalutamide are moderate to strong inducers of CYP3A4 and CYP2B6, moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19 and CYP3A4. Apalutamide and N-desmethylapalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations.

Coadministration of ERLEADA with single oral doses of sensitive CYP substrates resulted in a 92% reduction in the AUC of midazolam (a CYP3A4 substrate), an 85% reduction in the AUC of omeprazole (a CYP2C19 substrate), and a 46% reduction in the AUC of S-warfarin (a CYP2C9 substrate). ERLEADA did not cause clinically significant changes when exposed to a CYP2C8 substrate.

Substrates P-gp, BCRP and OATP1B1.

Coadministration of ERLEADA with single oral doses of transporter substrates reduced the AUC of fexofenadine (P-gp substrate) by 30% and the AUC of rosuvastatin (BCRP/OATPIB1 substrate) by 41%, but had no effect on _Cmax .

UGT substrates.

Apalutamide may induce UGT. Coadministration of ERLEADA with drugs that are UGT substrates may result in decreased exposure to these drugs.

Substrates OCT2, OAT1, OAT3 and MATES.

In vitro, apalutamide and N-desmethylapalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug resistance and toxin clearance (MATES) proteins, and do not inhibit organic cation transporter 1. Apalutamide is not expected to produce clinically significant changes when acting on the OAT3 substrate.

Analogue of GnRH.

In subjects with mCSPC treated with leuprolide acetate (a GnRH analogue) coadministered with apalutamide, PK data indicate that apalutamide had no significant effect on steady-state leuprolide exposure.

13. Preclinical toxicology.

13.1. Carcinogenesis, mutagenesis, reproductive dysfunction.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of apalutamide. Apalutamide did not induce mutations in the bacterial reverse mutation assay (Ames) and was not genotoxic in either the in vitro chromosomal aberration assay, the in vivo micronucleus detection assay in rat bone marrow, or the in vivo DNA comet assay in rats.

Repeated dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks) observed prostatic and seminal vesicle atrophy, aspermia/hypospermia, degenerative changes and/or tubular hyperplasia or interstitial cell hypertrophy in the reproductive system at >25 mg /kg/day in rats (1.4 times the human exposure based on AUC) and >2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC).

In a reproductive study in male rats, after 4 weeks of dosing >25 mg/kg/day (approximately 0.8 times the human exposure based on AUC), decreased sperm concentration and motility, increased abnormal sperm morphology, and decreased frequency sexual intercourse and fertility rate (when copulating with females who did not receive treatment), as well as a decrease in the weight of the secondary sex glands and epididymis. After 4 weeks of dosing at 150 mg/kg/day (5.7 times the human exposure based on AUC), a decrease in the number of live fetuses was observed due to an increased rate of miscarriage before and/or after implant loss. The effects in male rats were reversible 8 weeks after the last administration of apalutamide.

14. Clinical studies.

The effectiveness and safety of ERLEADA therapy was established in two randomized, placebo-controlled clinical trials.

TITAN (NCT02489318). Metastatic castration-sensitive prostate cancer (mCSPC).

The TITAN study was a double-blind, randomized, placebo-controlled, international clinical trial that randomized 1052 patients with mCSPC (1:1) to receive either ERLEADA 240 mg orally once daily (N=525) or placebo once daily ( N=527). All patients in the TITAN study simultaneously received an analogue

- 62 046078 gonadotropin-releasing hormone (GnRH), or have previously had a bilateral orchiectomy. Patients were stratified by Gleason score at diagnosis, previous use of docetaxel, and region of the world. Patients with high- and low-volume mCSPC met the inclusion criteria for the study. High-volume disease was defined as metastases involving internal organs with 1 bone lesion, or the presence of 4 or more bone lesions, at least 1 of which must be in a bony structure outside the spinal column and pelvic bones.

Below is patient information and baseline disease characteristics in the various treatment groups. The median age was 68 years (range 43–94), and 23% of patients were 75 years of age or older. The racial distribution was as follows: 68% Caucasian, 22% Mongoloid, and 2% Negroid. Sixty-three (63%) patients had high-volume disease and 37% had low-volume disease. 16% of patients had previously undergone prostate surgery, radiotherapy, or both. Most patients had a Gleason score of 8 or higher (67%). Sixty-eight percent (68%) of patients had previously been treated with an antiandrogen (bicalutamide, flutamide, or nilutamide). At the time of study enrollment, all but one patient in the placebo group had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1.

The study's primary outcome measures were overall survival (OS) and radiographic progression-free survival (PFS). Radiographic progression-free survival was based on investigator judgment and was defined as the time from randomization to radiographic progression or death. Radiographic disease progression was defined as the presence of 2 or more new bone lesions on a confirmation scan (Prostate Cancer Working Group 2 criteria) and/or progression of soft tissue disease.

Statistically significant improvements in OS and rPFS were demonstrated in patients randomized to receive ERLEADA compared with patients randomized to receive placebo. Results for OS are based on a prespecified interim efficacy analysis. The results of determining the effectiveness of TITAN are given in table. 5 and fig. 1 and 2.

Table 5

Efficacy Summary - mCSPC Intent-to-Treat Group _________________________________________(TITAN)___________________________________________

Final indicator ERLEADA N=525 Placebo N=527 Overall survival ^a Fatalities (%) 83 (16%) 117 (22%) Median value, months (CI 95%) ^d BUT BUT BUT) BUT BUT BUT) Hazard ratio (95% CI) ^b p-value ^c Radiographic progression-free survival Disease progression or 0.67 (0.51, 0.89) 0.0053 134 (26%) 231 (44%) mortality (%) Median value, months (CI 95%) ^d BUT BUT BUT) 22.1 (18, 33) Risk ratio (CI 95%) ^b p-value ^c 0.48 (0.39, 0.60) <0.0001

^a The interim analysis is based on 50% of the total number of events planned for the final analysis. Set alpha=0.01.

^b Hazard ratios obtained from a stratified proportional hazards model. A hazard ratio <1 indicates benefits of ERLEADA.

^c p-value determined by log-rank test stratified by Leeson G score at diagnosis (<7 or >7), region (CA/EU or rest of the world) and previous exposure to docetaxel (yes or no).

^d N/A - not subject to assessment 4.

Consistent improvement in rPFS was observed in the following patient subgroups: disease volume (high or low), prior use of docetaxel (yes or no), and Gleason score at diagnosis (<7 or >7).

Consistent improvement in OS was observed in the following patient subgroups: disease volume (high or low) and Gleason score at diagnosis (<7 or >7).

Treatment with ERLEADA statistically significantly delayed the initiation of cytotoxic chemotherapy (HR=0.39, CI 95%, 0.27, 0.56: p < 0.0001).

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Fig. 1. Kaplan-Meier plot of overall survival (OS); mCSPC intention-to-treat group (TITAN).

Months after randomization

Subjects at risk.

Placebo 527 524 509 502 473 456 387 263 142 59 163

ERLEADA 525 519 513 500 490 467 410 289 165 60 143

Fig. 2. Kaplan-Meier plot of radiographic progression-free survival (rPFS); mCSPC intention-to-treat group (TITAN).

Months after randomization

Subjects at risk.

Placebo 527 488 437 381 325 240 229 140 57 14 31

ERLEADA 525 498 469 434 389 326 315 194 89 21 21

SPARTAN (NCT01946204). Non-metastatic castration-resistant prostate cancer (nmCRPC).

The SPARTAN study was a double-blind, randomized (2:1), placebo-controlled clinical trial that randomized 1207 patients with nmCRPC (2:1) to receive either ERLEADA 240 mg orally once daily (N=806) or placebo alone. once a day (N=401). All patients in the SPARTAN study were concurrently receiving a gonadotropin-releasing hormone (GnRH) analogue or undergoing bilateral orchiectomy. Patients were stratified by prostate-specific antigen (PSA) doubling time (PSADT), use

- 64 046078 bone protecting agents and the presence of local-regional disease. Patients were required to have PSADT <10 months and non-metastatic disease confirmed by blinded independent central review (BICR). PSA test results were kept confidential and were not used to discontinue treatment. Patients randomized to either arm discontinued treatment if they developed radiographic evidence of disease progression confirmed by BICR, locoregional progression only, started a new treatment, experienced unacceptable toxicity, or were withdrawn from the study.

Below is patient information and baseline disease characteristics in the various treatment groups. The median age was 74 years (range 48–97 years), and 26% of patients were aged 80 years or older. The distribution by race was as follows: 66% Caucasian, 12% Mongoloid and 6% Negroid. Seventy-seven percent (77%) of patients in both treatment groups had previously undergone prostate surgery or radiotherapy. At study entry, the majority of patients had a Gleason score of 7 or higher (78%) percent and (15%) patients had pelvic lymph nodes measuring 2 cm. Seventy-three percent (73%) of patients had received prior antiandrogen treatment; 69% of patients received bicalutamide and 10% of patients received flutamide. At the time of study enrollment, all patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Among patients who discontinued study treatment (N=279 for placebo and N=314 for ERLEADA), a large proportion ( 80%) of patients treated with placebo received subsequent therapy compared with patients treated with ERLEADA (56%). Overall, local-regional progression was observed in 2% of patients.

The primary outcome measure in the study was metastasis-free survival (MFS), defined as the time from randomization to the first sign of BICR-confirmed distant metastases, defined as new or soft tissue lesions, or lymph node enlargement above the iliac bifurcation, or until death according to for any reason, depending on what happened before. Additional efficacy endpoints were time to metastasis (TTM), progression-free survival (PFS), which also includes locoregional progression, time to symptom progression, and overall survival (OS).

A statistically significant improvement in MFS was demonstrated in patients randomized to receive ERLEADA compared with patients randomized to receive placebo. Consistent results were observed across all patient subgroups, including PSADT (<6 months or >6 months), prior use of a bone-protecting agent (yes or no), and locoregional disease (N0 or N1). Primary efficacy measures were supported by statistically significant improvements in TTM, PFS, and time to symptom progression. Overall survival (OS) data were incomplete at the time of final MFS analysis (24% of the required number of events). The effectiveness results for MFS, TTM and PFS in the SPARTAN study are shown in FIG. 3 and in table. 6.

Fig. 3. Kaplan-Meier metastasis-free survival (MFS) curve from the SPARTAN trial (nmCRPC).

Months after randomization

Subjects at risk. Placebo 401 291 220 153 91 58 34 13 5 1 0 0 ERLEADA 806 713 652 514 398 282 180 96 36 1 3 0

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Table 6

Results of performance evaluation based on BICR (SPARTAN)

Final indicator Number of events (%) Median value [months (CI 95%)] HR (95% CI), value (log rank test) ERLEADA (n=806) Placebo (N=401) ERLEADA Placebo Metastasis-free survival 184 (23%) 194 (48%) 40.5 (N/O, N/O) 16.2 (15, 18) 0.28 (0.23, 0.35) <0.0001 Time until metastasis appears 175 (22%) 191 (48%) 40.5 (N/O, N/O) 16.6 (15, 18) 0.27, (0.22, 0.34) <0.0001 Progression-free survival 200 (25%) 204 (51%) 40.5 (N/O, N/O) 14.7 (14, 18) 0.29, (0.24, 0.36) <0.0001

'All analyzes were stratified by PSA doubling time, use of a bone-protecting agent, and locoregional disease status.

N/A=not gradable.

16. Release form/storage and handling.

ERLEADA (apalutamide) 60 mg film-coated tablets are slightly yellowish to grayish-green oblong tablets embossed with AR 60 on one side. ERLEADA 60 mg tablets are supplied in bottles containing 120 tablets. Each bottle contains a silica gel desiccant.

NDC number 59676D600D12.

Storage and handling.

Store at 20°C to 25°C (68°F to 77°F): tolerance 15°C to 30°C (59°F to 86°F) [see USP, controlled room temperature].

Store in original packaging. Do not throw away the desiccant. Protect from light and moisture.

17. Information for the patient.

The patient is advised to review the FDA-approved information provided with the drug (patient information).

Ischemic cardiovascular events.

Inform patients that ERLEADA has been associated with ischemic cardiovascular events. Advise patients to seek immediate medical attention if they experience any symptoms suggestive of a cardiovascular event [see. Warnings and precautions (5.1)].

Falls and fractures.

Inform patients that ERLEADA is associated with an increased incidence of falls and fractures [see. Warnings and precautions (5.2, 5.3)].

Convulsive attacks.

Inform the patient that taking ERLEADA is associated with an increased risk of seizure. Discuss conditions that may contribute to seizures and medications that may lower the seizure threshold. Inform patients of the risk of participating in any activity in which the patient could cause serious harm to himself or others if he suddenly loses consciousness. Inform patients that they should contact their healthcare provider immediately if they develop a seizure [see. Warnings and precautions (5.4)].

Rash.

Inform patients that taking ERLEADA has been associated with rash and that if a rash occurs they should notify their prescriber [see. Adverse reactions (6.1)].

Dose and route of administration.

Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they must continue this treatment during their course of treatment with ERLEADA.

Explain to patients that they need to take their dose at the same time every day (once daily). ERLEADA can be taken with or without food. Each tablet should be swallowed whole.

Inform patients that if they miss a daily dose of ERLEADA, they should take their regular dose as soon as possible on the same day and return to their regular dosing schedule the next day. The patient should not take additional tablets to make up for a missed dose [see. Dose and route of administration (2.1)].

Embryofetal toxicity.

Inform patients that ERLEADA may cause harm to a developing fetus. Recommend

- 66 046078 male patients with female partners of reproductive potential, use effective contraception during treatment and for 3 months after the last dose of ERLEADA. Advise male patients to use condoms if they have sexual contact with a pregnant woman [see Warnings and precautions (5.5)].

Infertility.

Inform male patients that ERLEADA may interfere with reproductive function and advise against becoming a sperm donor during therapy and for 3 months after the last dose of ERLEADA [see. Use in special populations (8.3)].

Manufacturer: Janssen Ortho LLC Gurabo, PR 00778.

Manufactured by: Janssen Products, LP Horsham, PA 19044 ©2019 Janssen Pharmaceutical Companies.______________________________________________________________

PATIENT INFORMATION ERLEADA® (er-li-da) (apalutamide) _____Tablets________________________________________________________________________________ What is ERLEADA?

ERLEADA is a prescription drug used to treat prostate cancer:

that has spread to other parts of the body and is still responding to medical or surgical treatment that lowers testosterone levels, OR that has not spread to other parts of the body and is no longer responding to medical or surgical testosterone.

The effectiveness or safety of ERLEADA in women is unknown.

_____The effectiveness or safety of ERLEADA in children is unknown.___________________________

Before taking ERLEADA, tell your doctor about all of your medical conditions, including:

a history of heart disease;

high blood pressure;

diabetes;

having abnormal amounts of fat or cholesterol in your blood (dyslipidemia);

a history of seizures, brain damage, stroke, or brain tumors; pregnancy or planning pregnancy. ERLEADA may harm your unborn baby and may cause miscarriage;

(miscarriage);

having a pregnant partner or a partner who may become pregnant.

Male people with female partners who may become pregnant should use effective birth control (contraception) during treatment and for 3 months after the last dose of ERLEADA.

Males should use a condom when having sex with a pregnant woman.

Any questions regarding contraception can be discussed with your doctor.

Currently breastfeeding or planning to breastfeed. It is not known whether ERLEADA passes into breast milk.

Tell your doctor about all the medications you take, including prescription and over-the-counter drugs, vitamins, and herbal supplements. ERLEADA may interact with many other drugs.

You should not start or stop taking any medications without discussing with your doctor who prescribed ERLEADA.

Keep track of all medications you take. Carry a list of these with you to show your doctor and pharmacist when you get a new drug.

How to take ERLEADA?

Take ERLEADA exactly as directed by your doctor.

Your doctor may change your dose if necessary.

Do not stop taking your prescribed dose of ERLEADA without first discussing with your doctor.

Take the prescribed dose of ERLEADA once daily, at the same time of day.

ERLEADA can be taken with or without food.

Swallow ERLEADA tablets whole.

If you miss a dose of ERLEADA, take your regular dose as soon as possible on the same day. The next day, return to your normal dosing regimen. You should not take extra tablets to make up for a missed dose.

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During treatment with ERLEADA, you will need to start or continue therapy with a gonadotropin-releasing hormone (GnRH) analogue unless you have had surgery to reduce the amount of testosterone in your body (surgical castration).

If you have taken too much ERLEADA, contact your doctor or the emergency department of your nearest hospital.__________________________________________________________

What are the possible side effects of ERLEADA?

ERLEADA may cause serious side effects, including:

Heart disease. Some people have had blockages in their heart arteries while being treated with ERLEADA, which can be fatal. Your doctor will monitor you for signs and symptoms of heart problems while you are treated with ERLEADA. Contact your healthcare provider or the nearest emergency room if you experience chest pain or discomfort at rest or during activities, or shortness of breath while taking ERLEADA.

Fractures and falls. Treatment with ERLEADA may weaken bones and muscles and may increase the risk of falls and fractures. Falls and fractures have occurred in people while being treated with ERLEADA. Your healthcare provider should monitor the risk of falls and fractures during treatment with ERLEADA.

Convulsive attack. Treatment with ERLEADA may increase the risk of seizures. You should avoid activities that could cause serious harm to yourself or others if you suddenly lose consciousness. Tell your doctor if you lose consciousness or have a seizure. Your doctor should stop ERLEADA if you have a seizure during treatment.

The most common side effects of ERLEADA include:

feeling very tired; weight loss;

joint pain; hypertension;

rash.Tell your doctor if you have hot flashes;

you get a rash. diarrhea;

decreased appetite; fracture

a fall;

ERLEADA may cause reproductive problems in men, which may affect the ability to conceive a child. Talk to your doctor if you have any concerns about your fertility. Do not become a sperm donor during treatment with ERLEADA and for 3 months after the last dose of ERLEADA.

Tell your doctor if you notice any bothersome or persistent side effects. Not all possible side effects of ERLEADA are listed. Ask your healthcare provider for medical advice regarding side effects. You may report side effects to the FDA at 1-800-FDA-1088.______________________________

How to store ERLEADA?

Store ERLEADA at room temperature between 68°F and 77°F (20°C and 25°C).

Store ERLEADA in its original packaging.

The ERLEADA bottle contains a desiccant packet that helps keep the medicine dry (protect it from moisture). Do not throw away (recycle) the desiccant.

Protect ERLEADA from light and moisture.

_____Keep ERLEADA and all other medicines out of the reach of children.___________________

General information about the safe and effective use of ERLEADA.

Drugs are sometimes prescribed for purposes other than those listed in the patient information leaflet. Do not use ERLEADA to treat a condition for which it is not prescribed. Do not give ERLEADA to other people, even if they have the same symptoms as you, as it may harm them. For more detailed information, contact your doctor. You can ask your doctor or pharmacist for information about ERLEADA prepared for health care professionals._______

What ingredients are included in ERLEADA?

Active ingredient: apalutamide.

Inactive Ingredients: Colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose and siliconized microcrystalline cellulose. The film shell contains black iron oxide, yellow iron oxide, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Manufacturer: Janssen Ortho LLC, Gurabo, PR 00778.

Manufactured by: Janssen Products, LP, Horsham, PA 19044 ©2019 Janssen Pharmaceutical Companies

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Claims (11)

For more information, contact Janssen Products, LPR 1800-526-7736 (1-800-JANSSEN) or www.erleada.com.____________________________________ This patient information has been approved by the US Food and Drug Administration. Reviewed: September 2019 The examples and embodiments described herein are for illustration purposes only, and various modifications or changes that may be suggested by those skilled in the art are intended to be included within the spirit and scope of this application and within the scope of the appended claims. CLAIM 1. A method of treating metastatic castration-sensitive prostate cancer in a male subject, comprising or consisting of administering a therapeutically effective amount of an antiandrogen in combination with androgen deprivation therapy to a male subject with metastatic castration-sensitive prostate cancer, wherein the antiandrogen is: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoroN-methylbenzamide, and in wherein the administration of an antiandrogen in combination with androgen deprivation therapy provides an increase in the overall survival of a male subject relative to the overall survival of a group of male subjects with metastatic castration-sensitive prostate cancer, which group was administered placebo in combination with androgen deprivation therapy; or wherein administration of an antiandrogen in combination with androgen deprivation therapy provides an increase in progression-free survival in a male subject relative to progression-free survival in a group of male subjects with metastatic castration-sensitive prostate cancer, which group was administered placebo in combination with androgen deprivation therapy. 2. The method of claim 1, wherein the male subject has received at least one prior therapy for treating cancer, wherein the prior therapy for treating cancer is radiation, surgery, or docetaxel therapy. 3. The method of claim 1, wherein the male subject has not previously received treatment. 4. The method according to any of the preceding claims, wherein 4-[7-(6-cyano-5-trifluoromethylpyridin3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-Nmethylbenzamide is administered to a male subject daily. 5. The method according to any of the preceding claims, wherein 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-Fluoro-Nmethylbenzamide is administered orally to a male subject, optionally on a continuous daily dosing schedule. 6. The method according to claim 5, in which 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]- 2-Fluoro-Nmethylbenzamide is administered orally to a male human at a dose of 30 mg per day to 480 mg per day, optionally at a dose of 180 mg per day to 480 mg per day. 7. The method according to claim 6, in which 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]- 2-fluoro-Nmethylbenzamide is administered orally to a male human in the following dose: (a) 30 mg per day; (b) 60 mg per day; (c) 90 mg per day; (d) 120 mg per day; or (d) 240 mg per day. 8. The method according to claim 7, in which 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl]- 2-Fluoro-Nmethylbenzamide is administered orally to a male human at a dose of 240 mg per day. 9. The method according to claim 8, in which the dose of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-yl] -2-fluoro-Nmethylbenzamide is reduced to 180 mg per day or to 120 mg per day if a male subject experiences grade 3 or higher toxicity. 10. The method according to any of the preceding claims, wherein the administration of an antiandrogen in combination with androgen deprivation therapy provides an increase in overall survival and a 33% reduction in the risk of death; or an increase in progression-free survival and a 52% reduction in the risk of radiographic progression or death. 11. The method according to any of the preceding claims, wherein 4-[7-(6-cyano-5trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl] -2-fluoro-Nmethylbenzamide is administered in combination with at least one gonadotropin agonist or antagonist -