WO2022195407A1

WO2022195407A1 - Methods for treating prostate cancer

Info

Publication number: WO2022195407A1
Application number: PCT/IB2022/052105
Authority: WO
Inventors: Suneel D. MUNDLE; Mohamed Samir SALEH; Laurent Paul ANTONI
Original assignee: Aragon Pharmaceuticals, Inc.
Priority date: 2021-03-19
Filing date: 2022-03-09
Publication date: 2022-09-22

Abstract

The disclosure provides methods of treating prostate cancer in a patient in need thereof, the methods comprising performing an imaging technique that is selected from an ultrasound imaging, magnetic resonance imaging, positron emission tomography imaging, computed tomography imaging, bone imaging, or a combination thereof on the patient; generating a conventional imaging result from the conventional imaging technique, wherein the conventional imaging result does not indicate metastasis of the prostate cancer; performing prostate -specific membrane antigen-positron emission tomography (PSMA-PET) on the patient; generating a first PSMA-PET result of the PSMA-PET, wherein the first PSMA-PET result indicates metastasis of the prostate cancer and is generated at substantially the same time as the conventional imaging result; and administering a therapeutically effective amount of apalutamide to the patient following generation of said first PSMA-PET result.

Description

METHODS FOR TREATING PROSTATE CANCER

TECHNICAL FIELD

[0001] Disclosed herein are, among other tilings, methods for treating prostate cancer.

BACKGROUND

[0002] Prostate cancer is currently the fifth leading cause of cancer deaths among men globally, with 1 million patients diagnosed per year and a mortality burden of over 300,000 deaths. Prostate cancer, particularly advanced prostate cancer, has many forms. These include castration-sensitive prostate cancers, castration-resistant prostate cancers, or high-risk localized prostate cancers. In some embodiments, the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer or non-metastatic castration resistant prostate cancer (NM-CRPC). In other embodiments, the castration-sensitive prostate cancer is metastatic castration-sensitive prostate cancer or non-metastatic castration -sensitive prostate cancer.

[0003] Approximately 25% to 35% of patients treated with radical prostatectomy for localized adenocarcinoma of the prostate will relapse in the form of rising serum prostate- specific antigen (PSA) without overt metastatic disease, termed biochemical recurrence, which can progress to metastases. A short PSA doubling time (PSADT) is one of the main predictors of metastases (detected by conventional ^99mTc-bone scan and computed tomography scan), prostate cancer-specific mortality, and overall mortality for patients with biochemical recurrence (BCR). PSADT is a mathematical determination of the length of time (in months) needed for the PSA level to double in a given patient. Risk stratification of patients based on PSADT has varied across studies; a recent systematic review and metaanalysis investigated the impact of BCR on endpoints and concluded that patients experiencing BCR are at an increased risk of developing metastases, prostate cancer-specific and overall mortality. Patients with high-risk BCR are therefore a discrete group of prostate cancer patients with a high unmet medical need for which management and treatment outcomes needs improving.

[0004] Apalutamide, enzalutamide, and darolutamide are androgen receptor inhibitors for the treatment of prostate cancer. These therapeutic drags are currently approved in multiple countries for the treatment of non-metastatic castration-resistant prostate cancer and/or metastatic castration-sensitive prostate cancer.

[0005] Positron emission tomography of radiolabeled prostate-specific membrane antigen (PSMA-PET) is an emerging imaging modality to assess the burden of prostate cancer. PSMA-PET is more sensitive than conventional imaging (e.g., "“Tc-bone scan, computed tomography and/or magnetic resonance imaging scans, transrecta! ultrasound scan, and/or conventional PET imaging). However, PSMA-PET is utilized most frequently after a cancer diagnosis is made and for monitoring for metastasis.

[0006] Methods are needed for earlier detection of prostate cancer with the aim of better managing patient outcomes including survival.

SUMMARY

[0007] The present invention relates to, for example, methods of treating prostate cancer in a patient in need thereof, the methods comprising, consisting of and/or consisting essentially of performing an imaging technique that is selected from an ultrasound imaging, magnetic resonance imaging, positron emission tomography imaging, computed tomography imaging, bone imaging, or a combination thereof on the patient; generating a conventional imaging result from the conventional imaging technique, wherein the conventional imaging result does not indicate metastasis of the prostate cancer; performing prostate-specific membrane antigen-positron emission tomography (PSMA-PET) on the patient; generating a first PSMA-PET result of the PSMA-PET, wherein the first PSMA-PET result indicates metastasis of the prostate cancer and is generated at substantially the same time as the conventional imaging result; and administering a therapeutically effective amount of apalutamide to the patient following generation of said first PSMA-PET result,

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is a scheme of the study described in Example 1.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0009] The methods described herein permit earlier diagnosis of prostate cancer and, thus, result in improved outcomes for patients. In doing so, the methods utilize PSMA- PET instead of or in addition to conventional imaging techniques that often fail to detect prostate cancer, particular at early stages of development or metastasis. Although conventional imaging techniques alone may be useful, PSMA-PET in combination with conventional imaging techniques provide a superior initial imaging technique to detect prostate cancer and, thereafter, manage treatment thereof. By detecting prostate cancer in its early stages, apalutamide can be incorporated at an early stage to increase survival rates of the patients.

Certain Terminology

[0010] Tire term “cancer^”' as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some eases, to metastasize (spread). The term “prostate cancer^’’ as used herein refers to histologically or cytologically confirmed adenocarcinoma of the prostate. The adenocarcinoma may be acinar or ductal. In some aspects, the adenocarcinoma is acinar. In other aspects, the adenocarcinoma is ductal. In some embodiments, the prostate cancer is localized prostate cancer, wherein the cancer is found only in the prostate . In other embodiments, the prostate cancer is metastatic prostate cancer, wherein the cancer has spread outside of the prostate. In further embodiments, the cancer is castration resistant prostate cancer. In yet other embodiments, the cancer is castrate-sensitive prostate cancer. In still further embodiments, the cancer is hormone- refractory prostate cancer.

[0011] Castration resistant prostate cancer (CRPC) is defined by disease progression despite androgen deprivation therapy and may present as either a continuous rise in serum PSA levels, the progression of pre-existing disease and/or the appearance of new metastases.

[0012] In some aspects, the cancer has metastasized. The metastasis may be new or recurrent. In some embodiments, the metastasis is new. In other embodiments, the metastasis if recurrent. The term “metastasis” as used herein refers to the spread of cancer from an initial or primary site to a different or secondary site within the body. In some embodiments, the cancer has spread within the prostate. In other embodiments, the cancer is a distant metastasis, i.e., where the cancer continues to spread outside of the prostate. The cancer may spread to other areas of the body including, without limitation, the bones, lungs, liver, brain, lymph nodes, or a combination thereof. Often, prostate cancer spreads to the hip of the patient. In certain embodiments, the patient treated according to the methods described herein have a prostate cancer metastasis that begins after treatment. In other embodiments, the patient treated according to the methods described herein have a prostate cancer metastasis that is existing prior to treatment. In further embodiments, the prostate cancer is recurrent prostate cancer, i. e. , the cancer is found after treatment, and after a period of time when the cancer couldn't be detected. Recurrent prostate cancer may return where it started, i.e., a local recurrence, or elsewhere in the body. In further embodiments, the patient has an adenocarcinoma of the prostate and one or more of a PSADT of about 12 months or less, a Gleason score of about 8 or greater, and prostate specific antigen of less than about 0.1 ng/mL, after pelvis radiography. In other embodiments, the prostate cancer is castration resistant prostate cancer (CRPC),

[0013] The prostate cancer may also be grouped or staged using categories known in the art. Thus, the prostate cancer may be Stage I, II, IIA, PB, IIC, III, IIIA, PIB, IIIC, IV, IVA, or IVB. In some embodiments, the prostate cancer is Stage I, i.e., a slow growing cancer, the tumor cannot be felt, the tumor involves one-half of one side of the prostate or less, PSA levels are low, cancer cells are well differentiated, or combinations thereof. In other embodiments, the prostate cancer is Stage II, i.e., tumor is found only in the prostate, PSA levels are medium or low, tumor is small but may have an increasing risk of growing and spreading, or combinations thereof. In further embodiments, the prostate cancer is Stage IIA, i.e., (i) the tumor cannot be felt, the tumor involves half of one side of the prostate or less, PSA levels are medium, the cancer cells are well differentiated, or combinations thereof; or (ii) larger tumors confined to the prostate with well differentiated cancer cells. In yet other embodiments, the prostate cancer is Stage IIB, i.e., tumor is found only inside the prostate, tumor is large enough to be felt during digital rectal exam (DRE), PSA level is medium, cancer cells are moderately differentiated, or combinations thereof. In still further embodiments, the prostate cancer is Stage IIC, i.e., tumor is found only inside the prostate, tumor may be large enough to be felt during DRE, PSA level is medium, cancer cells are moderately or poorly differentiated, or combinations thereof. In other embodiments, the prostate cancer is Stage III, i.e., PSA levels are high, tumor is growing, cancer is high grade, or combinations thereof. In further embodiments, the prostate cancer is Stage IIIA, i.e., cancer spread beyond the outer layer of the prostate into nearby tissues, cancer spread to the seminal vesicles, PSA level is high, or combinations thereof. In still other embodiments, the prostate cancer is Stage IIIB, i.e., tumor has grown outside of the prostate gland, tumor invaded nearby structures, such as the bladder or rectum, or combinations thereof. In yet further embodiments, the prostate cancer is Stage IIIC, i.e., cancer cells across the tumor are poorly differentiated. In other embodiments, the prostate cancer is Stage IV, i.e., cancer spread beyond the prostate. In further embodiments, the prostate cancer is Stage 1VA, i.e., cancer has spread to the regional lymph nodes. In yet other embodiments, the prostate cancer is Stage IVB, i.e., cancer spread to distant lymph nodes, other parts of the body, or to the bones.

[0014] The temi “co-administration” or the like, as used herein, encompass administration of apalutamide with another therapeutic agent or technique to a patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. For example, administration of on therapeutic agent may be administered prior to, subsequent to, or concurrently with another therapeutic agent.

[0015] The terms “treat” and “treatment” refer to the treatment of a patient afflicted with a pathological condition and refers to reducing or ameliorating such condition and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a pathological condition does not require that the condition or symptoms associated therewith be completely eliminated. Unless otherwise specified, the terms “treat” and “treatment” refers to the totality of effects described, but on other embodiments, the terms may also refer to any one of the effects described, or exclusive of at least one effect,

[0016] The terms “subject,” “patient,” and “human” are used interchangeably.

[0017] The transitional terms “comprising,” “consisting essentially of,” and “consisting” are intended to connote their generally in accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” or “containing” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel eharacteristie(s) of the disclosure.

[0018] Embodiments described in terms of the phrase “comprising” (or its equivalents), also provide, as embodiments, those which are independently described in terms of “consisting of’ and “consisting essentially of.” [0019] When a value is expressed as an approximation by use of the descriptor ‘"about,” it will he understood that the particular value forms another embodiment, in general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinab!e. That is, references to values stated in ranges include every value within that range. If not otherwise specified, the term “about” signifies a variance of ±10% of the associated value, but additional embodiments include those where the variance may be ±5%, ±15%, ±20%, ±25%, or ±50%.

[0020] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiments) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.

[0021] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0022] The present invention may be understood more readily by reference to the following description taken in connection with the accompanying drawing and example, all of which fonn a part of this disclosure. It is to be understood that this invention is not limited to die specific products, methods, conditions or parameters described or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by- way of example only and is not intended to be limiting of any claimed invention. Similarly, unless specifically otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not to be constrained by the correctness or incorrectness of any such suggested mechanism os- mode of action or reason for improvement. Throughout this text, it is recognized that the descriptions refer to various compounds, compositions and methods of using said compounds and compositions. That is, where the disclosure describes or claims a feature or embodiment associated with a composition or a method of using a composition, it is appreciated that such a description or claim is intended to extend these features or embodiment to embodiments in each of these contexts (i.e., compositions and methods of using).

METHODS

[0023] The methods described herein are for treating prostate cancer in a patient in need thereof. The methods use PSMA-PET imaging, but the first technique is performing an imaging technique on the patient. The term ‘^‘imaging technique” as used herein refers to an imagine technique that is conventionally used to detect prostate cancer or monitor its progression. One skilled in the art would readily be able to determine and select conventional imagine techniques. In some embodiments, the imaging technique is ultrasound imaging, magnetic resonance imaging, positron emission tomography imaging, computed tomography imaging, bone imaging, or a combination thereof. In other embodiments, the imaging technique is ultrasound imaging, such as transrectal ultrasound, color Doppler, power ultrasound, or 3-dimensional (3-D) ultrasound. In further embodiments, the imaging technique is magnetic resonance imaging, such as diffusion-weighted imaging (DWI), T2- weighted imaging, dynamic intravenous contrast-enhanced (DCE) imaging, or magnetic resonance spectroscopy (MRSI) imaging. Typically, magnetic resonance imaging uses a prostate imaging reporting and data system (PI-RADS) to characterize and assess all focal intraglandular prostate nodules. The PI-RADS system categorizes prostate lesions based on the likelihood of cancer according to a five-point scale as follows:

[0024] In yet other embodiments, the imaging technique is positron emission tomography (PET) imaging. Typically, PET imaging is used in combination with a PET imaging agent or tracer. Examples of PET tracers include ¹⁸F-sodmm fluoride; fluorodeoxyglucose; choline-based radiotracers such as ^{1 ]}C-choIine and ¹⁸F -choline; PSMA- targeted radiotracers such as ⁶⁸Ga-PSMA-11, ¹⁸F-PSMA-1007, ¹⁸F-DCFPy, and J591; ¹⁸F- fluciclovine; bombesin analogues such as ⁶⁸Ga-labelled bombesin antagonists; and PET- visible radiotracers linked to androgen analogues such as 16-β-¹⁸F-fluoro-5-α- dihydrotestosterone (¹⁸F-FDHT), In still further embodiments, the imaging technique is computed tomography (CT) imaging. Examples of CT imaging useful for treating prostate cancer include, without limitation, helical CT imaging, 3-D CT angiography, CT-guided biopsy, large bore CT scanner / RT with simulation, Multi-detector CT scanning, or combined PET/CT imaging. In other embodiments, the imaging technique is bone imaging which analyzes the osteoblastic response to bone destruction by tumor cell. Typically, bone imaging is performed using a radioactive substance.

[0025] After the imaging technique is performed, a conventional imaging result is generated from the conventional imaging technique. One of skill in the art would readily be able to generate the conventional imaging result using the data obtained during the imaging. In some embodiments, the conventional imaging result from the conventional imaging technique does not indicate metastasis of the prostate cancer. One of skill in the art would understand how to interpret the conventional imaging result depending on the conventional imaging technique employed.

[0026] As discussed, traditionally if a conventional imaging technique does not indicate metastasis of prostate cancer, then no additional imaging techniques are utilized and it is assumed that the patient’s prostate cancer has not metastasized. However, the methods described herein include performing prostate-specific membrane antigen-positron emission tomography (PSMA-PET) on the patient even though conventional imaging techniques show no signs of cancer metastasis. One skilled in the art would readily be able to utilize analytical techniques, knowledge and instalments to perform the PSMA-PET and produce results for use herein.

[0027] A first PSMA-PET result of the PSMA-PET is then generated and the results produced from the PSMA-PET result are then analyzed. One skilled in the art would readily be able to utilize analytical techniques and knowledge in the art to generate and analyze the PSMA-PET results. In some aspects, the first PSMA-PET result is utilized as the baseline PSMA-PET scan. This first PSMA-PET result may be utilized to compare subsequent PSMA-PET results for the purposes of monitoring cancer metastasis. In other aspects, the first PSMA-PET result may be indicative of cancer metastasis, thereby warranting analysis by the attending physician with an eye to treatment options.

[0028] The PSMA-MET result may differ from the conventional imaging result. In some embodiments, the first PSMA-PET result indicates metastasis of the prostate cancer, whereas the convention imaging result indications no metastasis. In further embodiments, the first PSMA-PET result show's lesions that are indicative of prostate cancer metastasis. In yet other embodiments, the first PSMA-PET result shows at least one prostate cancer lesion outside of the prostate. Ins still further embodiments, the first PSMA-PET result show_'s at least two prostate cancer lesions outside of the prostate . In other embodiments, the first PSMA-PET analysis shows PSMA-PET positive distant lesions. In further embodiments, the first PSMA-PET analysis show's PSMA-PET positive loco-regional lesions. In still other embodiments, the appearance of at least one new PSMA-PET positive distant lesion is indicative of metastatic progression of the cancer. In other embodiments, the appearance of at least one new PSMA-PET positive loco-regional lesion is indicative of loco-regional progression of the cancer.

[0029] The PSMA-PET result is generated at substantially the same time as the conventional imaging result. The term “substantially the same time” as used herein refers to a time that is representative of the patient’s condition as it relates to prostate cancer. In some embodiments, “substantially the same time” refers to a time period during which progression of the cancer is statistically minimal. “Substantially the same time” refers to a period of time between obtaining the convention imaging result and the PSMA-PET result. In some embodiments, “substantially the same time” means obtaining the PSMA-PET result and conventional imaging result within about three months of each other or less. In other embodiments, “substantially the same time” means obtaining the PSMA-PET result and conventional imaging result about 1 week to about 3 months, about 2 weeks to about 3 months, about 3 weeks to about 3 months, about 1 month to about 3 months, about 5 weeks to about 3 months, about 6 weeks to about 3 months, about 7 weeks to about three months, about 2 months to about 3 months, about 9 weeks to about 3 months, about 10 weeks to about 3 months, or about 11 weeks to about 3 months, of each other. The term ‘"substantially the same time” may also refer to even shorter periods of time, such as 1 week or less. In some embodiments, “substantially the same time” refers to about 1 day to about 7 days, about 1 day to about 6 days, about 1 day to about 5 days, about 1 day to about 4 days, about 1 day to about 3 days, about 1 day to about 3 days, about 1 day to about 2 days, about 2 days to about 7 days, about 2 days to about 6 days, about 2 days to about 5 days, about 2 days to about 4 days, about 2 days to about 3 days, about 3 days to about 7 days, about 3 days to about 6 days, about 3 days to about 5 days, about 3 days to about 4 days, about 4 days to about 7 days, about 4 days to about 6 days, about 4 days to about 5 days, about 5 days to about 7 days, about 5 days to about 6 days, or about 6 days to 7 days. Even further, the term

“substantially the same time” may refer obtaining the PSMA-PET result and conventional imaging result on the same day. In some aspects, the conventional imaging result is obtained before the PSMA-PET result. In further aspects, the PSMA-PET result is obtained before the conventional imaging result.

[0030] As noted, the first PSMA-PET result can indicate that the prostate cancer has metastasized. Thus, the methods include administering a therapeutically effective amount of apalutamide to the patient following generation of said first PSMA-PET result.

[0031] Apalutamide is an anti -androgen that binds directly to the ligand-binding domain of AR, impairing nuclear translocation, AR binding to DNA and AR target gene modulation, thereby inhibiting tumor growth and promoting apoptosis. Apalutamide binds AR with greater affinity than bicalutamide, and induces partial or complete tumor regression in non-castrate hormone-sensitive and bicalutamide-resistant human prostate cancer xenograft models. Apalutamide lacks the partial agonist activity seen with bicalutamide in the context of AR overexpression. Apalutamide 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 (ARN-509, or JNJ- 56021927; CAS No. 956104-40-8) and has the following structure.

[0032] In general, the ^‘'‘therapeutically effective amount” of apalutamide varies depending upon factors such as, but not limited to, condition and severity of the disease or condition, and the identity (e.g., weight) of the human, and any additional therapeutic agents that are administered. For apalutamide, the amount utilized may be in the range of about 10 mg/day to about 1000 mg/day. In some embodiments, apalutamide is administered orally to the human at a dose of about 30 mg/day to about 1200 mg/day. In other embodiments, apalutamide is administered orally to the human at a dose of about 30 mg/day to about 600 mg/day. In further embodiments, apalutamide is administered orally to the human at a dose of about 30 mg/day, about 60 mg/day, about 90 mg/day, about 120 mg/day, about 160 mg/day, about 180 mg/day, about 240 mg/day, about 300 mg/day, about 390 mg/day, about 480 mg/day, about 600 mg/day, about 780 mg/day, about 960 mg/day, or about 1200 mg/day.

[0033] The doses of apalutamide may be formulated to achieve a certain daily dose. For example, the therapeutically effective amount of apalutamide may have a range of about 30 to about 40 mg/day, about 40 to about 50 mg/day, about 50 to about 60 mg/day, about 60 to about 70 mg/day, about 70 to about 80 mg/day, about 80 to about 90 mg/day, about 90 to about 100 mg/day, about 100 to about 120 mg/day, about 120 to about 140 mg/day, about 140 to about 160 mg/day, about 160 to about 180 mg/day, about 180 to about 200 mg/day, about 200 to about 220 mg/day, about 220 to about 240 mg/day, about 240 to about 260 mg/day, about 260 to about 280 mg/day, about 280 to about 300 mg/day, about 300 to about 320 mg/day, about 320 to about 340 mg/day, about 340 to about 360 mg/day, about 360 to about 380 mg/day, about 380 to about 400 mg/day, about 400 to about 420 mg/day, about 420 to about 440 mg/day, about 440 to about 460 mg/day, about 460 to about 480 mg/day, or any range defined by two or more of these ranges, or any individual value cited in these ranges. In other embodiments, the therapeutically effective amount of apalutamide may have a range of about 0.3 to about 0.4 mg/kg/ day, about 0.4 to about 0.5 mg/kg/ day, about 0.5 to about 0.6 mg/kg/ day, about 0.6 to about 0.7 mg/kg/ day, about 0.7 to about 0.8 mg/kg/ day, about 0.8 to about 0.9 mg/kg/day, about 0.9 to about I mg/kg/ day, about 1 to about 1.2 mg/kg/day, about 1.2 to about 1.4 mg/kg/day, about 1.4 to about 1.6 mg/kg/day, about 1.6 to about 1.8 mg/kg/day, about 1.8 to about 2 mg/kg/day, about 2 to about 2.2 mg/kg/day, about 2.2 to about 2.4 mg/kg/day, about 2.4 to about 2.6 mg/kg/day, about 2.6 to about 2.8 mg/kg/day, about 2.8 to about 3.0 mg/kg/day, about 3.0 to about 3.2 mg/kg/day, about 3.2 to about 3.4 mg/kg/day, about 3.4 to about 3.6 mg/kg/day, about 3.6 to about 3.8 mg/kg/day, about 3.8 to about 4.0 mg/kg/day, about 4.0 to about 4.2 mg/kg/day, about 4.2 to about 4.4 mg/kg/day, about 4.4 to about 4.6 mg/kg/day, about 4.6 to about 4.8 mg/kg/day, or any range defined by two or more of these ranges, or any individual value cited in these ranges.

[0034] In further embodiments, the orally therapeutically effective amount of apalutamide is about 30 mg/day to about 480 mg/day. In still further embodiments, the orally therapeutically effective amount of apalutam ide is about 180 mg/day to about 480 mg/day.

In certain embodiments, the orally therapeutically effective amount of apalutamide is about 30 mg/day; or about 60 mg/day; or about 90 mg/day; or about 120 mg/day; or about 240 mg/day. In some embodiments, the orally therapeutically effective amount of apalutamide is about 240 mg/day.

[0035] In certain embodiments, wherein improvement in the status of the prostate cancer is not observed, the daily dose of apalutamide may be increased. In some embodiments, a once-a-day dosing schedule is changed to atwice-a-day dosing schedule. In further embodiments, a three times a day dosing schedule is employed to increase the amount of apalutamide.

[0036] After obtaining the initial PSMA-PET result, such as after administration of apalutamide, at least one additional PSMA-PET is performed. An additional PSMA-PET result is then generated from the additional PSMA-PET. In some embodiments, the first PSMA-PET result and the additional PSMA-PET result are obtained within about 6 months of one another. In other embodiments, the first PSMA-PET result and the additional PSMA- PET result are obtained about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or 6 months from one another.

[0037] The additional PSMA-PET result may be compared with the first PSMA- PET result. In some embodiments, the additional PSMA-PET result may be compared with the first PSMA-PET result to determine progression, if any, of the prostate cancer metastasis. In certain aspects, the additional PSMA-PET result show's no progression of the prostate cancer relative to said first PSMA-PET result. In other aspects, the additional PSMA-PET result shows regression of prostate cancer relative to said first PSMA-PET result. In further aspects, the additional PSMA-PET result show's substantially no evidence of prostate cancer.

[0038] The term “regression” as used herein refers to one or more signs that the treatment methods as described herein are effective in treating the patient’s prostate cancer. For example, regression of prostate cancer may include reduction in the Size of one or more prostate cancer lesions, a reduction in the number of prostate cancer lesions, or a combination thereof.

[0039] The additional PSMA-PET results may be utilized to determine future treatment options for the patient. In some embodiments, the additional PSMA-PET results may be utilized to determine the administration of apalutamide. In some embodiments, the additional PSMA-PET result may result in a determination to decrease the dose amount of apalutamide. In other embodiments, the additional PSMA-PET result may result in a determination to increase the dose of apalutamide. In further embodiments, the additional PSMA-PET result may result in a determination to terminate administration of apalutamide.

[0040] The patient may have received at least one prior androgen depri vation therapy prior to PSMA-PET analysis. The therapy includes surgical castration or administration of an additional therapeutic agent. In certain embodiments, the prior therapy is surgical castration.

[0041 ] In some embodiments, the prior therapy for the treatment of cancer is the use of an additional therapeutic agent. One of skill in the art would understand how' to prescribe the additional therapeutic agent in accordance with instructions, recommendations and practices. For example, the additional therapeutic agent may be a luteinizing hormone- releasing hormone agonist, luteinizing hormone-releasing hormone antagonist, Cyp-17 inhibitor,, an androgen receptor antagonist, an estrogen or combinations thereof. In other embodiments, the male human is treatment naive.

[0042] In some embodiments, the additional therapeutic agent is a luteinizing hormone-releasing hormone (“LHRH”) agonist. Examples of LITRE! agonists include goserelin, goserelin acetate, histrelin acetate, leuprolide, leuprolide acetate, triptoreiin palmoate, or triptoreiin acetate, or combinations thereof. In some embodiments, the luteinizing hormone-releasing hormone agonist is leuprolide, goserelin, or triptoreiin acetate, or combinations thereof. In other embodiments, the additional therapeutic agent is buserelin. In further embodiments, the additional therapeutic agent is naferelin. In yet other embodiments, the additional therapeutic agent is histre!in. In still further embodiments, the additional therapeutic agent is histrelin acetate. In other embodiments the additional therapeutic agent is goserelin. In other embodiments, the additional therapeutic agent is deslorelin. In further embodiments, the additional therapeutic agent is degarelix. In still other embodiments the additional therapeutic agent is ozarelix. In yet further embodiments, the additional therapeutic agent is ozarelix. In other embodiments, the additional therapeutic agent is ABT-620 (elagolix). In further embodiments, the additional therapeutic agent is TAK-385 (relugolix). In yet other embodiments, the additional therapeutic agent is EP-100. In still further embodiments, the additional therapeutic agent is KLH-2109. In other embodiments, the additional therapeutic agent is triptorelin.

[0043] In other embodiments, the additional therapeutic agent is a luteinizing hormone-releasing hormone antagonist. In further embodiments, the additional therapeutic agent is abiraterone. In yet other embodiments, the additional therapeutic agent is ketoconazoie. In still further embodiments, the additional therapeutic agent is an androgen receptor antagonist. In other embodiments, the additional therapeutic agent is an estrogen.

[0044] The additional therapeutic agent may also be a gonadotropin-releasing hormone agonist or antagonist. The GnRH agonist or antagonist may comprise leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109 or triptorelin.

[0045] The additional therapeutic agent may be other anti-androgens such as enzalutamide; bicaiutamine; flutamide; or darolutamide.

[0046] The patient may also have received radiotherapy prior to carrying out the PSMA-PET. In some embodiments, the radiotherapy is salvage radiotherapy to the whole pelvis, or stereotactic body radiation therapy. In other embodiments, the radiotherapy is salvage radiotherapy to the whole pelvis. In further embodiments, the radiotherapy is stereotactic body radiation therapy.

ADDITIONAL DIAGNOSTIC STEPS

[0047] Additional diagnostic techniques may be performed the treatment methods described herein. In some embodiments, the methods further comprise determining the level of prostate-specific antigen (PSA) in the patient. Techniques are readily known to those in the skill in the art to determine PSA and include blood tests. In some embodiments, serum PSA is measured.

[0048] In certain embodiments, the PSA level is determined prior to initiation of the methods described herein. In some aspects, one or more PSA levels are determined before earning out the first PSMA-PET. The serum PSA level of the patient may be any level and it’s specific value doesn’t dictate the need to perform PSMA-PET. However, PSA levels that are greater than about 0.2 ng/mL in a patient may be obtained prior to carrying out the first PSMA-PET.

[0049] Multiple PSA readings may be obtained prior to performing PSMA-PET. In some embodiments, these multiple PSA readings may exhibit rising PSA levels prior to performing PSMA-PET. In still other embodiments, the PSA level of the patient after two or more readings remains substantially unchanged prior to carrying out the PSMA-PET.

[0050] One or more PSA levels may be determined after carrying out the first PSMA-PET. In some embodiments, the patient’s PSA level is monitored following PSMA- PET, but prior to administration of apalutamide. In other embodiments, the patient^'s PSA level is monitored following PSMA-PET and after administration of apalutamide.

[0051] The PSA level may also be determined at specific intervals after PSMA-PET evaluation and/or apalutamide treatment. In some embodiments, PSA levels are determined in about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 month internals. In other embodiments, PSA levels are monitored in about 3 month intervals. In further embodiments, PSA levels are monitored in about 6 month intervals. In yet other embodiments, PSA levels are monitored in about 9 month intervals. In still further embodiments, PSA levels are monitored in about 12 month intervals.

[0052] Modulating or terminating treatment with apalutamide based on PSA levels may be determined by a physician skilled in the art of prostate cancer treatment. In some embodiments, administration of apalutamide is terminated. In certain embodiments, administration of apalutam ide is terminated when the patient’s PSA level following administration of apalutamide is lower than the PSA level prior to performance of said PSMA-PET. In other embodiments, the frequency or dosage of apalutamide administration is decreased. In further embodiments, the frequency or dosage of apalutamide administration is increased. Desirably, the patient’s PSA level decreases following the administration of apalutamide. [0053] The PSA may also be used to determine how often PSMA-PET is performed after its initial use. In some embodiments, if the patient’s prostate-specific antigen is about 0.2 ng/mL or greater, then PSMA-PET is performed every about 6 months after the first performance of PSMA-PET. In other embodiments, tf the patient’s prostate-specific antigen is less than about 0.2 ng/mL, then PSMA-PET is performed every about 12 months after the first performance of PSMA-PET. In further embodiments, if the patient’s prostate-specific antigen is less than about 0.2 ng/mL, then the patient’s prostate-specific antigen levels is assessed at every about 3 months after the first determination of the patient’s prostate-specific antigen.

ROUTES OF ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS

[0054] Therapeutic agents, such as apalutamide, described herein are administered in any suitable manner or suitable fonnulation. Suitable routes of administration include, but are not limited to, oral and parenteral (e.g., intravenous, subcutaneous, intramuscular). All formulations are in dosages suitable for administration to a human. A summary of pharmaceutical compositions can be found, e.g., 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 Drag Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0055] Studies that look at safety also seek to identify any potential adverse effects that may result from exposure to the drug. Efficacy is often measured by determining whether an active pharmaceutical ingredient demonstrates a health benefit over a placebo or other intervention when tested in an appropriate situation, such as a tightly controlled clinical trial.

[0056] Unless otherwise specified, the terms ‘"effective amount” or “therapeutically effective amount,” as used herein, refer to an amount of an anti-androgen being administered that treats the underlying disease or condition including, halting or slowing the progression of the disease or condition.

[0057] The term “acceptable” with respect to a fonnulation, composition or ingredient, as used herein, means that the beneficial effects of that formulation, composition or ingredient on the general health of the male human being treated substantially outweigh its detrimental effects, to the extent any exist,

[0058] In some embodiments, the therapeutic agent is present in a solid dosage form. In certain embodiments, the therapeutic agent is formulated as a tablet. In some embodiments, the therapeutic agent is present in a solid oral dosage form. In some embodiments, the therapeutic agent is formulated as an oral dose form, a unit oral dose form, or a solid dose form (e.g., a capsule, tablet, or pill). In some embodiments, e.g., the therapeutic agent is formulated as a tablet. Solid oral dosage forms containing the therapeutic agent may be provided as soft gel capsules as disclosed in WO2014113260 and CN104857157, each of which is incorporated herein by reference, or as tablets as disclosed in WO2016090098, W02016090101, W02016090105, and W02014043208, each of which is incorporated herein by reference. Techniques suitable for preparing solid oral dosage forms are described in Remington's Pharmaceutical Sciences, 18th edition, edited by AR. Gennaro, 1990, Chapter 89, and in Remington - The Science, and Practice of Pharmacy, 21st edition, 2005, Chapter 45.

[0059] In certain embodiments, the therapeutic agent is present in a solid unit dosage form, and a solid unit dosage form suitable for oral administration. For example, the unit dosage form may contain about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, or about 240 mg of apalutamide per unit dose form or an amount in a range bounded by two of these values.

[0060] To prepare the pharmaceutical compositions, the active pharmaceutical ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g., oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0061] In solid oral preparations such as, e.g., dry pow'ders for reconstitution or inhalation, granules, capsules, caplets, gelcaps, pills and tablets (each including immediate release, timed release and sustained release formulations), suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidamts, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in winch case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.

[0062] Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means.

[0063] These formulations are manufactured by conventional formulation techniques. For preparing solid pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents, and g!idants.

[0064] Suitable diluents include, but are not limited to, starch (i.e. com, wheat, or potato starch, which may be hydrolyzed), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to about 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e, AVICEL microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like.

[0065] Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacantli gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylce!lu!ose, hydroxypropylmethylcellulose, hydroxypropylcellulose, cellulose acetate, carboxymethyl cellulose calcium, liydroxypropyl methylceiluiose and the like), water soluble or dispersible binders (i. e. aJginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e. XYLOSE available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch) and the like. The binder in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form,

[0066] Sweeteners and flavorants may be added to ehewable solid dosage forms to improve the palatability of the oral dosage fomi. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drag or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.

[0067] Examples of tillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof. The filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0068] Disintegrants can be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch g!yeoiates, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, croscarmellose sodium, crospovidone, pregelatinized starches (i.e. com starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross-linked polyvinylpyrrolidone, mixtures thereof, and the like. The disintegrant may he present in a concentration from about 4%w/w to about 20%w/w or from about 7%w/w to about 15%w/w. A salt may be also present, which may be sodium chloride, potassium chloride or a combination thereof. The combination of salts and disintegrant is present at a concentration from about 5%w/w to about 35%w/w of the final pharmaceutical composition. [0069] Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, oils such as mineral oil and light mineral oil, glycerin, sorbitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), ethyl oleate, ethyl laureate, agar, stearates (magnesium, calcium, sodium, zinc), 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 and mixtures thereof. Lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0070] Suitable glidants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-O-SIL silica available from Cabot, SYLOID silica available from W.R. Grace/Davison, and AEROSIL silica available from Degussa) and the like.

[0071 ] Compressed tablet formulations may optionally be film-coated to provide color, light protection, and/or taste-masking. Tablets may also be coated so as to modulate the onset, and/or rate of release in the gastrointestinal tract, so as to optimize or maximize the biological exposure.

[0072] Hard capsule formulations may be produced by filling a blend or granulation of the therapeutic agent into shells consisting of, e.g. , gelatin, or hypromellose. Soft gel capsule formulations also may be produced.

[0073] Pharmaceutical compositions intended for oral use may be prepared from the solid dispersion formulations, and blended materials described above in accordance with the methods described herein, and other methods known to the art for the manufacture of pharmaceutical compositions. Such compositions may further contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

[0074] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, e.g., inert diluents, granulating, and disintegrating agents, binding agents, glidants, lubricating agents, and antioxidants, for example, propyl gallate, butylated hydroxyanisole, and butylated hydroxy toluene. The tablets may be uncoated or they may be film coated to modify their appearance or may be coated with a functional coat to delay disintegration, and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period.

[0075] Compositions for oral use may also be presented as capsules (e.g. , hard gelatin) wherein the active ingredient is mixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate or starch, or as soft gelatin capsules wherein the active ingredient is mixed with liquids or semisolids, e.g., peanut oil, liquid paraffin, fractionated glycerides, surfactants or olive oil. Aqueous suspensions contain the active materials in mixture with excipients suitable for the manufacture of aqueous suspensions. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. In certain embodiments, the pharmaceutical compositions include a diluent system, disintegrant, salt, lubricant, glidant, and filmcoat, at concentrations of from about 3%w/w to about 58%w7w, from about 4%w7w to about 20%w/w , from about 4%w/w to about 20%w/w, from about 0.5%w/w to about 4%w/w, from about 0%w/w to about 2%w/w, and from about 1 %w/w to about 5%w/w respectively, or at from about 18% w/w to about 40%w/w, from about 7%w/w to about I5%w/w , from about 7%w/w to about 18%w/w , from about 1.0%w/w to about 3.0%, from about 0.1 %w/w to about 1.0%w/w, and from about 2,.0%w/w to about 4.0%w/w, respectively. In certain embodiments, the solid dispersion formulations are blended with a diluent, one or more disintegrating agents, lubricants, and glidants. An exemplar}' blended composition or oral dosage form includes mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silica, sodium stearyl fumarate, and magnesium stearate.

[0076] In certain embodiments, inactive ingredients of the core tablet include: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. In other embodiments, the tablets are finished with a film-coating consisting of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide

[0077] In other embodiments, a single unit dosage of the pharmaceutical composition comprises, consists of, or consists essentially of the therapeutic agent, such as apalutamide. In some embodiments, multiple doses of the single unit dosage pharmaceutical composition comprising, consisting of, or consisting essentially of the therapeutic agent, such as apaiutamide, e.g. , 4 multiple or individual unit dosage forms, are administered to the human.

[0078] All formulations for oral administration are in dosage form suitable for such administration.

USE OF AN APPROVED DRUG PRODUCT

[0079] The methods provided herein may comprise administering an approved drug product, such as apaiutamide, in an amount that is described in a drag product label for said drag product. In some embodiments, the approved drug product comprising apaiutamide is an AND A drag product or a supplemental New Drag Application drug product. In certain embodiments, the method is clinically proven safe.

[0080] The term, “drag product” or “approved drag product” is product that contains an active pharmaceutical ingredient that has been approved for marketing for at least one indication by a governmental authority, e.g., the Food and Drag Administration or the similar authority in other countries.

[0081] Tire term “Reference Listed Drug (RED)” is a drag product to which new generic versions are compared to show' that they are bioequivalent. (21 CFR 314.3(b)) It is also a medicinal product that has been granted marketing authorization by a Member State of the European Union or by the Commission on the basis of a completed dossier, i. e, , with the submission of quality, pre-clinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which the application for marketing authorization for a generic/hybrid medicinal product refers, by demonstration of bioequivalence, usually through the submi ssi on of the appropri ate bioavailability studies.

[0082] In the United States, a company seeking approval to market a generic equivalent must refer to the RLD in its Abbreviated New Drug Application (ANDA). For example, an ANDA applicant relies on the FDA’s finding that a previously approved drag product, i.e., the RLD, is safe and effective, and must demonstrate, among other things, that the proposed generic drug product is the same as the RLD in certain ways. Specifically, with limited exceptions, a drug product for which an ANDA is submitted must have, among other things, the same active ingredient(s), conditi ons of use, route of administration, dosage form, strength, and (with certain pennissible differences) labeling as the RLD. The RLD is the listed drug to which the ANDA applicant must show its proposed AN DA drug product is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use, among other characteristics. In the electronic Orange Book, there will is a column for RLDs and a column for reference standards. In the printed version of the Orange Book, the RLDs and reference standards are identified by specific symbol. For an ANDA based on an approved suitability petition (a petitioned ANDA), the reference listed drug generally is the listed drug referenced in the approved suitability petition.

[0083] A reference standard is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval. FDA generally selects a single reference standard that ANDA applicants must use in in vivo bioequivalence testing. Ordinarily, FDA will select the reference listed drug as the reference standard. However, in some instances (e.g., where the reference listed drug has been withdrawal from sale and FDA has determined it was not withdrawn for reasons of safety or effectiveness, and FDA selects an ANDA as the reference standard), the reference listed drug and the reference standard may be different.

[0084] FDA identifies reference listed drags in the Prescription Drug Produet, OTC Drug Product, and Discontinued Drug Product Lists. Listed drags identified as reference listed drugs represent drag products upon which an applicant can rely in seeking approval of an ANDA. FDA intends to update periodically the reference listed drugs identified in the Prescription Drug Product, OTC Drag Product, and Discontinued Drug Product Lists, as appropriate.

[0085] FDA also identifies reference standards in the Prescription Drag Product and OTC Drag Product Lists. Listed drugs identified as reference standards represent the FDA’s best judgmen t at this time as to the appropriate comparator for purposes of conducting any in vivo bioequivalence studies required for approval.

[0086] In some instances when FDA has not designated a listed drag as a reference listed drag, such listed drag may be shielded from generic competition. If FDA has not designated a reference listed drug for a drug product the applicant intends to duplicate, the potential applicant may ask FDA to designate a reference listed drug for that drug product.

[0087] FDA may, on its own initiative, select a new⁷ reference standard when doing so will help to ensure that applications for generic drugs may be submitted and evaluated, e.g. , in the event that the listed drug currently selected as the reference standard has been withdrawn from sale for other than safety and efficacy reasons.

[0088] In Europe, Applicants identify in the application form for its generic/hybrid medicinal product, which is the same as a AND A or sNDA drug product, the reference medicinal product (product name, strength, pharmaceutical form, MAH, first authorization, Member State/Community), which is synonymous with a RLD, as follows:

1. The medicinal product that is or has been authorized in the EEA, used as the basis for demonstrating that the data protection period defined in the European pharmaceutical legislation has expired. This reference medicinal product, identified for the purpose of calculating expiry of the period of data protection, may be for a different strength, pharmaceutical form, administration route or presentation than the generic/hybrid medicinal product.

2. The medicinal product, the dossier of which is cross-referred to in the generic/hybrid application (product name, strength, pharmaceutical form, MAH, marketing authorization number). This reference medicinal product may have been authorized through separate procedures and under a different name than the reference medicinal product identified for the purpose of calculating expiry of the period of data protection. Tire product information of this reference medicinal product will, in principle, serve as the basis for the product information claimed for the generic/hybrid medicinal product.

3. The medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the bioequivalence study(ies) (where applicable). Hie different abbreviated approval pathways for drag products under the FD&C Act — the abbreviated approval pathways 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. 355(b)(2), respectively).

[0089] According to the FDA

(https:/7www. fda.gov/downloads/Drags/GuidanceComplianceRegulatorylnformation/Guidan ces/ UCM579751.pdf), the contents of which is incorporated herein by reference), NDAs and AND As can be divided into the following four categories:

(1) A ‘"stand-alone NDA” is an application submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use. (2) A 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use.

(3) An ANDA is an application for a duplicate of a previously approved drug product that was submitted and approved under section 505(j) of the FD&C Act. An ANDA relies on FDA’s finding that the previously approved drug product, i.e., the reference listed drug (RLD), is safe and effective. An ANDA generally must contain information to show that the proposed generic product (a) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are necessary- to establish the safety and effectiveness of the proposed product.

(4) A petitioned ANDA is a type of ANDA for a drag product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient) and for which FDA has determined, in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act (suitability petition), that studies are not necessary to establish the safety and effectiveness of the proposed drug product.

[0090] A scientific premise underlying the Hatch-Waxman Amendments is that a drag product approved in an AN DA under section 505 (j ) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling. In contrast to an ANDA, a 505(b)(2) application allows greater flexibility as to the characteristics of the proposed product. A 505(b)(2) application will not necessarily be rated therapeutically equivalent to the listed drug it references upon approval.

[0091] The term “therapeutically equivalent to a reference listed drag” is means that the drag product is a generic equivalent, i.e., pharmaceutical equivalents, of the reference listed drug product and, as such, is rated an AB therapeutic equivalent to the reference listed drug product by the FDA whereby actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.

[0092] “Pharmaceutical equivalents” means drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient as the reference listed drag.

[0093] FDA classifies as therapeutically equivalent those products that meet the following general criteria: (1) they are approved as safe and effective; (2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the same active drag ingredient in the same dosage form and route of admini stration, and (b) meet compendial or other applicable standards of strength, quality, purity, and identity; (3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard; (4) they are adequately labeled; and (5) they are manufactured in compliance with Current Good Manufacturing Practice regulations

[0094] The term “bioequivalent” or “bioequivalence” is the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action 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 a test and reference listed drug shall be considered bioequivalent: the rate and extent of absorption of the [test] drug do not show a significant difference from the rate and extent of absorption of the [reference] drag when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or the extent of absorption of the [test] drug does not show' a significant difference from the extent of absorption of the [reference] drag when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the [reference] drug in the rate of absorption of the drug is intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drag concentrations on chronic use, and is considered medically insignificant for the drag. [0095] Where these above methods are not applicable ( e.g . , for drug products that are not intended to be absorbed into the bloodstream), other scientifically valid in vivo or in vitro test methods to demonstrate bioequivalence may be appropriate.

[0096] For example, bioequivalence may sometimes be demonstrated using an in vitro bioequivalence standard, especially when such an in vitro test has been correlated with human in vivo bioavailability data. In other situations, bioequivalence may sometimes be demonstrated through comparative clinical trials or pharmacodynamic studies.

[0097] Also provided herein are pharmaceutical products comprising a clinically proven safe and clinically proven effective amount of apaiutamide, wherein the pharmaceutical product is packaged and wherein the package includes a label that identifies apaiutamide as a regulatory approved chemical entity.

[0098] As used herein, unless otherwise noted, the term “safe” mean without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner. Similarly, unless otherwise noted, the term “effecti v e” means the efficacy of treatment has been demonstrated for the treatment of patients with prostate cancer when dosed in a therapeutically effective dose. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In further embodiments, the methods described herein are safe and effective. In yet other embodiments, the therapeutically effective amount of apaiutamide is safe. In still further embodiments, the therapeutically effective amount of apaiutamide is effective. In other embodiments, the therapeutically effective amount of apaiutamide is safe and effective.

[0099] As used herein, unless otherwise noted, the term “clinically proven” (used independently or to modify the terms “safe” and/or “effective”) mean that proof has been proven by clinical trial that are is sufficient to meet approval standards of U.S. Food and Drag Administration or similar study for market authorization by EMEA.

[00100] As used herein, unless otherwise noted, the term “clinically proven effective” means the efficacy of treatment has been proven by a clinical trial as statistically significant

the results of the clinical trial are not likely to be due to chance with an alpha level less than 0.05 or the clinical efficacy results are sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by EMEA. [00101J As used herein, unless otherwise noted, the term “clinically proven safe” means the safety of treatment has been proven by a clinical trial by analysis of the trial data and results establishing that the treatment is without undue adverse side effects and commensurate with the statistically significant clinical benefit (e.g., efficacy) sufficient to meet approval standards of U.S. Food and Drag Administration or similar study for market authorization by Europe, the Middle East, and Africa (EMEA).

[00102] Example 1

[00103] In this example, the primary objective is to determine if the addition of apalutamide to RT+LHRHa delays metastatic progression as assessed by PSMA-PET or death compared with RT+LHRHa alone. Thus, the primary endpoint is to determine the ppMPFS. ppMPFS is defined as the time from randomization to the scan date of metastatic progression by PSMA-PET or death from any cause. PSMA-PET metastatic progression is defined as the appearance of at least 1 new PSMA-PET- positi ve distant lesion compared with the previous scan. Final analysis of the primary' endpoint will be event-driven and will take place when 192 events have occurred; an interim analysis is planned to be performed when approximately 96 events are reached.

[00104] Other objectives include secondary' and exploratory objectives and endpoints as follow's:

[00108] Patients receive radiotherapy+luteinizing hormone-releasing hormone agonist (RT+LHRHa) plus apalutamide or RT+LHRHa alone . Patients will have no evidence of metastasis on conventional imaging but have at least one loco-regional lesion (with or without distant lesions, i.e., nodal invasion above iliac bifurcation, bone lesions, metastatic lesions at other sites) on PSMA-PET scan. “Radiotherapy” is defined as prostate-bed plus pelvic lymph node salvage external-beam radiotherapy, with or without optional SBRT.

[00109] There will be 3 phases: Treatment Phase, Post-treatment Phase, and an Exploratory Post-PSMA-PET Progression Phase. Major evaluations include PSMA-PET scans, WB-MRI (for the sub-analysis), PSA and testosterone levels, and patient-reported outcomes. See, e.g,, the Schedule of Activities in Table 1.

[00110] Patients will be randomized (1:1 ratio) to receive either RT+LHRHa or RT+LHRHa plus apalutamide. Permitted LHRHas include leuprolide, goserelin, triptorelin acetate and are administered as a 3 -monthly depot preparation at Day 1 and the end of Week 12 or as a 6-monthly depot preparation at Day 1. Radiotherapy includes receive prostate -bed plus pelvic lymph node salvage external-beam radiotherapy (with or without optional SBRT for patients with ≤3 metastases). Examples of radiotherapy include whole pelvic salvage radiotherapy or stereotactic body radiation therapy. For whole pelvic salvage radiotherapy, IMRT may be performed using either Step-and-Shoot-Technique, Sliding-Window- Technique or VMAT using multileaf collimators ≤1 cm.

Table 2: Dose Prescription and Fractionation

Table 3: Dose Constraints

Stereotactic body radiation therapy is for patients with oligometastatic lesions (≤3 distant lesions) on PSMA-PET. The total dose for SBRT is 30 Gy delivered in 3 fractions.

[00111] Apalutamide is administered for 180 days (approximately 26 weeks) starting with first administration of the LHRHa (Day 1). Apalutamide is administered orally on a continuous once-daily dosing schedule. The therapeutic dose is 240 mg (4 x 60 mg tablets) once daily. Apalutamide dose reductions are described in Table 4. Apalutamide dose may be reduced as follows: first dose-level reduction to 180 mg/day; second dose -level reduction to 120 mg/day.

[00112] All PSMA-PET scans and conventional imaging (CT/MR1 and "“Tc-bone scans) will be assessed. The starting PSMA-PET scan will also be assessed to allow SBRT. For patients in the WB-MRT sub-analysis, all WB-MRI scans will be assessed. [00113] PSMA-PET assessments: PSMA-PET scans will be performed at the start, end of Week 26, Month 12, then at least annually until the end of the study. For each individual patient, the same PET tracer should be used for all PSMA-PET scans. PET tracers are “Ga-PSMA-ll, ¹⁸F-labeled PSMA-1007, ¹⁸F-DCFPyL, and/or ⁱ⁸F-PSMA-ll, depending on local approval. The frequency of PSMA-PET assessments will increase (from once yearly) as soon as a patient's PSA level reaches >0.2 ng/mL at the end of Week 26 or in the Post-treatment Phase. Where PSA is >0.2 ng/mL, a PSMA-PET assessment will be performed at that time- point and then every 6 months until reaching PSMA-PET metastatic progression (primary endpoint) or end of the study. This PSA threshold is based on a metaanalysis of predictors of PSMA-PET positivity at first BCR, which suggested that more than 45% of patients with PSA >0.2 ng/mL would be PSMA-PET-positive.

[00114] Conventional imaging : includes ^99mTc -Bone and CT/MR1 scans, including the diagnostic CT/MRI component of PSMA-PET). The TNM classification will be used for the reporting and localization of CT/MRI-positive lesions (Tables 5 and 6).

Claims

What is Claimed Is:

1. A method of treating prostate cancer in a patient in need thereof, the method comprising:

• performing an imaging technique that is selected from an ultrasound imaging, magnetic resonance imaging, positron emission tomography imaging, computed tomography imaging, hone imaging, or a combination thereof on the patient;

• generating a conventional imaging result from the conventional imaging technique, wherein the conventional imaging result does not indicate metastasis of the prostate cancer;

• performing prostate-specific membrane antigen-positron em ission tomography (PSMA-PET) on the patient;

• generating a first PSMA-PET result of the PSMA-PET, wherein the first PSMA- PET result indi cates metastasis of the prostate cancer and is generated at substantially the same time as the conventional imaging result; and

• administering a therapeutically effective amount of apalutamide to the patient following generation of said first PSMA-PET result,

2. The method of claim 1, wherein a prostate-specific antigen (PSA) level of the patient is greater than about 0.2 ng/mL prior to earning out the first PSMA-PET,

3. The method of claim 1 or 2, wherein multiple PSA readings exhibit rising PSA levels prior to carrying out the PSMA-PET.

4. The method of any one of the preceding claims, wherein the PSA level of the patient after two or more readings remains substantially unchanged prior to earning out the PSMA-PET.

5. The method of any one of the preceding claims, wherein the patient has been administered androgen deprivation therapy prior to carrying out the PSMA-PET.

6. The method of claim 5, wherein the androgen deprivation therapy is surgical castration or administration of an additional therapeutic agent.

7. The method of claim 6, wherein the additional therapeutic agent is selected from a luteinizing hormone -releasing hormone agonist, luteinizing hormone-releasing hormone antagonist, abiraterone, ketoconazole, an androgen receptor antagonist, an estrogen or combinations thereof.

8. The method of claim 7, wherein the luteinizing hormone-releasing hormone agonist is selected from leuprolide, goserelin, or triptorelin acetate, or combinations thereof.

9. The method of any one of the preceding claims, wherein the patient has recei ved radiotherapy prior to carrying out the PSMA-PET,

10. The method of claim 9, wherein the radiotherapy is salvage radiotherapy to the whole pelvis, or stereotactic body radiation therapy.

11. The method of any one of the preceding claims, wherein the patient’s PSA level is monitored following the administration of apahitamide.

12. The method of claim 11, wherein said PSA level is monitored in about 6 month intervals.

13. The method of claim 11, wherein the patient’s PSA level decreases following the administration of apalutamide.

14. The method of any one of the preceding claims, wherein the administration of apalutamide is terminated.

15. The method of claim 14, wherein administration of apalutamide is terminated when the male patient’s PSA level following administration of apalutamide is lo wer than the PSA level prior to performance of said PSMA-PET^'.

16. The method of any one of claims 1 to 12, wherein the PSMA-PET result show¾ progression of prostate cancer.

17. The method of claim 16, wherein the PSMA-PET result shows at least one prostate cancer lesion outside of the prostate.

18. The method of claim 16 or 17, wherein the PSMA-PET result shows at least two prostate cancer lesions outside of the prostate.

19. The method of any one of claims 1 to 12 or 16 to 18, comprising increasing the dosage amount of apalutamide.

20. The method of any one of the preceding claims, further comprising performing at least one additional PSMA-PET after administration of apalutamide.

21. The method of claim 20, further comprising generating an additional PSMA-PET result from the additional PSMA-PET.

22. The method of claim 21 , wherein the first PSMA-PET result and the additional PSMA-PET result are obtained within about 6 months of one another.

23. The method of claim 21, wherein said additional PSMA-PET result shows no progression of the prostate cancer relative to said first PSMA-PET resuit.

24. The me thod of claim 21, wherein the additional PSMA-PET result shows regression of prostate cancer relative to said first PSMA-PET result.

25. The method of claim 24, wherein the regression is selected from a reduction in the size of one or m ore prostate cancer lesions, a reduction in the number of prostate cancer lesions, or a combination thereof.

26. The method of claim 21, wherein the additional PSMA-PET result shows substantially no evidence of prostate cancer.

27. The method of any one of claims 1 to 13, 24 or 25, comprising decreasing the dose amount of apalutamide.

28. The method of any one of the preceding claims, wherein the patient has castration resistant prostate cancer, castrate-sensitive prostate cancer, or hormone-refractory prostate cancer.

29. The method of any one of the preceding claims, wherein the metastasis is new or recurrent.