Anti-androgens for the treatment of metastatic castration-sensitive prostate cancer

Abstract

The present text describes a method for treating metastatic castration-sensitive prostate cancer with an anti-androgen, which anti-androgen includes but is not limited to 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

Description

[0001] Cross-reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 901,694, filed Sep. 17, 2019; U.S. Provisional Patent Application No. 62 / 836,920, filed Apr. 22, 2019; U.S. Provisional Patent Application No. 62 / 833,371, filed Apr. 12, 2019; U.S. Provisional Patent Application No. 62 / 822,312, filed Mar. 22, 2019; U.S. Provisional Patent Application No. 62 / 803,096, filed Feb. 8, 2019; and U.S. Provisional Patent Application No. 62 / 798,836, filed Jan. 30, 2019, all of which are hereby incorporated by reference in their entirety. Technical Field

[0003] Disclosed herein are methods of treating metastatic castration-sensitive prostate cancer with an antiandrogen, the antiandrogen including but not limited to 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide. Background Art

[0004] For men, prostate cancer is the second most commonly diagnosed cancer and the sixth leading cause of cancer death, accounting for 14% (903,500) of total new cancer cases and 6% (258,400) of total cancer deaths among men worldwide. The progression of prostate cancer from diagnosis to death is most appropriately classified into the following series of clinical stages based on the extent of the disease, hormonal status, and the presence or absence of detectable metastases: local disease, elevated levels of prostate-specific antigen (PSA) after radiotherapy or surgery but no detectable metastases, and clinical metastases during non-castration or castration. While surgery, radiation, or a combination of the two may be effective for patients with local disease, a significant proportion of these patients will relapse, as evidenced by elevated levels of PSA, and the relapse can lead to further progression of metastases, particularly to the lethal stage of the disease in high-risk groups.

[0005] Based on current guidelines, androgen deprivation therapy (ADT) with or without docetaxel is considered the appropriate active control therapy for patients with metastatic hormone-sensitive prostate cancer. However, there is a clear unmet medical need for alternative treatment options for mCSPC. Treatments that can delay disease progression and reduce associated morbidity would have significant clinical benefits in this patient population. The methods disclosed in the present invention address these and other important needs. Summary of the Invention

[0006] The present invention describes a method for treating metastatic castration-sensitive prostate cancer in male humans, the method comprising, consisting essentially of, or consisting of the following steps: administering to a male human having metastatic castration-sensitive prostate cancer a therapeutically effective amount of an antiandrogen. In these methods, the antiandrogen can be: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-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-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or N-{ (2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. In some embodiments, relative to the overall survival rate of a control group of male humans having metastatic castration-sensitive prostate cancer, administration of the antiandrogen prolongs the overall survival of the male human, the control group having received a placebo in combination with androgen deprivation therapy. In other embodiments, the control group is untreated. In further embodiments, relative to the progression-free survival rate of a control group of male humans having metastatic castration-sensitive prostate cancer, administration of the antiandrogen prolongs the progression-free survival of the male human, the control group having received a placebo in combination with androgen deprivation therapy. In other embodiments, the control group is untreated.

[0007] In some embodiments, the male human has received at least one prior therapy for treating cancer before administering the antiandrogen, wherein the prior therapy for treating cancer is radiotherapy, surgical intervention therapy, or docetaxel therapy. In some embodiments, the male human is untreated.

[0008] In some embodiments, the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide. In additional embodiments, the antiandrogen is typically administered daily to male humans, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered daily to male humans. In still other additional embodiments, the antiandrogen is typically administered orally to male humans, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans. In some embodiments, the antiandrogen is typically administered orally to male humans on a continuous daily dosing schedule, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans on a continuous daily dosing schedule. In additional embodiments, the antiandrogen is typically administered orally to male humans at a dose of about 30 mg / day to about 480 mg / day, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans at this dose. In still other additional embodiments, the antiandrogen is typically administered orally to male humans at a dose of about 180 mg / day to about 480 mg / day, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans at this dose. In certain embodiments, the antiandrogen is typically administered orally to male humans at the following doses, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans at the following doses: (a) about 30 mg / day; (b) about 60 mg / day; (c) about 90 mg / day; (d) about 120 mg / day; or (d) about 240 mg / day. In some embodiments, the antiandrogen is typically administered orally to male humans at a dose of about 240 mg / day, and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans at this dose.In some embodiments, if a male human experiences toxicity greater than or equal to grade 3, the dose of the antiandrogen is typically reduced to 180 mg / day or 120 mg / day, specifically the dose of 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is reduced to that dose.

[0009] In certain embodiments, the antiandrogen is generally not co-administered with the following substances, specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is not co-administered with the following substances: (a) drugs that are strong CYP2C8 or CYP3A4 inhibitors; (b) drugs that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9; (c) drugs that are substrates of UDP-glucuronosyltransferase (UGT); or (d) drugs that are substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transporting polypeptide 1B1 (OATP1B1).

[0010] In some embodiments, the antiandrogen is generally co-administered in combination with androgen deprivation therapy, more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is co-administered in combination with androgen deprivation therapy. In additional embodiments, the antiandrogen is generally co-administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist, more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is co-administered in combination with at least one gonadotropin-releasing hormone agonist or antagonist. In other additional embodiments, the at least one GnRH agonist or antagonist is or includes leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, degarelix, ozerelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109, or triptorelin. In certain embodiments, the antiandrogen is generally used in combination with bilateral orchiectomy, more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is used in combination with bilateral orchiectomy.

[0011] 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-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is orally administered to male humans at a dose of about 160 mg / day.

[0012] 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.

[0013] In some embodiments, the antiandrogen is N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (darolutamide). In additional embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is orally administered to male humans at a dose of 600 mg twice a day. In additional embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is orally administered to male humans at a dose of 600 mg twice a day with food.

[0014] Also disclosed herein is a method for treating metastatic castration-sensitive prostate cancer in male humans, the method consisting of or consisting essentially of the steps of: administering to a male human having metastatic castration-sensitive prostate cancer a therapeutically effective amount of an antiandrogen, wherein the antiandrogen is one or more 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 N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.

[0015] The present invention also discloses a method for treating metastatic castration-sensitive prostate cancer in male humans, the method comprising: (a) determining whether a male human has metastatic castration-sensitive prostate cancer; and (b) administering to the male human a therapeutically effective amount of an antiandrogen for treating metastatic castration-sensitive prostate cancer, wherein the antiandrogen is: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-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-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.

[0016] The present invention also discloses a method for treating metastatic castration-sensitive prostate cancer, the method comprising administering to a male human having metastatic castration-sensitive prostate cancer an amount described in the drug product label of an approved drug product comprising apalutamide. In some embodiments, the approved drug product comprising apalutamide is an ANDA drug product, a supplemental new drug application drug product or a 505(b)(2) drug product. In some embodiments, the method is clinically proven to be safe and / or effective.

[0017] The present invention also discloses a drug product comprising apalutamide in a clinically proven safe and clinically proven effective amount, wherein the drug product is packaged and wherein the package comprises a label that (a) identifies apalutamide as a regulatory-approved chemical entity, and (b) directs the use of apalutamide in the treatment of castration-sensitive prostate cancer.

[0018] The present invention also discloses a method of selling an approved drug product comprising apalutamide, the method comprising selling such a drug product, wherein the drug product label of the reference listed drug of such a drug product comprises instructions for treating castration-sensitive prostate cancer. The present invention further discloses a method of offering for sale an approved drug product comprising apalutamide, the method comprising offering for sale such a drug product, wherein the drug product label of the reference listed drug of such a drug product comprises instructions for treating castration-sensitive prostate cancer. In some embodiments, the drug product is an ANDA drug product, a supplemental new drug application drug product or a 505(b)(2) drug product. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] When read in conjunction with the accompanying drawings, the invention content and the following detailed embodiments are further understood. To illustrate the disclosed method, the drawings show exemplary embodiments of the method; however, the method is not limited to the specific embodiments disclosed. In the drawings:

[0020] Figure 1 is a schematic diagram of the design of the apalutamide Phase III clinical trial. ADT = androgen deprivation therapy.

[0021] Figures 2A-2B shows the Kaplan - Meier estimates of radiographic progression - free survival ( Figure 2A ) and the forest plot of radiographic progression - free survival by baseline patient characteristics ( Figure 2B ). Analysis was performed using the log - rank test, stratified by Gleason score at diagnosis (≤7 vs. >7), region (North America and EU vs. all other countries), and prior docetaxel treatment (yes vs. no).

[0022] Figures 3A-3B shows the Kaplan - Meier estimates of overall survival ( Figure 3A ) and the forest plot of overall survival by baseline patient characteristics ( Figure 3B ). Analysis was performed using the log - rank test, stratified by Gleason score at diagnosis (≤7 vs. >7), region (North America and EU vs. all other countries), and prior docetaxel treatment (yes vs. no).

[0023] Figure 4 shows the Kaplan - Meier estimates of the time to initiation of cytotoxic chemotherapy. Analysis was performed using the log - rank test, stratified by Gleason score at diagnosis (≤7 vs. >7), region (North America and EU vs. all other countries), and prior docetaxel treatment (yes vs. no).

[0024] Figure 5 shows the Kaplan - Meier estimates of the time to PSA progression. Based on Prostate Cancer Working Group 2 criteria, the time to PSA progression is the time from randomization to the date of PSA progression. Analysis was performed using the log - rank test, stratified by Gleason score at diagnosis (≤7 vs. >7), region (North America and EU vs. all other countries), and prior docetaxel treatment (yes vs. no).

[0025] Figure 6Shows the Kaplan-Meier estimate of the second progression-free survival time. The second progression-free survival is the time from randomization to the date of the first occurrence of disease progression (PSA progression, progression on imaging, or clinical progression) determined by the researchers or death from any cause (whichever occurs first) when the patient is receiving the first subsequent therapy for prostate cancer. Analysis was performed using the log-rank test, stratified by Gleason score at diagnosis (≤7 vs. >7), region (North America and EU vs. all other countries), and prior docetaxel treatment (yes vs. no).

[0026] Figure 7 Shows a repeated measures mixed effects analysis of the mean change from baseline in the FACT-P total score. Error bars are the standard error of the mean. The original FACT-P score ranges from 0 to 156, where a higher score indicates a more favorable health-related quality of life; a 6- to 10-point change in the FACT-P total score would be the least important difference. However, the figure presents the mean change in the total score compared to baseline (rather than the original total score). FACT-P, Functional Assessment of Cancer Therapy - Prostate. Detailed Description

[0027] It should be understood that, for clarity, certain features of the invention are set forth in the context of separate embodiments, but may also be provided in combination in a single embodiment. That is, unless clearly incompatible or explicitly excluded, each separate embodiment is considered combinable with any other embodiment, and such combination is considered another embodiment. Conversely, for brevity, the various features of the invention are set forth in the context of a single embodiment and may also be provided separately or in any sub-combination. Ultimately, although an embodiment may be described as part of a series of steps or a more general structure, each of the recited steps may itself be considered an independent embodiment and combinable with other embodiments.

[0028] The transitional terms "comprising," "consisting essentially of," and "consisting of" are intended to connote their recognized meanings in patent terminology; that is, (i) "comprising" is synonymous with "including," "containing," or "characterized by," and 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 the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the invention claimed. More specifically, the basic and novel characteristics relate to the ability of the method to provide at least one of the benefits described herein, which benefits include, but are not limited to, the ability to improve the viability of a male human population relative to a comparative male human population described elsewhere herein.

[0029] Embodiments are also provided that are described by the phrase "comprising" (or an equivalent thereof), as those independently described by "consisting of" and "consisting essentially of."

[0030] When a value is expressed as an approximation by use of the descriptor "about," it is to be understood that the specific value constitutes another embodiment. In general, the use of the term "about" connotes approximations that may vary depending on the desired characteristics sought to be obtained by the disclosed subject matter and will be interpreted based on their functionality in the particular context in which they are used. Those skilled in the art will be able to interpret these approximations in a conventional manner. In some instances, the number of significant digits used for a particular value may be a non-limiting method for determining the scope for the word "about." In other instances, the gradients used in a series of values may be used to determine the expected scope for the term "about" for each value. Where ranges are provided, all ranges are inclusive of the end values and are combinable. That is, reference to a value within a range includes each value within that range.

[0031] If not otherwise specified, the term "about" denotes a variance of ±10% of the relevant value, but additional embodiments include those in which the variance may be ±5%, ±15%, ±20%, ±25%, or ±50%.

[0032] It should be understood that, for clarity, certain features of the present invention are set forth in the context of separate embodiments, but may also be provided in combination in a single embodiment. That is, unless clearly incompatible or explicitly excluded, each separate embodiment is considered combinable with any other embodiment, and such combination is considered another embodiment. Conversely, for brevity, the various features of the present invention are set forth in the context of a single embodiment and may also be provided individually or in any sub-combination. Ultimately, although an embodiment may be described as part of a series of steps or a more general structure, each of the said steps may itself be considered an independent embodiment and combinable with other embodiments.

[0033] When a list is provided, unless otherwise indicated, it should be understood that each individual element of the list and each combination of the list are separate embodiments. For example, a list of embodiments provided as "A, B, or C" will be considered to include the embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0034] The present invention can be more readily understood with reference to the following description in conjunction with all of the drawings and examples that form a part of the present disclosure. It should be understood that the present invention is not limited to the specific products, methods, conditions, or parameters described or illustrated herein, and the terms used herein are for the purpose of describing specific embodiments by way of example only and are not intended to limit the present invention as claimed. Similarly, unless otherwise specifically stated, any description of possible mechanisms or modes of action or reasons for improvement is for illustrative purposes only, and the present invention herein is not bound by the correctness or incorrectness of any such proposed mechanisms or modes of action or reasons for improvement. In the present text, it should be recognized that the description refers to various compounds, compositions, and methods of using such compounds and compositions. That is, in the case where the present disclosure describes or claims features or embodiments associated with a composition or a method of using a composition, it should be understood that such description or claim is intended to extend these features or embodiments to embodiments of each of these contexts (i.e., the composition and its method of use).

[0035] The androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily. In this large family of proteins, only five vertebrate steroid receptors are known and include the androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor, and mineralocorticoid receptor. AR is a soluble protein with an intracellular transcription factor function. The function of AR is regulated by the binding of androgens, which initiates successive conformational changes in the receptor that affect receptor-protein interactions and receptor-DNA interactions.

[0036] AR is mainly expressed in androgen target tissues such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest expression levels observed in the prostate, adrenal gland, and epididymis. AR can be activated by the binding of endogenous androgens including testosterone and 5-dihydrotestosterone (5α-DHT).

[0037] The androgen receptor (AR), located on Xq11-12, is an 110-kD nuclear receptor that, when activated by androgens, mediates the transcription of target genes that regulate the growth and differentiation of prostatic epithelial cells. Similar to other steroid receptors, unbound AR is mainly located in the cytoplasm and is associated with a complex of heat shock proteins (HSPs) through interactions with the ligand-binding domain. Upon agonist binding, AR undergoes a series of conformational changes: the heat shock proteins dissociate from AR, and the deformed AR undergoes dimerization, phosphorylation, and translocation to the nucleus mediated by a nuclear localization signal. The translocated receptor then binds to androgen response elements (AREs), which are characterized by a hexanucleotide half-site consensus sequence 5′-TGTTCT-3′ separated by three random nucleotides and are located in the promoter or enhancer regions of AR gene targets. The recruitment of other transcriptional co-regulators (including coactivators and corepressors) and the transcriptional machinery further ensures the transactivation of AR-regulated gene expression. All these processes are initiated by ligand-induced conformational changes in the ligand-binding domain.

[0038] AR signaling is crucial for the development and maintenance of male reproductive organs including the prostate, as genetically male individuals with loss-of-function AR mutations and engineered mice with AR deficiency do not develop a prostate or prostate cancer. This dependence of prostate cells on AR signaling persists even after neoplastic transformation. Androgen depletion (such as using GnRH agonists) remains the mainstay of prostate cancer treatment. However, androgen depletion is usually effective for a limited duration, and prostate cancer evolves to regain the ability to grow despite low levels of circulating androgens.

[0039] Castration-resistant prostate cancer (CRPC) is a lethal phenotype, and almost all patients will die of prostate cancer. Interestingly, although a small fraction of CRPCs do bypass the requirement for AR signaling, the vast majority of CRPCs, although often referred to as "androgen-independent prostate cancer" or "hormone-refractory prostate cancer", still maintain their lineage dependence on AR signaling.

[0040] Prostate cancer is the second most common cause of cancer death in American men, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men, who develop recurrent disease that typically first presents as an elevation of plasma prostate-specific antigen (PSA), followed by spread to distant sites. Given that the proliferation and survival of prostate cancer cells depend on the androgen receptor (AR), these men are treated with agents that block testosterone production (such as GnRH agonists) alone or in combination with antiandrogens (such as bicalutamide) that antagonize the effect of any residual testosterone on the AR. This approach is effective, as demonstrated by a decrease in PSA in some patients and regression of visible tumors (if present). However, this is followed by the regrowth of castration-resistant prostate cancer (CRPC), and most patients ultimately die of this CRPC. Recent studies of the molecular basis of CRPC have confirmed that CRPC continues to depend on AR signaling, and the key mechanism of acquired resistance is an increase in AR protein levels (Nat. Med, 2004, 10, 33 - 39). AR-targeted agents that are active in both castration-sensitive and castration-resistant prostate cancer have great promise in the treatment of this lethal disease.

[0041] Based on the extent of the disease, the hormonal status, and the presence or absence of detectable metastases, the course of prostate cancer from diagnosis to death is most appropriately classified into the following series of clinical states: local disease, elevation of the prostate-specific antigen (PSA) level after radiotherapy or surgery but no detectable metastases, and clinical metastases in the non-castrated or castrated state. Although surgery, radiation, or a combination of the two may be effective for patients with local disease, a significant proportion of these patients will relapse, as demonstrated by an elevation in the PSA level, and the relapse can lead to further progression of metastases, particularly in high-risk groups, to the lethal phenotype of the disease.

[0042] Androgen depletion is the standard treatment with the following generally predictable outcomes: a decrease in the PSA level, a stable period during which the tumor does not proliferate, followed by an increase in the PSA level and regrowth into castration-resistant disease. Molecular profiling of castration-resistant prostate cancer often shows increased androgen receptor (AR) expression, which can occur through AR gene amplification or other mechanisms.

[0043] Antiandrogens can be used to treat prostate cancer in its early stages. However, prostate cancer often progresses to a "hormone refractory" state, in which the disease progresses in the presence of continuous androgen deprivation therapy or antiandrogen therapy. Cases of antiandrogen withdrawal syndrome have also been reported after long-term antiandrogen treatment. Antiandrogen withdrawal syndrome is frequently observed clinically and is defined based on tumor regression or symptom relief observed when antiandrogen therapy is stopped. AR mutations that cause receptor promiscuity and the ability of these antiandrogens to exhibit agonist activity can at least partially explain this phenomenon. For example, hydroxyflutamide and bicalutamide act as AR agonists in the T877A and W741L / W741C AR mutants, respectively.

[0044] In cases of prostate cancer cells that have become castration refractory due to overexpression of AR, it has been demonstrated that certain antiandrogen compounds such as bicalutamide have mixed antagonist / agonist properties (Science, May 8, 2009, Vol. 324, No. 5928, pp. 787-790). This agonist activity helps to explain the clinical observation known as antiandrogen withdrawal syndrome, as approximately 30% of men in whom the disease progresses while using an AR antagonist experience a decline in serum PSA when treatment is stopped (J Clin. Oncol, 1993, Vol. 11, No. 8, pp. 1566-1572).

[0045] Prostate Cancer Staging

[0046] In the early stages of prostate cancer, the cancer is confined to the prostate. In these early stages, treatment typically involves surgical removal of the prostate or radiation therapy to the prostate, or for some patients, simply conservative observation without active intervention. In the early stages when prostate cancer is localized and requires intervention, surgery or radiation therapy is effective by eradicating the cancer cells. In approximately 30% of cases, these treatment procedures fail and the prostate cancer continues to progress, as typically evidenced by an elevated PSA level. Men in whom prostate cancer progresses after receiving these early treatment strategies are said to have advanced or recurrent prostate cancer.

[0047] Since prostate cancer cells rely on the androgen receptor (AR) for proliferation and survival, men with advanced prostate cancer are treated with agents that block testosterone production (e.g., GnRH agonists) alone or in combination with anti-androgens (e.g., bicalutamide) that antagonize the effects of any residual testosterone on the AR. These treatments reduce serum testosterone to castrate levels, which typically slows disease progression for some time. The method is effective, as demonstrated by the decline in PSA and the regression of visible tumors in some patients. However, ultimately, this is followed by regrowth of cancer cells known as castration-resistant prostate cancer (CRPC), and most patients will eventually die from CRPC. Castration-resistant prostate cancer (CRPC) is classified as non-metastatic or metastatic depending on whether the prostate cancer has spread to other parts of the body.

[0048] Estimated data from specific European country registries indicate that approximately 15% to 30% of men diagnosed with prostate cancer have metastatic (M1) castration-sensitive prostate cancer (mCSPC). See, for example, Flamand V et al., Prog Urol., 2008, Vol. 18, pp. 53-59; in the United States, patients presenting with mCSPC account for approximately 4% of all prostate cancer diagnoses. Cetin K et al., Urology, 2010, Vol. 75, pp. 1396-1405. This difference may be due to different PSA screening used in different geographical regions. FH et al., Eur Urol., 2012, Vol. 62, pp. 745-752. However, since the United States Preventive Services Task Force (USPSTF) issued recommendations regarding PSA screening in 2012, and now PSA screening seems to have decreased, the percentage of men presenting with mCSPC in the United States may increase. Drazer MW et al., J Clin Oncol, 2015, Vol. 33, pp. 2416-2423; Lin K et al., Agency for Healthcare Research and Quality, 2011, No. 12-05160-EF-1.

[0049] Given that the proliferation and survival of prostate cancer cells rely on AR signaling, the standard treatment for patients with mCSPC disease is androgen deprivation therapy (ADT). Androgen deprivation therapy is defined as medical castration (i.e., gonadotropin-releasing hormone analogs [GnRHa; agonists or antagonists]) or surgical castration (i.e., bilateral orchiectomy). To prevent tumor expansion in subjects with significant metastases, first-generation anti-androgens can be used for short-term treatment to reduce testosterone amplification in the case of initiating GnRH agonists.

[0050] Antiandrogens

[0051] As used herein, the term "antiandrogen" has its recognized meaning and refers to a class of hormone receptor antagonist compounds that are capable of preventing or inhibiting the biological effects of androgens on normal responsive tissues in 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.

[0052] As used herein, the terms "AR antagonist" or "AR inhibitor" are used interchangeably herein and refer to an agent that inhibits or reduces at least one activity of an AR polypeptide. Exemplary AR activities include, but are not limited to, coactivator binding, DNA binding, ligand binding, or nuclear translocation.

[0053] As used herein, a "full antagonist" refers to an antagonist that substantially completely inhibits the activity of an AR polypeptide at an effective concentration. As used herein, a "partial antagonist" refers to an antagonist that is capable of partially inhibiting the activity of an AR polypeptide but is not a full antagonist even at the highest concentration. By "substantially completely" is meant that 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 higher of the AR polypeptide activity is inhibited.

[0054] As used herein, the term "first-generation antiandrogen" refers to an agent that exhibits antagonist activity against wild-type AR polypeptides. However, first-generation antiandrogens differ from second-generation antiandrogens in that first-generation antiandrogens may act as agonists in castration-resistant prostate cancer (CRPC). Exemplary first-generation antiandrogens include, but are not limited to, flutamide, nilutamide, and bicalutamide.

[0055] As used herein, the term "second-generation antiandrogen" refers to an agent that exhibits full antagonist activity against the 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, for example, in castration-resistant prostate cancer (CRPC). Exemplary second-generation antiandrogens include 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-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-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (also known as MDV3100 or enzalutamide; CAS No.: 915087-33-1); 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (RD162; CAS No.: 915087-27-3); and N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (also known as darolutamide). In some embodiments, the second-generation antiandrogen binds to the AR polypeptide at or near the ligand-binding site of the AR polypeptide.

[0056]

[0057] 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide)

[0058]

[0059] 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (enzalutamide)

[0060]

[0061] 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (RD162)

[0062]

[0063] N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (darolutamide). In some embodiments, the antiandrogens contemplated in the methods described herein inhibit AR nuclear translocation (such as darolutamide), DNA binding to androgen response elements, and coactivator recruitment. In some embodiments, the antiandrogens contemplated in the methods described herein do not exhibit agonist activity in prostate cancer cells with overexpression of AR.

[0064] Apalutamide is a second-generation antiandrogen that directly binds to the ligand-binding domain of AR, which weakens nuclear translocation, the binding of AR to DNA, and the regulation of AR target genes, thereby inhibiting tumor growth and promoting apoptosis. Apalutamide binds to AR with higher affinity than bicalutamide and induces partial or complete tumor regression in non-castrate hormone-sensitive and bicalutamide-resistant human prostate cancer xenograft models (Clegg et al., Clinical Cancer Research, March 15, 201272; 1494). Apalutamide lacks the partial agonist activity exhibited by bicalutamide in the presence of AR overexpression.

[0065] Darolutamide, BAY1841788, or ODM-201 are AR antagonists that include two diastereomers, ORM-16497 and ORM-16555. The chemical name is N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. It is active against known AR mutants that confer resistance to other second-generation antiandrogens. Darolutamide binds to AR with high affinity and weakens subsequent AR androgen-induced nuclear translocation and transcription of AR gene targets (Matsubara, N., Mukai, H., Hosono, A. et al., Cancer Chemother Pharmacol, 2017, Vol. 80, p. 1063).

[0066] Certain Terms

[0067] The terms used herein have their recognized meanings, but for the sake of clarity, some of these definitions are provided herein.

[0068] As used herein, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, refers to metastasis (spread).

[0069] As used herein, the term "prostate cancer" refers to prostate adenocarcinoma confirmed by histology or cytology.

[0070] The term "androgen deprivation therapy (ADT)" refers to the reduction of androgen levels to castrate levels of testosterone (<50 ng / dL) in patients with prostate cancer. Such treatment can include orchiectomy or the use of gonadotropin-releasing hormone agonists or antagonists. ADT includes surgical castration (orchiectomy) and / or the administration of luteinizing hormone-releasing hormone ("LHRH") / gonadotropin-releasing hormone (GnRH) agonists or antagonists to a human. Examples of GnRH agonists or antagonists are or include leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, degarelix, oteracil, 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 pamoate.

[0071] The term "locally advanced prostate cancer" refers to prostate cancer in which all active cancer cells appear to be limited to the prostate and associated or adjacent organs (such as the seminal vesicles, bladder neck, and rectal wall).

[0072] The term "high-risk localized prostate cancer" refers to locally advanced prostate cancer that has a likelihood of developing metastases or recurrent disease after initial treatment with an attempt at cure. In some embodiments, the high risk of metastasis development is defined as a prostate-specific antigen doubling time (PSADT) <20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, <12 months, <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, the high risk of metastasis development is defined as a prostate-specific antigen doubling time (PSADT) <10 months. In some embodiments, the high risk of metastasis development is defined as having a high Gleason score or a large-volume tumor.

[0073] For the avoidance of doubt, the terms "castration-sensitive prostate cancer" and "hormone-sensitive prostate cancer" are equivalent and can be used interchangeably.

[0074] The terms "castration-sensitive prostate cancer" and "hormone-sensitive prostate cancer" refer to cancer that responds to androgen deprivation therapy (ADT) as a local disease, biochemical recurrence, or in a metastatic situation.

[0075] 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 bone, lymph nodes, or other parts of the male body and responds to androgen deprivation therapy (ADT).

[0076] The term "non-metastatic castration-sensitive prostate cancer" refers to cancer in men that has not spread (metastasized) and responds to androgen deprivation therapy (ADT). In some embodiments, non-metastatic castration-sensitive prostate cancer is evaluated using a bone scan and a computed tomography (CT) or magnetic resonance imaging (MRI) scan. As used herein, the term "CRPC" refers to castration-resistant prostate cancer. CRPC is prostate cancer that continues to grow despite the inhibition of androgens that fuel the growth of prostate cancer cells.

[0077] The term "metastatic castration-resistant prostate cancer" refers to castration-resistant prostate cancer that has spread to other parts of the body.

[0078] Metastatic castration-sensitive prostate cancer (CSPC) refers to prostate cancer that still responds to testosterone suppression therapy.

[0079] As used herein, the term "NM-CRPC" refers to non-metastatic castration-resistant prostate cancer. In some embodiments, NM-CRPC is evaluated using a bone scan and a computed tomography (CT) or magnetic resonance imaging (MRI) scan.

[0080] The term "chemotherapy-naive metastatic castration-resistant prostate cancer" refers to metastatic castration-resistant prostate cancer that has not been previously treated with chemotherapeutic agents.

[0081] The term "metastatic castration-resistant prostate cancer after treatment with abiraterone acetate plus prednisone" refers to metastatic castration-resistant prostate cancer that has been treated with abiraterone acetate.

[0082] The term "high-risk NM-CRPC" refers to men with NM-CRPC who have a high probability of developing metastases. In some embodiments, a high risk of metastasis development is defined as a prostate-specific antigen doubling time (PSADT) < 20 months, < 19 months, < 18 months, < 17 months, < 16 months, < 15 months, < 14 months, < 13 months, < 12 months, < 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, a high risk of metastasis development is defined as a prostate-specific antigen doubling time (PSADT) < 10 months. In some embodiments, a high risk of metastasis development is defined as having locoregional recurrence (e.g., primary tumor bed, bladder neck, anastomotic area, pelvic lymph nodes).

[0083] As used herein, terms such as "co-administer" encompass the administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which these agents are administered by the same or different routes of administration or at the same or different times.

[0084] As used herein, the term "drug combination" refers to a product resulting from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient, such as apalutamide, and the adjuvant are both administered to a patient simultaneously in the form of a single unit or a single dosage form. The term "non-fixed combination" refers to the active ingredient, such as apalutamide, and the adjuvant being administered to a patient simultaneously, concurrently, or sequentially as separate units or separate dosage forms, without a specific intervening time limit, where such administration provides a safe and effective level of both active ingredients in a male body. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0085] The term "FDHT-PET" refers to 18F-16P-fluoro-5α-dihydrotestosterone positron emission tomography, which is a technique using a dihydrotestosterone-based tracer that allows for a visual assessment of the binding of a ligand to an androgen receptor in a patient. This technique can be used to evaluate the pharmacodynamics of androgen receptor-directed therapies.

[0086] The term "continuous daily dosing schedule" refers to the administration of a particular therapeutic agent without any drug holidays. In some embodiments, a continuous daily dosing schedule for a particular therapeutic agent includes administering the particular therapeutic agent at approximately the same time each day.

[0087] The terms "treat" and "treatment" refer to the treatment of a patient suffering from a pathological condition and refer to the effect of alleviating the condition by killing cancer cells and also refer to the effect of causing the progression of the condition to be inhibited, and include a slowdown in the rate of progression, a termination of the rate of progression, an improvement in the condition, and a cure of the condition. Treatment as a prophylactic measure (i.e., prevention) is also included. Unless otherwise specified, the term "treatment" refers to the full effect of the stated effects, but in other embodiments, the term may also refer to any one of the stated effects, or exclude at least one effect.

[0088] The term "metastasis-free survival" or "MFS" refers to the percentage of subjects in a study who have survived a specified period of time without cancer spread or have not died. MFS is typically reported as the time from the start of enrollment, randomization, or treatment in the study. MFS is reported for an individual or a study population. In the context of treating CRPC with antiandrogens, the extension of metastasis-free survival is the additional time observed, compared to treatment with placebo, without cancer spread or death (whichever occurs first). In some embodiments, the extension of 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 greater than 20 months. In some embodiments, administering a safe and effective amount of an antiandrogen provides an extension of metastasis-free survival in male humans, optionally wherein the extension of metastasis-free survival is relative to the average survival rate of a population of male humans with non-metastatic castration-resistant prostate cancer treated with placebo. In some embodiments, metastasis-free survival refers to the time from randomization to the first evidence of BICR-confirmed bone or soft tissue distant metastasis or death from any cause (whichever occurs first).

[0089] The term "time to metastasis" is the time from randomization to the time of the scan showing the first evidence of a radiographically detectable bone or soft tissue distant metastasis confirmed by BICR. In some embodiments, administering a safe and effective amount of an antiandrogen provides improved anti-tumor activity as measured by time to metastasis (TTM).

[0090] The term "radiographic progression-free survival" is the time from randomization to the first imaging-recorded progressive disease or death, whichever occurs first. A subject is considered to have radiographic progressive disease if the subject has progression of a soft tissue lesion measured by computed tomography or magnetic resonance imaging or new lesions on a bone scan.

[0091] The term "progression-free survival" is based on RECIST v1.1 and is defined as follows: For subjects with at least one measurable lesion, progressive disease is defined as an increase in the sum of the diameters of target lesions of at least 20%, using the smallest sum in the study as a reference (if the baseline sum is the smallest in the study, this includes the baseline sum). In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm. Additionally, the appearance of one or more new lesions is also considered progression. For subjects with only non-measurable disease observed on CT or MRI scans, definite progression (representing a change in the overall disease state) or the appearance of one or more new lesions is considered progression. For new bone lesions detected by bone scan, a second imaging modality (e.g., CT or MRI) is required to confirm progression. In some embodiments, administering a safe and effective amount of an antiandrogen provides improved anti-tumor activity, as measured by progression-free survival.

[0092] The term "prostate cancer-specific survival" is defined as the time from randomization to the date of death attributed to prostate cancer.

[0093] The term "PFS2" means the time from initial study randomization to the second disease progression or death from any cause.

[0094] The term "time to symptomatic progression" is defined as the time from randomization to the time recorded in the CRF (whichever occurs earlier) for any of the following: (1) development of a skeletal-related event (SRE): pathologic fracture, spinal cord compression, or the need for surgical intervention or radiotherapy to bone; (2) pain progression or worsening of disease-related symptoms that requires initiation of a new systemic anti-cancer therapy; or (3) development of clinically significant symptoms due to local tumor progression that requires surgical intervention or radiotherapy. In some embodiments, administering a safe and effective amount of an antiandrogen provides improved anti-tumor activity, as measured by time to symptomatic progression.

[0095] The term "time to pain progression" is defined as the time from randomization to pain progression (observed as a mean increase of 2 points from baseline in the worst pain intensity at two consecutive assessment intervals ≥ 3 weeks in the Brief Pain Inventory - Short Form [BPI - SF], and a mean worst pain score > 4 in patients who have not had a reduction in opioids, or a mean worst pain score > 4 in patients not receiving long-term opioids, whichever occurs first). The BPI - SF worst pain (item 3) is used for the pain progression endpoint time. The score ranges from 0 to 10, and the lower the score, the lower the level of pain intensity; a change of 2 is the smallest difference that matters.

[0096] The term "time to skeletal-related event (SRE)" is defined as the time from the date of randomization to the date of the first observed SRE (symptomatic pathologic fracture, spinal cord compression, bone radiation, or bone surgery).

[0097] The term "time to long-term opioid use" is defined as the time from the date of randomization to the date of first confirmed long-term opioid use. Long-term opioid use is defined as oral administration of an opioid analgesic for ≥ 3 weeks or administration of a non-oral formulation for ≥ 7 days. For patients who have already received an opioid at the time of study enrollment, long-term opioid use is defined as an increase in the total daily dose of the opioid analgesic of ≥ 30%, with oral administration continuing for ≥ 3 weeks or administration of a non-oral formulation continuing for ≥ 7 days. Administration of an opioid analgesic as needed (e.g., non-fixed or non-scheduled dosing) or extension of opioid use for treatment other than the patient's prostate cancer does not require discontinuation of study treatment.

[0098] The term "time to symptomatic local progression" is defined as the time from the date of randomization to the date of symptomatic local progression, whichever occurs first. Examples of symptomatic local progression include, but are not limited to, urinary tract obstruction or bladder outlet obstruction.

[0099] The term "time to ECOG PS grade deterioration" is defined as the time from the date of randomization to the date of the first deterioration in ECOG PS grade (defined as a worsening of the ECOG PS grade by at least 1 point).

[0100] The term "overall survival" is defined as the time from randomization to the date of death from any cause. The survival data for subjects who are alive at the time of analysis are reviewed at their last known date of survival. In addition, for subjects with no post-baseline information on survival, the data are reviewed at the date of randomization; for subjects who are lost to follow-up or withdraw consent, the data are reviewed at their last known date of survival. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved anti-tumor activity, as measured by overall survival.

[0101] The term "time to cytotoxic chemotherapy" is defined as the time from randomization to the recording of new cytotoxic chemotherapy.

[0102] The term "progression-free survival of the first subsequent treatment (PFS2)" is defined as the time from randomization to investigator-assessed disease progression (PSA, radiographic, symptomatic, or any combination) or death (from any cause) during the first subsequent anti-cancer treatment before the start of the second subsequent anti-cancer treatment, whichever occurs first.

[0103] The term "time to PSA progression" is defined as the time from randomization to the date of PSA progression based on Prostate Cancer Working Group 2 criteria (Scher HI et al., J Clin Oncol, 2008, Vol. 26, pp. 1148-1159).

[0104] The term "second progression-free survival time" is defined as the time from randomization to the first occurrence of disease progression (PSA progression, progression on imaging, or clinical progression) determined by the investigator or death from any cause (whichever occurs first) when the patient is receiving the first subsequent therapy for prostate cancer.

[0105] Progression data for subjects with no recorded progression after subsequent therapy are reviewed at the last date known to be progression-free or the date of death. In some embodiments, administration of a safe and effective amount of an antiandrogen provides improved anti-tumor activity, as measured by progression-free survival of the first subsequent therapy.

[0106] Prostate-specific antigen response and time to PSA progression are evaluated at the initial analysis of MFS according to Prostate Cancer Working Group (PCWG2) criteria. Time to PSA progression is calculated as the time from randomization to the time when the PSA progression criteria according to PCWG2 are met.

[0107] As used herein, the term "placebo" means administration of a pharmaceutical composition that does not contain a second-generation antiandrogen. In the case of treating metastatic castration-sensitive prostate cancer, men receiving an antiandrogen or placebo will need to continue to maintain castrate levels of testosterone by co-administration of a GnRH agonist / antagonist or by orchiectomy.

[0108] As used herein, the term "survival benefit" refers to an increase in patient survival rate from the time of randomization in a drug trial to death. In some embodiments, the survival benefit is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 80, about 100 months or greater than 100 months.

[0109] As used herein, the term "delay in symptoms associated with disease progression" refers to an increase in the time to development of symptoms such as pain, urinary obstruction, and quality of life considerations starting from the time of randomization in a drug trial.

[0110] The term "randomization" when referring to a clinical trial means the time when a patient is confirmed eligible for a clinical trial and is assigned to a treatment group.

[0111] The terms "kit" and "manufactured article" are used as synonyms.

[0112] The terms "subject", "patient", and "person" are used interchangeably.

[0113] Route of Administration and Pharmaceutical Compositions

[0114] The therapeutic agents described herein are administered in any suitable manner or formulation. Suitable routes of administration of the therapeutic agents include, but are not limited to, oral or parenteral (e.g., intravenous, subcutaneous, intramuscular) routes of administration. All formulations are in a dosage suitable for administration to a human. An overview of pharmaceutical compositions can be found in the following literature, for example: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington: 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, 7th Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0115] Safety-oriented studies also seek to identify any potential adverse effects that may be caused by exposure to the drug. When tested under appropriate circumstances, such as in a tightly controlled clinical trial, efficacy is generally measured by determining whether the active pharmaceutical ingredient exhibits health benefits superior to those of a placebo or other intervention.

[0116] Unless otherwise specified, as used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of antiandrogen administered to treat a potential disease or disorder (including halting or slowing the progression of the disease or disorder).

[0117] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that the beneficial effects of the formulation, composition, or ingredient on the overall health of the male human being being treated substantially outweigh its detrimental effects to any extent that they exist.

[0118] In some embodiments, the antiandrogen is in a solid oral dosage form. In some embodiments, the antiandrogen is formulated as an oral dosage form, a unit oral dosage form, or a solid dosage form (e.g., 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-3-yl)-8-oxo-6-thia-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-4-oxo-2-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide. In some embodiments, the antiandrogen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide. In some embodiments, the antiandrogen is N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. The formulation may also comprise a combination of two or more of these materials. The solid oral dosage form containing the antiandrogen may be provided as a soft gel capsule as disclosed in WO2014113260 and CN104857157, each of which is incorporated herein by reference; or as a tablet as disclosed in WO2016090098, WO2016090101, WO2016090105, and WO2014043208, each of which is incorporated herein by reference. Techniques suitable for preparing the solid oral dosage forms of the present invention are described in the following references: Remington: Pharmaceutical Sciences, 18th Edition, edited by A.R. Gennaro, 1990, Chapter 89; and Remington: The Science, and Practice of Pharmacy, 21st Edition, 2005, Chapter 45.

[0119] In certain embodiments, the antiandrogen is present in a solid unit dosage form and a solid unit dosage form suitable for oral administration. The unit dosage form may contain about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, or 240 mg of the antiandrogen per unit dosage form, or an amount of the antiandrogen within a range defined by two of these values.

[0120] To prepare the pharmaceutical composition of the present invention, according to conventional pharmaceutical compounding techniques, the active pharmaceutical ingredient can be intimately mixed with a pharmaceutical carrier, which can take various forms depending on the dosage form required for administration (such as oral or parenteral administration). 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.

[0121] In solid oral dosage forms such as, for example, dry powders for reconstitution or inhalation, granules, capsules, cachets, soft gelatin capsules, 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, glidants, disintegrants, etc. Tablets and capsules represent the most advantageous oral unit dosage forms due to their convenience in administration, and in such cases, a solid pharmaceutical carrier is clearly employed. If desired, tablets can be sugar-coated, gelatin-coated, film-coated, or enteric-coated by standard techniques.

[0122] 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 aerosols or liquid sprays, drops, or suppositories, for oral administration, nasal administration, sublingual administration, intraocular administration, transdermal administration, rectal administration, vaginal administration, dry powder inhaler administration, or other inhalation or insufflation routes of administration.

[0123] These formulations are manufactured by conventional formulation techniques. To prepare solid pharmaceutical compositions such as tablets, the main active ingredient is mixed with pharmaceutical carriers such as conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, anti-adhesives and glidants. Suitable diluents include, but are not limited to, starches (i.e., corn, wheat or potato starch, which may be hydrolyzed), lactose (granular, spray-dried or anhydrous), sucrose, sucrose-based diluents (sugar confectionery; sucrose plus about 7% to 10% by weight of invert sugar; sucrose plus about 3% by weight of modified dextrin; sucrose plus invert sugar, about 4% by weight of invert sugar, about 0.1% to 0.2% by weight of corn starch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e., AVICEL microcrystalline cellulose from FMC Corporation), dibasic calcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate, etc. Suitable binders and adhesives include, but are not limited to, gum arabic, guar gum, tragacanth, sucrose, gelatin, glucose, starch and cellulose (i.e., methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, etc.), water-soluble or water-dispersible binders (such as alginic acid and its salts, magnesium aluminum silicate, hydroxyethylcellulose [i.e., TYLOSE from Hoechst Celanese], polyethylene glycol, polysaccharide acid, bentonite, polyvinylpyrrolidone, polymethacrylate and pregelatinized starch), etc. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium carboxymethyl starch, pregelatinized starch, clays (magnesium aluminum silicate), cellulose (such as croscarmellose sodium and microcrystalline cellulose), alginates, pregelatinized starch (i.e., corn starch, etc.), gums (i.e., agar, guar gum, locust bean gum, karaya gum, pectin and tragacanth), crospovidone, etc. Suitable lubricants and anti-adhesives include, but are not limited to, stearates (magnesium stearate, calcium stearate and sodium stearate), stearic acid, talc, wax, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium lauryl magnesium sulfate, etc. Suitable glidants 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), etc. Sweeteners and flavoring agents may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. In addition, coloring agents and coating agents may be added to or coated on the solid dosage form for easy identification of the drug or for aesthetic purposes. These carriers are formulated with the drug active substance to provide an accurate and appropriate dose of the drug active substance with therapeutic release characteristics.

[0124] One aspect of the invention is a solid dispersion comprising an antiandrogen. There are various techniques for preparing the solid dispersions of the invention, including melt extrusion (e.g., hot melt extrusion), spray drying, and evaporation of solutions, especially hot melt extrusion and spray drying, with spray drying being preferred. One aspect of the invention is particles composed of the solid dispersions as described herein. In one aspect of the invention, the particles as described herein can be obtained, specifically obtained by spray drying a mixture typically comprising an antiandrogen (more specifically, ARN-509) and HPMCAS in a suitable solvent. In one aspect, the particles can be obtained by melt extrusion, specifically by melt extrusion.

[0125] HPMCAS, or hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (CAS No. 71138-97-1), is a mixture of acetate and monosuccinate esters of hydroxypropyl methylcellulose (IUPAC name: cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogenated succinate). There can be different grades distinguished based on the degree of substitution / substitution rate (acetyl content, succinyl content) and particle size (micronized and granular). In one aspect of the invention, the HPMCAS in the dispersion with ARN-509 is HPMCAS LG (granular grade) or HPMCAS LF (micronized grade) (Shin-Etsu Chemical Co., Ltd.), specifically HPMCAS LG.

[0126] Binders suitable for the pharmaceutical compositions provided herein include, but are not limited to, starch, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose), polyvinylpyrrolidone, and mixtures thereof.

[0127] Examples of fillers suitable for 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.

[0128] Binders or fillers in the pharmaceutical compositions are typically present in the pharmaceutical composition or dosage form in an amount of about 50 wt% to about 99 wt%.

[0129] Disintegrants can be used in a composition to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while those containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little and that does not adversely alter the release of the active ingredient should be used to form a solid oral dosage form. The amount of disintegrant used varies according to the type of formulation and is readily recognizable to one of ordinary skill in the art. Typical pharmaceutical compositions contain from about 0.5 wt% to about 15 wt% of a disintegrant, specifically from about 1 wt% to about 5 wt% of a disintegrant. Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, sodium croscarmellose, crospovidone, sodium carboxymethyl starch, potato or tapioca starch, pregelatinized starch, other starches, other celluloses, gums, and mixtures thereof.

[0130] 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 diols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Lubricants are generally used in an amount less than about 1 wt% of the pharmaceutical composition or dosage form into which they are incorporated.

[0131] Tablet formulations can optionally be film-coated to provide color, light protection, and / or taste masking. Tablets can also be coated to modulate the occurrence and / or rate of release in the gastrointestinal tract, thereby optimizing or maximizing the patient's bioexposure to the API.

[0132] Hard capsule formulations can be prepared by filling a blend or granulation of apalutamide or enzalutamide into a shell composed of, for example, gelatin or hydroxypropyl methylcellulose.

[0133] Soft gel capsule formulations can be prepared.

[0134] Pharmaceutical compositions intended for oral administration can be prepared from the solid dispersion formulations and blending materials described herein and other methods known in the art for preparing pharmaceutical compositions. Such compositions can also contain one or more agents selected from sweeteners, flavorants, colorants, and preservatives to provide a pharmaceutically elegant and palatable formulation.

[0135] Tablets may contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets. These excipients may be, for example, inert diluents, granulating and disintegrating agents, binders, glidants, lubricants and antioxidants such as propyl gallate, butylated hydroxyanisole and butylated hydroxytoluene. Tablets may be uncoated, or they may be film-coated to alter the appearance or may be coated with a functional coating to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.

[0136] Compositions for oral administration may also be provided as capsules (e.g., hard gelatin), wherein the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules, wherein the active ingredient is admixed with a liquid or semi-solid such as peanut oil, liquid paraffin, fractionated glycerides, surfactants or olive oil. Aqueous suspensions contain the active substance admixed with excipients suitable for the manufacture of aqueous suspensions. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient admixed 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 contain a diluent system, a disintegrant, a salt, a lubricant, a glidant and a film coating in the following concentrations: from about 3% w / w to about 58% w / w, from about 4% w / w 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 from about 18% w / w to about 40% w / w, from about 7% w / w to about 15% 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 formulation is blended with a diluent, one or more disintegrants, a lubricant and a glidant. Exemplary blend compositions or oral dosage forms include mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0137] The disintegrant may be present in a concentration of from about 4% w / w to about 20% w / w or from about 7% w / w to about 15% w / w. A salt may also be present, which may be sodium chloride, potassium chloride or a combination thereof. The combination of the salt and the disintegrant is present in a concentration of from about 5% w / w to about 35% w / w of the final pharmaceutical composition.

[0138] In certain embodiments, the inactive ingredients of the tablet core are: colloidal anhydrous silica, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and siliconized microcrystalline cellulose. In other embodiments, the finished tablet has a film coating composed of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

[0139] In other embodiments, a single unit dose of the pharmaceutical composition comprises about 60 mg of apalutamide, consists of or consists essentially of the same. In some embodiments, multiple doses of the single unit dose pharmaceutical composition comprising about 60 mg of apalutamide, consisting of or consisting essentially of the same (e.g., 4 multi-unit dosage forms or individual unit dosage forms) are administered to a human. The total daily dose of apalutamide can be about 240 mg / day.

[0140] In some embodiments, a single unit dose of the pharmaceutical composition comprises about 40 mg of enzalutamide, consists of or consists essentially of the same. In some embodiments, multiple doses of the single unit dose pharmaceutical composition comprising about 40 mg of enzalutamide, consisting of or consisting essentially of the same (e.g., 4 multi-unit dosage forms or individual unit dosage forms) are administered to a human. The total daily dose of enzalutamide can be about 160 mg / day.

[0141] In additional embodiments, a single unit dose of the pharmaceutical composition comprises about 300 mg of darolutamide, consists of or consists essentially of the same. In some embodiments, multiple doses of the single unit dose pharmaceutical composition comprising about 300 mg of darolutamide, consisting of or consisting essentially of the same (e.g., 2 multi-unit dosage forms or individual unit dosage forms) are administered to a human. The total daily dose of darolutamide can be about 600 mg / day twice. The total daily dose of darolutamide can be about 1200 mg / day.

[0142] All orally administered formulations are in dosage forms suitable for such administration.

[0143] Methods of Administration and Treatment Regimens

[0144] In one aspect, the present disclosure provides a method of treating metastatic castration-sensitive prostate cancer in a human male, the method comprising, consisting essentially of, or consisting of the steps of: administering to a human male having metastatic castration-sensitive prostate cancer a therapeutically effective amount of an antiandrogen, wherein the antiandrogen is at least one of the following: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-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-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, or N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. In the following disclosure, the "method of treating metastatic castration-sensitive prostate cancer" may alternatively be recited as the "method of treating a human male having metastatic castration-sensitive prostate cancer". For the sake of brevity, not every possible alternative has been analyzed, but each alternative is considered to be considered separately as if it had been fully described.

[0145] The present disclosure also provides a method of treating metastatic castration-sensitive prostate cancer in a human male, the method consisting essentially of, or consisting of the steps of: administering to a human male having metastatic castration-sensitive prostate cancer a therapeutically effective amount of an antiandrogen, wherein the antiandrogen is one or more of the following: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-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-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, or N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.

[0146] In another aspect described herein, relative to the overall survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the overall survival of male humans, said comparator group having received placebo in combination with androgen deprivation therapy, said placebo having been administered before or during administration of the anti-androgen. In other embodiments, the comparator group is untreated. In another aspect described herein, relative to the overall survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the overall survival of male humans, said comparator group having received androgen deprivation therapy. In certain embodiments, relative to the overall survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the overall survival of male humans, said comparator group not having received treatment. In certain embodiments, relative to the overall survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the overall survival of male humans, said comparator group having received a first-generation anti-androgen with or without androgen deprivation therapy. In some embodiments, both the group receiving the anti-androgen and the comparator group have been previously treated by the same or a similar prior treatment regimen.

[0147] In additional embodiments, relative to the progression-free survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the progression-free survival of male humans, said comparator group having received placebo in combination with androgen deprivation therapy. In another aspect described herein, relative to the progression-free survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the progression-free survival of male humans, said comparator group having previously received androgen deprivation therapy. In certain embodiments, relative to the progression-free survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the progression-free survival of male humans, said comparator group having not received treatment previously. In certain embodiments, relative to the progression-free survival rate of a male human comparator group with metastatic castration-sensitive prostate cancer, administration of an anti-androgen prolongs the progression-free survival of male humans, said comparator group having previously received a first-generation anti-androgen with or without androgen deprivation therapy. Similarly, in preferred embodiments, both the group receiving the anti-androgen and the comparator group have previously undergone the same or a similar prior treatment regimen.

[0148] In one aspect, the present disclosure describes a method of treating metastatic castration-sensitive prostate cancer, the method comprising, consisting essentially of, or consisting of the steps of: administering to a human male having metastatic castration-sensitive prostate cancer a therapeutically effective amount of an antiandrogen, 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 weekly. In some embodiments, the antiandrogen is administered twice weekly. In some embodiments, the antiandrogen is administered every other week. In some embodiments, the antiandrogen is administered orally according to a continuous daily dosing schedule.

[0149] In one embodiment, the required dose is suitably provided as a single dose or divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four or more sub-doses per day. In some embodiments, the antiandrogen is conveniently provided as divided doses administered simultaneously (or over a short period of time), once daily. In some embodiments, the antiandrogen is conveniently provided as divided doses administered in equal portions, twice daily. In some embodiments, the antiandrogen is conveniently provided as divided doses administered in equal portions, three times daily. In some embodiments, the antiandrogen is conveniently provided as divided doses administered in equal portions, four times daily.

[0150] In certain embodiments, the desired dose may be delivered in 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 sub-unit doses throughout the day such that the total amount of antiandrogen delivered by the sub-unit doses throughout the day provides the total daily dose.

[0151] In further embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide is administered daily to a human male. In still further embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male. In some embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male according to a continuous daily dosing schedule.

[0152] In additional embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered daily to male humans. In other additional embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered orally to male humans. In some embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered orally to male humans on a continuous daily dosing schedule.

[0153] In additional embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered daily to male humans. 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-N-methylbenzamide is administered orally to male humans. In some embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to male humans on a continuous daily dosing schedule.

[0154] In additional embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is administered daily to male humans. In other additional embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is administered orally to male humans. In some embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is administered orally to male humans on a continuous daily dosing schedule.

[0155] 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.

[0156] Generally, the dosage of an anti-androgen for treating the human diseases or disorders described herein is typically in the range of 10 mg / day to 1000 mg / day. In some embodiments, the anti-androgen is orally administered to a human at a dosage of about 30 mg / day to about 1200 mg / day. In some embodiments, the anti-androgen is orally administered to a human at a dosage of about 30 mg / day to about 600 mg / day. In some embodiments, the anti-androgen is orally administered to a human at a dosage 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.

[0157] In certain embodiments, the dosage of an anti-androgen for treating the human diseases or disorders described herein can be in the range of 30 mg / day to 40 mg / day, 40 mg / day to 50 mg / day, 50 mg / day to 60 mg / day, 60 mg / day to 70 mg / day, 70 mg / day to 80 mg / day, 80 mg / day to 90 mg / day, 90 mg / day to 100 mg / day, 100 mg / day to 120 mg / day, 120 mg / day to 140 mg / day, 140 mg / day to 160 mg / day, 160 mg / day to 180 mg / day, 180 mg / day to 200 mg / day, 200 mg / day to 220 mg / day, 220 mg / day to 240 mg / day, 240 mg / day to 260 mg / day, 260 mg / day to 280 mg / day, 280 mg / day to 300 mg / day, 300 mg / day to 320 mg / day, 320 mg / day to 340 mg / day, 340 mg / day to 360 mg / day, 360 mg / day to 380 mg / day, 380 mg / day to 400 mg / day, 400 mg / day to 420 mg / day, 420 mg / day to 440 mg / day, 440 mg / day to 460 mg / day, 460 mg / day to 480 mg / day, or in any range defined by two or more values from these ranges, or any individual value cited within these ranges.

[0158] In some embodiments, the dose of the anti-androgen for treating the human diseases or disorders described herein can be in the range of 0.3 mg / kg / day to 0.4 mg / kg / day, 0.4 mg / kg / day to 0.5 mg / kg / day, 0.5 mg / kg / day to 0.6 mg / kg / day, 0.6 mg / kg / day to 0.7 mg / kg / day, 0.7 mg / kg / day to 0.8 mg / kg / day, 0.8 mg / kg / day to 0.9 mg / kg / day, 0.9 mg / kg / day to 1 mg / kg / day, 1 mg / kg / day to 1.2 mg / kg / day, 1.2 mg / kg / day to 1.4 mg / kg / day, 1.4 mg / kg / day to 1.6 mg / kg / day, 1.6 mg / kg / day to 1.8 mg / kg / day, 1.8 mg / kg / day to 2 mg / kg / day, 2 mg / kg / day to 2.2 mg / kg / day, 2.2 mg / kg / day to 2.4 mg / kg / day, 2.4 mg / kg / day to 2.6 mg / kg / day, 2.6 mg / kg / day to 2.8 mg / kg / day, 2.8 mg / kg / day to 3.0 mg / kg / day, 3.0 mg / kg / day to 3.2 mg / kg / day, 3.2 mg / kg / day to 3.4 mg / kg / day, 3.4 mg / kg / day to 3.6 mg / kg / day, 3.6 mg / kg / day to 3.8 mg / kg / day, 3.8 mg / kg / day to 4.0 mg / kg / day, 4.0 mg / kg / day to 4.2 mg / kg / day, 4.2 mg / kg / day to 4.4 mg / kg / day, 4.4 mg / kg / day to 4.6 mg / kg / day, 4.6 mg / kg / day to 4.8 mg / kg / day, or in any range defined by two or more values from these ranges, or any individual value cited within these ranges.

[0159] In 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 is orally administered to male humans at a dose of from about 30 mg / day to about 480 mg / day. 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 is orally administered to male humans at a dose of from about 180 mg / day to about 480 mg / 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 orally administered to male humans at the following doses: (a) about 30 mg / day; (b) about 60 mg / day; (c) about 90 mg / day; (d) about 120 mg / day; or (d) about 240 mg / 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-N-methylbenzamide is orally administered to male humans at a dose of about 240 mg / day.

[0160] In some embodiments, if a male human experiences toxicity greater than or equal to grade 3, the dose of 4-[7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is reduced to 180 mg / day. Alternatively or in addition, the initial dose may be maintained until the toxicity symptoms improve to less than or equal to grade 1 toxicity; then the dose may be reduced as proposed herein, or resumed at the initial dose, and monitoring continued. In some embodiments, if a male human experiences an intolerable side effect, the dose of 4-[7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is reduced to 180 mg / day. In some embodiments, if a male human experiences toxicity greater than or equal to grade 3, the dose of 4-[7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is reduced to 120 mg / day. Alternatively or in addition, the initial dose may be maintained until the toxicity symptoms improve to less than or equal to grade 1 toxicity; then the dose may be reduced as proposed herein, or resumed at the initial dose, and monitoring continued. In some embodiments, if a male human experiences an intolerable side effect, the dose of 4-[7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is reduced to 120 mg / day.

[0161] In some embodiments, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is orally administered at a dose of about 160 mg / day. In some embodiments, enzalutamide is administered at a dose greater than 160 mg / day.

[0162] In some embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is orally administered to male humans at a dose of about 30 mg / day to about 480 mg / day. In other additional embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is orally administered to male humans at a dose of about 180 mg / day to about 480 mg / day. In certain embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is orally administered to male humans at the following doses: (a) about 30 mg / day; (b) about 60 mg / day; (c) about 90 mg / day; (d) about 120 mg / day; or (d) about 240 mg / day. In some embodiments, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is orally administered to male humans at a dose of about 240 mg / day.

[0163] In some embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is orally administered at a dose of about 1200 mg / day. In some embodiments, N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide is administered at a dose greater than 1200 mg / day.

[0164] In certain embodiments where no improvement in the state of a human disease or disorder is observed, the daily dose of the antiandrogen is increased. In some embodiments, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, a three-times-daily dosing schedule is employed to increase the amount of antiandrogen administered.

[0165] In some embodiments, the amount of antiandrogen administered to a human varies according to a variety of factors such as, but not limited to, the condition and severity of the disease or disorder and the characteristics of the human (e.g., body weight), as well as the particular additional therapeutic agent administered (if applicable).

[0166] In some embodiments, a male human has received at least one prior therapy for treating cancer, wherein the prior therapy for treating cancer is radiotherapy, surgical intervention therapy, or docetaxel therapy. In some embodiments, the male human is untreated.

[0167] In some embodiments, an antiandrogen is administered in combination with androgen deprivation therapy. In additional embodiments, an antiandrogen is administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist. In still other additional embodiments, the at least one GnRH agonist or antagonist is or comprises leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, degarelix, ozerelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109, or triptorelin.

[0168] Physicians can prescribe GnRH agonists according to instructions, recommendations, and practices. 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 at a dose of about 0.01 mg to about 200 mg of leuprolide over a period of about 3 days to about 12 months, preferably at a dose of 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 nafarelin. 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, histrelin acetate is administered at a dose of about 50 mg of histrelin acetate over a 12-month period 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 at a dose of about 0.01 mg to about 20 mg of goserelin over a period of about 28 days to about 3 months, preferably at a dose of about 3.6 mg to about 10.8 mg of goserelin over a period of about 28 days 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 elagolix. In some embodiments, the GnRH agonist or antagonist is elagolix. 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 at a dose of about 0.01 mg to about 20 mg of triptorelin over a period of about 1 month, preferably at a dose of about 3.75 mg of triptorelin over a 1-month period.

[0169] In certain embodiments, an antiandrogen is used in combination with bilateral orchiectomy. In certain embodiments, the antiandrogen is administered after bilateral orchiectomy.

[0170] In other additional embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is not co-administered with: (a) a drug that is a strong CYP2C8 or CYP3A4 inhibitor; (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 P-glycoprotein, BCRP, or OATP1B1 substrate. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is not co-administered with a drug that is a strong CYP2C8 or CYP3A4 inhibitor. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is not co-administered 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-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is not co-administered with a drug that is a UDP-glucuronosyltransferase (UGT) substrate or (d) a drug that is a P-glycoprotein, BCRP, or OATP1B1 substrate.

[0171] A non-limiting example of a strong CYP2C8 inhibitor is gemfibrozil.

[0172] 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, clarithromycin, voriconazole, clotrimazole, diltiazem, erythromycin, fluconazole, verapamil, and oleandomycin.

[0173] Non-limiting examples of moderate to strong CYP3A4 inducers include alvimopan, St. John's wort, carbamazepine, efavirenz, phenytoin, etravirine, bosentan, nafcillin, rifampin, modafinil, rifabutin, and barbiturates.

[0174] Non-limiting examples of drugs metabolized mainly by CYP3A4 are imidazolidinones. Non-limiting examples of drugs metabolized mainly by CYP2C19 are omeprazole. Non-limiting examples of drugs metabolized mainly by CYP2C9 are S-warfarin.

[0175] Non-limiting examples of drugs that are substrates of P-glycoprotein are fexofenadine.

[0176] Non-limiting examples of drugs that are substrates of BCRP are rosuvastatin.

[0177] Non-limiting examples of drugs that are substrates of OATP1B1 are rosuvastatin.

[0178] In another aspect, the present disclosure provides a method for treating metastatic castration-sensitive prostate cancer in a human male, the method comprising the steps of, consisting of, or consisting essentially of: (a) determining whether a human male has metastatic castration-sensitive prostate cancer; and (b) administering to the human male a therapeutically effective amount of an antiandrogen to treat metastatic castration-sensitive prostate cancer, wherein the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-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-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, or N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.

[0179] Treatment Methods Involving Approved Pharmaceutical Products

[0180] The present disclosure also provides a method for treating metastatic castration-sensitive prostate cancer in a human male, the method comprising administering to the human male having metastatic castration-sensitive prostate cancer the pharmaceutical product in an amount described in the drug product label of an approved pharmaceutical product comprising apalutamide. In some embodiments, the approved pharmaceutical product comprising apalutamide is an ANDA pharmaceutical product, a supplemental new drug application pharmaceutical product, or a 505(b)(2) pharmaceutical product. In certain embodiments, the method is clinically demonstrated to be safe and / or effective. In certain embodiments, the method is clinically demonstrated to be safe. In certain embodiments, the method is clinically demonstrated to be effective.

[0181] The term "drug product" or "approved drug product" is a product containing an active pharmaceutical ingredient that has been approved by a government agency (e.g., the Food and Drug Administration or a similar agency in other countries and regions) for marketing for at least one indication.

[0182] Similarly, "label" or "drug product label" refers to the information provided to patients that provides relevant information about the drug product. Such information includes, but is not limited to, one or more of the following: drug description, clinical pharmacology, indications (uses of the drug product), contraindications (groups of patients who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use during pregnancy, use during lactation, use in pediatric and geriatric patients, method of drug supply, safety information for patients, or any combination thereof. In certain embodiments, the label or drug product label provides instructions for use in patients with metastatic castration-sensitive prostate cancer. In additional embodiments, the label or drug product label identifies apalutamide as a regulatory-approved chemical entity. In still other additional embodiments, the label contains data on superior efficacy in prolonging radiographic progression-free survival or overall survival relative to placebo. In yet other additional embodiments, the label instructs the patient or physician to administer apalutamide if the patient has metastatic castration-sensitive prostate cancer.

[0183] The term "Reference Listed Drug (RLD)" is a drug product to which new generic versions will be compared to show that they are bioequivalent (see 21 CFR 314.3(b)). It is also a medicinal product for which a marketing authorization has been granted in a Member State of the European Union or by the European Commission on the basis of a complete dossier, i.e., quality, preclinical and clinical data have been submitted in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001 / 83 / EC, and the marketing authorization application for a generic / mixed medicinal product involves demonstrating bioequivalence (usually by submitting appropriate bioavailability studies).

[0184] In the United States, companies seeking approval to market a generic equivalent must mention the RLD in their own Abbreviated New Drug Application (ANDA). For example, the ANDA applicant relies on the FDA's finding that the previously approved drug product, i.e., the RLD, is safe and effective and must, among other things, demonstrate that the proposed generic drug product is the same as the RLD in certain respects. Specifically, with limited exceptions, the drug product for which an ANDA is submitted must, among other things, have the same active ingredient, conditions of use, route of administration, dosage form, strength, and (with certain permitted variations) labeling as the RLD. The RLD is the marketed drug product to which the ANDA applicant must show that its proposed ANDA drug product is the same in terms of active ingredient, dosage form, route of administration, strength, labeling, and other characteristics such as conditions of use. In the Electronic Orange Book, there are columns for the RLD and for the reference standard. In the printed version of the Orange Book, the RLD and the reference standard are identified by specific symbols. For an ANDA based on an approved petition for adaptation (petition ANDA), the reference-listed drug is usually the marketed drug product referenced in the approved petition for adaptation.

[0185] The reference standard is the drug product selected by the FDA that an applicant seeking ANDA approval must use in conducting the in vivo bioequivalence studies required for approval. The FDA generally selects a single reference standard that an ANDA applicant must use in in vivo bioequivalence testing. Typically, the FDA will select the reference-listed drug as the reference standard. However, in some cases (e.g., where the reference-listed drug has been withdrawn from the market but the FDA has determined that it was withdrawn for reasons other than safety or effectiveness and the FDA selects an ANDA as the reference standard), the reference-listed drug and the reference standard may be different.

[0186] The FDA identifies the reference-listed drugs in the lists of prescription drug products, OTC drug products, and discontinued drug products. The marketed drug product identified as the reference-listed drug represents the drug product on which an applicant may rely to seek ANDA approval. The FDA anticipates updating the list of reference-listed drugs in the prescription drug products, OTC drug products, and discontinued drug products lists periodically as appropriate.

[0187] The FDA also identifies the reference standards in the lists of prescription drug products and OTC drug products. The marketed drug product identified as the reference standard represents the FDA's current best judgment for the appropriate comparator for any in vivo bioequivalence studies required for approval.

[0188] In some cases, when the FDA has not designated a listed drug as the reference listed drug for a marketed drug, such a marketed drug may be protected from competition by generic drugs. If the FDA has not designated the reference listed drug for the drug product that an applicant intends to copy, the potential applicant may request that the FDA designate the reference listed drug for that drug product.

[0189] The FDA may spontaneously select a new reference standard, and doing so will help ensure that applications for generic drugs can be submitted and evaluated, for example, in cases where the marketed drug currently selected as the reference standard has been withdrawn from the market for reasons other than safety and efficacy reasons.

[0190] In Europe, the applicant identifies the reference drug product (product name, strength, pharmaceutical form, MAH, first authorization, member state / community) in the application form for its generic / mixed drug product (identical to an ANDA or supplementary NDA (sNDA) drug product), which is synonymous with the RLD, as described below:

[0191] 1. A drug product authorized or already authorized in the EEA, used as the basis for demonstrating that the data protection period defined in European drug product regulations has expired. This reference drug product is determined for the purpose of calculating the expiration of the data protection period and may differ from the generic / mixed drug product in strength, pharmaceutical form, route of administration, or presentation.

[0192] 2. A drug (product name, strength, drug form, MAH, marketing authorization number) that cross-references its file in a generic / mixed application. For the purpose of calculating the expiration of the data protection period, this reference drug product may have been authorized through a separate procedure and under a different name from the identified reference drug product. The product information of this reference drug product will, in principle, be used as the basis for the product information protected by the claims for the generic / mixed drug product.

[0193] 3. A drug product (product name, strength, drug form, MAH, source member state) used for bioequivalence studies (where applicable).

[0194] The different abbreviated approval pathways for drug products under the Federal Food, Drug, and Cosmetic (FD&C) Act of the United States are the abbreviated approval pathways described in Sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 355(b)(2), respectively).

[0195] According to the FDA (https: / / www.fda.gov / downloads / Drugs / GuidanceComplianceRegulatoryInformation / Guidances / UCM579751.pdf, the content of which is incorporated herein by reference), NDAs and ANDAs can be classified into the following four categories:

[0196] (1) A "stand-alone NDA" is an application submitted under section 505(b)(1) of the FD&C Act and approved under section 505(c), containing a complete report of the safety and effectiveness investigation conducted by or for the applicant or to which the applicant has the right of reference or use.

[0197] (2) A 505(b)(2) application is an NDA submitted under section 505(b)(1) of the FD&C Act and approved under section 505(c), containing a complete report of the safety and effectiveness investigation, where at least some of the information required for approval is from studies not conducted by or for the applicant and to which the applicant does not yet have the right of reference or use.

[0198] (3) An ANDA is an application for a copy of a previously approved drug product submitted and approved under section 505(j) of the FD&C Act. The ANDA relies on the 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 in terms of active ingredient, conditions of use, route of administration, dosage form, strength, and label (with certain permitted differences), and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are needed to establish the safety and effectiveness of the proposed product.

[0199] (4) A petitioning ANDA is a type of ANDA for a drug product that is different from the RLD in terms of its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient), and the FDA has ruled, in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act (adaptive request), that studies are not needed to establish the safety and effectiveness of the proposed drug product.

[0200] The scientific premise of the Hatch-Waxman Amendments is that a drug product approved in an ANDA under section 505(j) of the FD&C Act is assumed to be therapeutically equivalent to its RLD. When administered to patients under the conditions specified on the label, products classified as therapeutically equivalent may be substituted, and it is fully expected that the substituted product will produce the same clinical effect and safety profile as the prescribed product. Compared to an ANDA, a 505(b)(2) application allows for greater flexibility with respect to the characteristics of the proposed product. A 505(b)(2) application will not necessarily be rated as therapeutically equivalent to the listed drug product to which it refers at the time of approval.

[0201] The term "therapeutically equivalent to the reference listed drug" means that the drug product is a generic equivalent of the reference listed drug product, i.e., a drug equivalent, and is thus rated by the FDA as an AB therapeutic equivalent of the reference listed drug product, for which any actual or potential bioequivalence issues have been resolved with adequate in vivo and / or in vitro evidence supporting bioequivalence.

[0202] "Drug equivalent" means a drug product that contains the same amount of the same active drug ingredient as the reference listed drug, in the same dosage form and route of administration.

[0203] The FDA classifies those products that meet the following general criteria as therapeutically equivalent: (1) they are approved as safe and effective; (2) they are drug equivalents because they (a) contain the same amount of the same active drug ingredient in the same dosage form and route of administration, and (b) meet the pharmacopeial or other applicable standards of strength, quality, purity, and identity; (3) they are bioequivalent because (a) they do not have known or potential bioequivalence issues and they meet acceptable in vitro standards, or (b) if they do have such known or potential issues, they are shown to meet appropriate bioequivalence standards; (4) they are adequately labeled; and (5) they are manufactured in accordance with current good manufacturing practice regulations.

[0204] The term "bioequivalent" or "bioequivalence" means that there are no significant differences in the rate and extent to which the active ingredient or moiety in a pharmaceutical equivalent or pharmaceutical alternative becomes available at the site of action of the drug when administered in the same molar dose under similar conditions in a properly designed study. Section 505(j)(8)(B) of the FD&C Act describes a set of conditions under which a test and a reference listed drug shall be considered bioequivalent: when 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] drug when the therapeutic moiety of the same molar dose is administered as a single dose or multiple doses under similar experimental conditions; or when the extent of absorption of the [test] drug does not show a significant difference from the extent of absorption of the [reference] drug when the therapeutic moiety of the same molar dose is administered as a single dose or multiple doses under similar experimental conditions, and the difference in the rate of absorption of the [test] drug from the [reference] drug is intentional, is reflected in its proposed labeling, is not necessary to achieve an effective body drug concentration for chronic use, and is considered medically insignificant for the drug.

[0205] In situations where these methods are not applicable (e.g., for drug products not intended to be absorbed into the bloodstream), other scientifically valid in vivo or in vitro test methods for demonstrating bioequivalence may be appropriate.

[0206] For example, bioequivalence can sometimes be demonstrated using in vitro bioequivalence criteria, especially when such in vitro tests are correlated with human in vivo bioavailability data. In other cases, bioequivalence can sometimes be demonstrated by comparative clinical trials or pharmacodynamic studies.

[0207] This document also provides a pharmaceutical product comprising a clinically proven safe and clinically proven effective amount of apalutamide, wherein the pharmaceutical product is packaged and wherein the packaging includes a label that (a) identifies apalutamide as a regulatory-approved chemical entity, and (b) directs the use of apalutamide in the treatment of metastatic castration-sensitive prostate cancer. In certain embodiments, the label provides data on radiographic progression-free survival and / or overall survival relative to placebo. In certain embodiments, the label lists ischemic cardiovascular events, fractures, falls, and seizures as adverse reactions. In certain embodiments, the label includes data indicating an increase in ischemic cardiovascular events, fractures, falls, or seizures relative to the standard of care. In certain embodiments, the standard of care is the administration of androgen deprivation therapy.

[0208] As used herein, unless otherwise specified, the term "safe" means without undue adverse side effects (such as toxicity, irritation or allergic reactions), commensurate with a reasonable benefit-risk ratio when used in the manner of the present invention. Similarly, unless otherwise specified, the term "effective" means that when administered at a therapeutically effective dose, therapeutic efficacy has been demonstrated for the treatment of patients with metastatic castration-sensitive prostate cancer. 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 both safe and effective. In still other additional embodiments, a therapeutically effective amount of apalutamide is safe. In other additional embodiments, a therapeutically effective amount of apalutamide is effective. In other embodiments, a therapeutically effective amount of apalutamide is both safe and effective.

[0209] As used herein, unless otherwise specified, the term "clinically proven" (used independently or modifying the terms "safe" and / or "effective") means that the evidence has been demonstrated by Phase III or IV clinical trials, and the evidence is sufficient to meet the approval criteria of the US Food and Drug Administration or similar studies for marketing authorization by the EMEA. Preferably, studies of sufficient size, randomized, placebo-controlled, double-blind are used to clinically prove the effect of apalutamide. Most preferably, to clinically prove the effect of apalutamide in the treatment of metastatic castration-sensitive prostate cancer, this would be a randomized, placebo-controlled, double-blind study of apalutamide plus androgen deprivation therapy compared to androgen deprivation therapy, in which the condition of the patients is evaluated by radiographic progression-free survival or overall survival. For example, the evidence can be provided by the clinical trials described in Example 1.

[0210] As used herein, unless otherwise specified, the term "clinically proven effective" means that the efficacy of the treatment has been demonstrated to be statistically significant by Phase III or IV clinical trials, i.e., the results of the clinical trials are unlikely to be due to chance with an alpha level of less than 0.05, or the clinical efficacy results are sufficient to meet the approval criteria of the US Food and Drug Administration or similar studies for marketing authorization by the EMEA. For example, apalutamide has been clinically proven to be effective in prolonging radiographic progression-free survival and overall survival in the treatment of patients with metastatic castration-sensitive prostate cancer when orally administered at a therapeutically effective dose of 240 mg and in combination with androgen deprivation therapy, as compared to patients treated with placebo plus androgen deprivation therapy, and as specifically shown in the Examples.

[0211] As used herein, unless otherwise specified, the term "clinically proven safe" means that the safety of a treatment has been demonstrated in a Phase III or Phase IV clinical trial, i.e., it has been determined through analysis of the trial data and results that the treatment has no undue adverse side effects and is comparable to a statistically significant clinical benefit (e.g., efficacy) sufficient to meet the approval criteria of the US Food and Drug Administration or a similar study for market authorization by the European Medicines Agency (EMEA). For example, apalutamide has been clinically proven safe for the treatment of patients with metastatic castration-sensitive prostate cancer when orally administered at a therapeutically effective dose of 240 mg and in combination with androgen deprivation therapy, as specifically shown in the Examples.

[0212] Sales Methods

[0213] Provided herein are methods of selling an approved pharmaceutical product comprising apalutamide, the methods comprising, consisting essentially of, or consisting of the steps of: selling such a pharmaceutical product, wherein the drug product label of the reference listed drug of such a pharmaceutical product includes instructions for treating metastatic castration-sensitive prostate cancer. In certain embodiments, the pharmaceutical product is an ANDA pharmaceutical product, a supplemental new drug application pharmaceutical product, or a 505(b)(2) pharmaceutical product.

[0214] The term "sell" or "sale" means the transfer of a pharmaceutical product, such as a pharmaceutical composition or an oral dosage form, from a seller to a buyer.

[0215] Also provided herein are methods of offering for sale an approved pharmaceutical product comprising apalutamide, the methods comprising, consisting essentially of, or consisting of the steps of: offering for sale such a pharmaceutical product, wherein the drug product label of the reference listed drug of such a pharmaceutical product includes instructions for treating metastatic castration-sensitive prostate cancer. In certain embodiments, the pharmaceutical product is an ANDA pharmaceutical product, a supplemental new drug application pharmaceutical product, or a 505(b)(2) pharmaceutical product.

[0216] The term "offer for sale" means a proposal by a seller to sell a pharmaceutical product, such as a pharmaceutical composition and an oral dosage form, to a buyer.

[0217] In another aspect, described herein are methods of selling apalutamide, the methods comprising, consisting essentially of, or consisting of the steps of: placing apalutamide into the commercial stream, wherein the apalutamide includes a package insert that contains instructions for using apalutamide safely and effectively to treat metastatic castration-sensitive prostate cancer.

[0218] In other aspects, methods of offering to sell apalutamide are described herein, the methods comprising, consisting essentially of, or consisting of the steps of: offering to bring apalutamide into the commercial stream, wherein the apalutamide comprises a package insert that includes instructions for the safe and effective treatment of metastatic castration-sensitive prostate cancer with apalutamide.

[0219] Examples

[0220] The provided examples are for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0221] Example 1: A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study of Apalutamide Plus Androgen Deprivation Therapy (ADT) Versus ADT in Subjects With Metastatic Hormone-Sensitive Prostate Cancer (mCSPC) Objectives

[0222] Primary Objectives

[0223] Secondary Objectives

[0224] Determine whether adding apalutamide to androgen deprivation therapy (ADT) provides superior efficacy in prolonging radiographic progression-free survival (rPFS) or overall survival (OS) in subjects with mCSPC.

[0225] Other Objectives

[0226] · Evaluate clinically relevant improvements caused by adding apalutamide to ADT, including delay of pain progression and opioid use, skeletal-related events, and need for cytotoxic chemotherapy for prostate cancer;

[0227] · Characterize the safety of adding apalutamide to ADT in subjects with mCSPC;

[0228] · Characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of apalutamide;

[0229] · Evaluate the concentration of leuprolide when used alone or in combination with apalutamide and assess the PD effect of leuprolide on testosterone concentration;

[0230] · Evaluate the treatment effect of adding apalutamide to ADT in subsets of subjects with low-volume or high-volume mCSPC.

[0231] Study Design

[0232] · Evaluate the predictive role of exploratory biomarkers for treatment response and resistance;

[0233] · Evaluate patient-related outcomes, which include symptoms (i.e., pain, fatigue, urination) and function (i.e., physical, emotional, social function) as well as health-related quality of life;

[0234] · Evaluate improvements in other clinically relevant endpoints of apalutamide plus ADT compared to ADT alone;

[0235] · Collect medical resource utilization (MRU) data that can be used for future economic modeling.

[0236] Figure 1

[0237] The study described in Example 1 has been at least partially completed and is continuing according to the criteria described herein. This is a randomized, double-blind, placebo-controlled, multinational and multicenter Phase 3 study to determine whether subjects with mCSPC benefit from adding apalutamide to ADT. The data presented herein associated with this study reflect the status of the study at the time of filing of this application. The study was conducted at 260 sites in 23 countries. The review boards of all participating institutions approved the study, which was conducted in accordance with the current International Conference on Harmonization guidelines on Good Clinical Practice and in accordance with the principles of the Declaration of Helsinki. All patients gave written informed consent. The sponsor appointed an independent Data Monitoring Committee to monitor safety and efficacy before unblinding and to make recommendations for conducting the study. The staff at each site transcribed data from source documents into electronic case report forms prepared by the sponsor. The randomization code was kept blinded to the investigators, patients, study site personnel, and sponsor study team until the study was completed, the independent Data Monitoring Committee recommended otherwise, or the individual patient's medical needs.

[0238] The study is planned to enroll approximately 1,000 subjects. Subjects who meet all inclusion criteria and do not have exclusion criteria are stratified according to Gleason score at diagnosis (≤7 vs. >7), region (North America [NA] and European Union [EU] vs. other countries and regions), and prior use of docetaxel (yes or no).

[0239] In addition to continuing ADT, patients were randomly assigned 1:1 to receive oral administration of apalutamide (240 mg) once daily or a matching placebo. Patients were stratified by Gleason score at diagnosis (≤7 vs. >7), region (North America and the EU vs. all other countries and regions), and prior docetaxel treatment (yes vs. no). The screening phase, up to 28 days prior to randomization, established study eligibility. Subjects received treatment within 28-day cycles during the treatment phase until disease progression or unacceptable treatment-related toxicity occurred or the sponsor terminated the study. If a subject had radiographic progression without clinical progression and had not initiated alternative therapy, treatment could continue until clinical progression was observed; subjects with documented clinical progression based on protocol-specified criteria had to discontinue study medication. After discontinuing study medication, subjects had an end-of-treatment visit within 30 days after the last dose of study medication. During the follow-up phase, data collection (every 4 months) included the first subsequent therapy for prostate cancer and survival in subsequent therapies for prostate cancer, additional data on secondary endpoints, and the date and type of disease progression (radiographic, PSA, clinical, or a combination thereof). Data collection during follow-up continued until the subject died, withdrew consent, was lost to follow-up, or the sponsor terminated the study. Brief Pain Inventory Short Form (BPI SF), Brief Fatigue Inventory (BFI), and EQ-5D-5L patient-reported outcome (PRO) measures were also continued during the follow-up phase for up to 12 months after treatment discontinuation. In the event of positive study results at any time during the interim analysis or at the final analysis, all subjects in the treatment phase would have the opportunity to enroll in an open-label extension trial phase, which would allow subjects to receive active drug (apalutamide) for approximately 3 years.

[0240] Subject safety was monitored from the signing of the informed consent form until 30 days after the last dose of study medication. Adverse events (AEs, including laboratory AEs) were graded and summarized using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE; version 4.03). Dose modifications were made according to the dose modification rules outlined in the protocol.

[0241] Study Population A diagram of the study design is provided in

[0242] Overview of Patient Eligibility

[0243] Each potential subject met all of the following criteria for enrollment in the study.

[0244] Inclusion Criteria

[0245] In cases with or without visceral or lymph node involvement, eligible patients need to have documented prostate cancer and distant metastatic disease documented by ≥1 lesion on a bone scan. All patients have an "Eastern Cooperative Oncology Group Performance Status (on a 5-point scale, where higher numbers reflect more severe morbidity)" of 0 or 1. Patients are castration-sensitive (i.e., the patient has not received ADT at the time of progression). Prior treatment for prostate cancer is limited to prior docetaxel treatment (up to six cycles, with no evidence of progression during treatment or prior to randomization), ADT for metastatic castration-sensitive prostate cancer ≤6 months or for localized prostate cancer with a total duration ≤3 years, one course of radiation or surgical therapy for symptoms associated with metastatic disease, and other localized treatments (e.g., radiation therapy, prostatectomy) completed ≥1 year prior to randomization. Patients who have received gonadotropin-releasing hormone agonists ≤28 days prior to randomization need to have taken a first-generation antiandrogen (i.e., bicalutamide, flutamide, or nilutamide) ≥14 days prior to randomization. The antiandrogen must be discontinued prior to randomization. Patients with severe angina, myocardial infarction, congestive heart failure, arterial / venous thromboembolic events, a history of epilepsy or precipitating factors, or recent ventricular arrhythmias are excluded.

[0246] Exclusion Criteria

[0247] · Subjects must be male ≥18 years of age (or the legal age in the jurisdiction where the study is conducted);

[0248] · Diagnosed with prostate cancer confirmed by the investigator;

[0249] · Distant metastatic disease documented by ≥1 bone lesion on a technetium-99m (99mTc) bone scan, with or without visceral or lymph node involvement. Subjects with a single bone lesion must have bone metastases confirmed by computed tomography (CT) or magnetic resonance imaging (MRI);

[0250] · All patients have a grade 0 or 1 "Eastern Cooperative Oncology Group (ECOG) PS";

[0251] · Androgen deprivation therapy (i.e., medical or surgical castration) must be started ≥14 days prior to randomization. Subjects who start a GnRH agonist ≤28 days prior to randomization need to have taken a first-generation antiandrogen ≥14 days prior to randomization. The antiandrogen must be discontinued prior to randomization;

[0252] · Subjects are castration-sensitive, and subjects receiving docetaxel treatment must meet the following criteria:

[0253] a. Receive up to 6 cycles of docetaxel therapy for mCSPC;

[0254] b. Received the last dose of docetaxel ≤2 months prior to randomization;

[0255] c. Maintained a response to docetaxel of stable disease or better, as evaluated by the investigator for imaging and PSA, prior to randomization;

[0256] · Able to swallow the entire study drug tablet;

[0257] · To avoid the risk of exposure to the drug through ejaculation (even in men who have had a vasectomy), subjects must use a condom during sexual activity while taking the study drug and for 3 months after the last dose of the study drug. Donation of sperm is not permitted while taking the study drug and for 3 months after the last dose of the study drug;

[0258] · Each subject must sign an informed consent form (ICF) indicating that he understands the purpose and procedures of the study and is willing to participate. The subject must be willing and able to comply with the prohibitions and restrictions specified in this protocol.

[0259] · Other permitted prior treatments for mCSPC:

[0260] a. Up to 1 course of radiotherapy or surgical intervention for metastatic disease, and other locoregional treatments completed >1 year prior to randomization; radiotherapy for metastatic lesions must be completed prior to randomization;

[0261] b. ADT for mCSPC ≤6 months or for locoregional prostate ≤3 years total duration prior to randomization;

[0262] · Permitted prior treatments for locoregional prostate cancer (all treatments must be completed ≥1 year prior to randomization)

[0263] a. ADT for a total of ≤3 years;

[0264] b. All other forms of prior therapy, including radiotherapy, prostatectomy, lymph node dissection, and systemic therapy.

[0265] Treatment Allocation

[0266] Any potential subject who meets any of the following criteria is excluded from participating in this study.

[0267] · Pathological confirmation consistent with small cell carcinoma, ductal carcinoma, or neuroendocrine carcinoma of the prostate;

[0268] · Known brain metastases;

[0269] · Lymph nodes as the sole site of metastasis;

[0270] · Visceral (i.e., liver or lung) metastasis as the sole site of metastasis;

[0271] · Other prior malignancies ≤ 5 years before randomization (except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other carcinoma in situ currently in complete remission);

[0272] · Clinical laboratory values during the screening phase:

[0273] a. Hemoglobin < 9.0 g / dL;

[0274] b. Neutrophils < 1.5 × 109 / L;

[0275] c. Platelets < 100 × 109 / L;

[0276] d. Total bilirubin > 1.5 × upper limit of normal (ULN) [Note: In subjects with Gilbert syndrome, if total bilirubin > 1.5 × ULN, measure direct and indirect bilirubin, and if direct bilirubin ≤ 1.5 × ULN, the subject may be eligible];

[0277] e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × ULN;

[0278] f. Serum creatinine > 2.0 × ULN;

[0279] g. Serum albumin < 3.0 g / dL.

[0280] · Prior treatment with other next-generation anti-androgens (e.g., enzalutamide), CYP17 inhibitors (e.g., abiraterone acetate), immunotherapy (e.g., sipuleucel-T), radiopharmaceutical agents, or other treatments for prostate cancer (other than those listed in the inclusion criteria);

[0281] · Initiation of treatment with bisphosphonates or denosumab ≤ 28 days before randomization to manage bone metastases;

[0282] · Drugs known to lower the seizure threshold must be discontinued or replaced ≥ 28 days before randomization;

[0283] · Administration of other study agents, blood product support, growth factor support, or invasive surgery (excluding surgical castration) ≤ 28 days before randomization or currently enrolled in an investigational study;

[0284] · Currently or previously treated for epilepsy with anti-epileptic drugs. A history of epilepsy or conditions that can induce epilepsy (including but not limited to previous cerebrovascular events, transient ischemic attacks, or loss of consciousness within 1 year prior to randomization; cerebral arteriovenous malformations; or intracranial masses such as schwannomas or meningiomas that cause edema or mass effect);

[0285] · Current evidence of any of the following diseases:

[0286] a. Severe / unstable angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant arterial or venous thromboembolic events (such as pulmonary embolism), or clinically significant ventricular arrhythmias ≤6 months prior to randomization;

[0287] b. Gastrointestinal diseases that affect absorption;

[0288] c. Active infections that require systemic therapy, such as human immunodeficiency virus (HIV);

[0289] d. Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to liver function defects;

[0290] · Known allergy, hypersensitivity, or intolerance of the subject to apalutamide or its excipients.

[0291] · Any condition or situation that the researchers believe will prevent the subject from participating in this study.

[0292] Procedures for Stratification and Randomization

[0293] Dose and Administration

[0294] Subjects are stratified according to Gleason score at diagnosis (≤7 vs. >7), region (North America [NA] and European Union [EU] vs. other countries and regions), and previous use of docetaxel (yes or no). Subjects are randomly assigned to the active group or the control group at a ratio of 1:1. Randomization is balanced by using randomly varying blocks. The Interactive Web Response System (IWRS) assigns unique treatment codes that specify the treatment assignment for the subject and match the study drug kits. When contacting the IWRS, the requester uses his own user identification and personal identification number, and then provides relevant subject details to uniquely identify the subject.

[0295] Apalutamide Administration

[0296] ADT Administration

[0297] Apalutamide was administered continuously, but for the purposes of scheduling study assessments and treatment compliance, the treatment cycle was defined as 28 days. Subjects were randomly assigned in a 1:1 ratio to receive apalutamide or matching placebo:

[0298] · Apalutamide 240 mg (4 × 60-mg tablets); orally administered once daily with or without food, or

[0299] · Placebo (4 tablets); orally administered once daily with or without food.

[0300] If a dose of apalutamide (or placebo) was missed, the dose was omitted and not made up, and it was not taken with the next dose the following day.

[0301] Toxicity and Rash Management

[0302] All subjects who did not undergo surgical castration received and maintained a stable regimen of ADT. The choice of GnRHa (agonist or antagonist) was at the discretion of the investigator. The dosing (dose and frequency of administration) was in accordance with the prescribing information.

[0303] Table 1: Dose Modifications of Apalutamide / Placebo

[0304] Table 1 summarizes the apalutamide / placebo dose modifications for drug-related toxicities. Dose modifications were also available for drug-related rashes. Once the dose was reduced due to drug-related toxicity, the re-escalation of the dose was discussed with the sponsor.

[0305] Pre-Study and Concomitant Therapies

[0306]

[0307] If the rash had any signs of desquamation, mucosal involvement, or pustules, the administration of apalutamide / placebo was stopped, the subject was referred to dermatology for evaluation, and a skin biopsy was recommended (in addition to dose modification). If the rash was grade 3 or higher, the subject may be asked to consent to photographic documentation and further evaluation by a dermatologist.

[0308] Permitted Supportive Care Therapies

[0309] Prohibited Concomitant Therapies

[0310] The use of supportive care medications was permitted in accordance with institutional guidelines. The following supportive care therapies were considered permissible during the study:

[0311] · Intermittent short-course opioid analgesics were permitted to control pain;

[0312] · Surgical interventions and procedures such as transurethral resection of the prostate (TURP) and ureteral stent placement for managing complications due to local progression;

[0313] · Bisphosphonates and denosumab for managing bone-related metastases should be used according to the labels approved in their marketing authorizations. Subjects should have been taking a stable dose of such agents for ≥28 days prior to randomization or agree not to initiate such therapy until radiographic progression is documented. Prophylactic osteoporosis doses of bisphosphonates and denosumab are permitted;

[0314] · Conventional multivitamins, selenium, and soy supplements;

[0315] · Transfusions and hematopoietic growth factors in accordance with institutional practice guidelines (note that blood product support and growth factor support are not permitted within a period of ≤28 days prior to randomization);

[0316] · Immunoglobulin therapy for non-cancer-related treatments in accordance with institutional practice guidelines.

[0317] Restricted Concomitant Medications

[0318] As a class effect, AR antagonists are associated with seizures due to off-target mechanisms of action (γ-aminobutyric acid chloride channel [GABAA] inhibition). The use of drugs known to lower the seizure threshold or cause seizures is prohibited, including the following representative list:

[0319] · Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone);

[0320] · Bupropion;

[0321] · Lithium;

[0322] · Meperidine / pethidine;

[0323] · Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine);

[0324] · Tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine);

[0325] · Aminophylline / theophylline;

[0326] Other prohibited therapies include the following:

[0327] · Investigational drugs;

[0328] · Abiraterone acetate or other CYP17 inhibitors;

[0329] · Other hormonal agents for the treatment of prostate cancer;

[0330] · Other anti-tumor agents;

[0331] · Radiation therapy for new painful metastatic prostate cancer lesions not present on baseline imaging;

[0332] · 5-α-reductase inhibitors;

[0333] · Chemotherapy;

[0334] · Immunotherapy or vaccine therapy for cancer treatment;

[0335] · Other anti-androgens (e.g., bicalutamide, nilutamide, flutamide, cyproterone acetate, enzalutamide);

[0336] · Bisphosphonates or denosumab for managing bone metastases, unless such therapy was started >28 days before randomization and the subject has been on a stable dose. Bisphosphonates or denosumab at prophylactic osteoporosis doses are permitted;

[0337] · Systemic ketoconazole (or other azole drugs such as fluconazole or itraconazole);

[0338] · Diethylstilbestrol (DES) or analogs;

[0339] · Other preparations thought to have an endocrine effect on prostate cancer, such as pomegranate or pomegranate juice or Sabal serrulata;

[0340] · Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) or analogs such as radium-223 (223Ra);

[0341] · Spironolactone.

[0342] Efficacy Evaluation / Endpoints

[0343] Drug interactions are highlighted and summarized below.

[0344] · Strong CYP3A4 inducers: The potential for drug-drug interactions with apalutamide has not been clinically tested. Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort) should be avoided if possible;

[0345] · Apalutamide may also involve CYP3A4; therefore, caution should be exercised when co-administered with CYP3A4 substrates with a narrow therapeutic index;

[0346] · Strong CYP2C8 inhibitors (e.g., gemfibrozil) should be used with caution with apalutamide;

[0347] · Long-term use of systemically administered corticosteroids is not allowed during the study. Short-term use (≤4 weeks, including tapering) and locally administered steroids (e.g., inhaled, topical, ophthalmic, and intra-articular) are allowed if clinically indicated.

[0348] Evaluations

[0349] Soft tissue lesions by computed tomography (CT) / magnetic resonance imaging (MRI) are evaluated for radiographic progression according to the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1), or radiographic progression is evaluated by progression of bone lesions on bone scan. Survival data are collected during the entire treatment phase and follow-up phase.

[0350] Patient-Reported Outcomes

[0351] During the screening period (≤6 weeks before randomization), chest, abdomen, and pelvis computed tomography or magnetic resonance imaging is used according to the modified Response Evaluation Criteria in Solid Tumors version 1.1, and bone scan is used according to Prostate Cancer Working Group 2 criteria to evaluate the efficacy of the patient during cycle 3, cycle 5, and every fourth cycle thereafter. Progression events are evaluated by the researchers. Scans from approximately 60% of the patients are randomly selected for independent central review. Adverse events are evaluated monthly and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3. FACT-P assessments are collected on day 1 of cycles 2-7, then every other cycle, at the end of treatment, and every 4 months for up to 1 year after discontinuation. BPI-SF assessments are collected 6 days before cycle 1, then at each cycle, at the end of treatment, and every 4 months for up to 1 year after discontinuation.

[0352] More specifically, the efficacy evaluation includes the following:

[0353] · Tumor measurement results (CT or MRI [abdomen, chest, and pelvis], 99mTc bone scan). The same imaging modality should be used for tumor assessment throughout the evaluation of an individual subject. If signs or symptoms suggesting disease progression are recorded (including pain escalation not attributable to another cause, deterioration of ECOG PS status grade, or physical examination findings consistent with disease progression), then unscheduled tumor assessments and appropriate imaging should be considered;

[0354] · Scans from approximately 60% of the patients are randomly selected for independent central review;

[0355] · Serum PSA evaluation (performed at the central laboratory);

[0356] · Skeletal-related events (SREs) are defined as the occurrence of symptomatic pathologic fracture, spinal cord compression, bone radiation, or bone surgery;

[0357] · Pain progression was defined as: in the BPI-SF questionnaire, an increase of 2 points from baseline in the worst pain intensity (item 3) observed at two consecutive assessments ≥4 weeks apart; and an average worst pain score >4 in subjects who had not had a reduction in opioids or an average worst pain score >4 in subjects who had not been on opioids long-term, whichever occurred first.

[0358] Tumor Response Criteria

[0359] Patient-reported outcomes included administration of various questionnaires, including the Brief Pain Inventory - Short Form (BPI-SF), Analgesic Use Log, Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy - Prostate (FACT-P), and EQ-5D-5L (a standardized measure of health status developed by the EuroQoL Group to provide a simple generic health measure for clinical and economic evaluation (EuroQoL Group, 1990)). Patient-reported outcome questionnaires were collected throughout the study and during the follow-up phase (up to 12 months after treatment discontinuation) and the open-label extension trial phase.

[0360] Endpoints

[0361] Tumor response was evaluated using imaging measurements, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In this study, RECIST was modified based on the Prostate Cancer Working Group 2 (PCWG2) criteria specific to this patient population. Prostate-specific antigen measurements were evaluated according to the PCWG2 criteria. The assessment of rPFS was evaluated by the researchers.

[0362] Efficacy in the patients in the conducted study was evaluated according to the modified Response Evaluation Criteria in Solid Tumors version 1.1 and the Prostate Cancer Working Group 2 criteria. The Prostate Cancer Working Group 2 criteria for progression were as follows:

[0363] · PSA: First, an increase ≥25% from baseline and ≥2 ng / mL above the nadir (confirmed by a second value after 3 or more weeks)

[0364] · Soft tissue lesions: Follow the Response Evaluation Criteria in Solid Tumors, described as follows:

[0365] ο Imaging should include at a minimum computed tomography scan or magnetic resonance imaging; centers with relevant expertise should utilize endorectal magnetic resonance imaging or transrectal ultrasound

[0366] ο Only report changes in lymph nodes with a diameter ≥2 cm at baseline

[0367] ο Record changes in nodal and visceral soft tissue sites separately

[0368] ο Record the complete elimination of the disease at any site separately

[0369] ο Confirm favorable changes by a second scan

[0370] ο Record changes using a waterfall plot

[0371] ο The progress at the first assessment must be confirmed by a second scan after ≥6 weeks

[0372] · Bone: ≥2 new lesions appear, and for the first re - evaluation only, a confirmation scan is performed after ≥6 weeks, indicating at least ≥2 new lesions

[0373] Dual Primary Endpoints

[0374] Secondary Endpoints

[0375] The dual primary endpoints are radiographic progression - free survival (rPFS) and overall survival (OS).

[0376] Exploratory Endpoints

[0377] The secondary endpoints are time to cytotoxic chemotherapy, time to pain progression (measured by the Brief Pain Inventory - Short Form (BPI - SF); worst pain [item 3] is used for the time - to - pain - progression endpoint; the score range is 0 to 10, and the lower the score, the lower the pain intensity level; a change of 2 is the least important difference), time to long - term opioid use, and time to skeletal - related events. A pre - specified subgroup analysis is planned based on data from patients with low - volume or high - volume metastatic castration - sensitive prostate cancer, and the evaluation of treatment outcomes in these groups is a secondary objective. The definition of high - volume disease is adjusted as follows according to Sweeney CJ, Chen YH, Carducci M, et al., "Chemohormonal therapy in metastatic hormone - sensitive prostate cancer", N Engl J Med, 2015, vol. 373, pp. 737 - 746: 1) visceral metastases and ≥1 bone lesion, or 2) ≥4 bone lesions, with ≥1 lesion outside the axial skeleton. Low - volume disease is defined as the presence of bone lesions that do not meet the definition of high - volume disease

[0378] Population Pharmacokinetic Evaluation

[0379] Exploratory endpoints included time to prostate-specific antigen (PSA) progression, second progression-free survival, and time to symptomatic local progression. Second progression-free survival was defined as the time from randomization to the first occurrence of disease progression (PSA progression, progression on imaging, or clinical progression) determined by the investigator or death from any cause (whichever occurred first) when the patient was receiving the first subsequent therapy for prostate cancer. Outcomes of patient-reported health-related quality of life were assessed by the Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire. The original FACT-P score ranged from 0 to 156, with higher scores indicating more favorable health-related quality of life. A change of 6 to 10 points in the total FACT-P score was the least important difference.

[0380] Leuprolide PK Sub-Study

[0381] Collect crude PK samples. Predose blood samples for the analysis of the concentrations of apalutamide and the active metabolite (JNJ-56142060) were collected on Day 1 of Cycle 2, Cycle 3, Cycle 4, Cycle 5, and Cycle 6.

[0382] Biomarker Evaluation

[0383] Optional PK samples were collected from at least 60 consenting subjects (in the selected countries) who received leuprolide acetate as a GnRH agonist at randomization. Samples for the analysis of leuprolide and testosterone concentrations were collected on Day 1 of Cycle 1, Cycle 3, Cycle 4, Cycle 5, and Cycle 6.

[0384] Safety Evaluation

[0385] Plasma-based circulating DNA was used to assess the presence of the androgen receptor (AR) F876L mutation, and whole blood or plasma DNA was used to assess other markers that may be associated with apalutamide resistance. Archived formalin-fixed paraffin-embedded (FFPE) tumor blocks or tumor slides were collected to evaluate the mRNA expression of genes representing AR signaling to compare the biology of high-volume and low-volume disease with the outcomes, and to evaluate the expression of immunomarkers such as OX40, GITR, and FOXP3.

[0386] Electrocardiogram (ECG)

[0387] Safety assessments include AEs, vital signs measurements (blood pressure), physical examinations, ECOG PS, and clinical laboratory tests (including but not limited to hematology panel, serum chemistry panel, liver function tests, and fasting lipid panel). In the case of additional safety monitoring, unscheduled laboratory assessments are performed as needed. Vital signs and ECOG performance status are evaluated at screening and at each scheduled visit during treatment. Safety is evaluated continuously, and adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3. FACT-P assessments are collected on Day 1 of Cycles 1 through 7, then every other cycle, at the end of treatment, and every 4 months for up to 1 year after discontinuation.

[0388] Vital Signs

[0389] An electrocardiogram (ECG) (12-lead) is recorded at screening.

[0390] Physical Examinations

[0391] Temperature, heart rate, respiratory rate, and blood pressure are recorded at screening. At all other visits, only blood pressure will be measured.

[0392] Eastern Cooperative Oncology Group (ECOG) PS

[0393] The screening physical examination includes at least the general appearance, height, weight, skin examination, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system of the subject. During the treatment phase and at the EOT visit, a limited symptom-directed physical examination and weight assessment are required.

[0394] Subject Completion / Withdrawal

[0395] At the time of scheduling, an ECOG PS assessment, such as a PRO questionnaire, is obtained before any other study procedures on the planned same day.

[0396] Completion

[0397] Discontinuation of Apalutamide

[0398] If a subject dies before the end of the study, or has not been lost to follow-up or withdrawn consent before the end of the study, he is considered to have completed the study.

[0399] Statistical Methods

[0400] If the study drug of a subject must be discontinued before disease progression, it will not result in the subject automatically withdrawing from this study. If a subject has radiographic progression without clinical progression and has not initiated alternative therapy, treatment can continue until clinical progression is observed. All attempts should be made to capture radiographic progression even in subjects with evidence of clinical progression.

[0401] However, the study treatment of a subject must be discontinued for the following reasons:

[0402] · Clinical progression defined as follows:

[0403] · ECOG PS grade deteriorates to grade 3 or higher (related to prostate cancer progression)

[0404] · Due to tumor progression (even in the absence of radiographic evidence of disease), the need to initiate any of the following therapies:

[0405] · Subsequent anti-cancer therapy for metastatic prostate cancer

[0406] · Radiotherapy for metastatic prostate cancer lesions (palliative radiotherapy for lesions present at baseline is not considered clinical progression)

[0407] · Surgical intervention for complications resulting from metastatic prostate cancer progression.

[0408] · Requirement for long-term opioid analgesics: For subjects entering the study without receiving opioids, long-term use of opioids is defined as oral administration of opioid analgesics for ≥ 3 weeks or administration of non-oral formulations for ≥ 7 days. For subjects entering the study who have already received opioids, long-term use of opioids is defined as a ≥ 30% increase in the total daily dose of opioid analgesics, oral administration for ≥ 3 weeks or non-oral formulations for ≥ 7 days.

[0409] · More than 2 dose level reductions due to grade 3 or higher treatment-related AEs (Table 1)

[0410] · Seizures of any grade or grade 4 neurotoxicity

[0411] · The treatment assignment of a subject is unblinded for any reason other than the IDMC's recommendation to unblind the study

[0412] · The investigator believes that discontinuing the study treatment for safety reasons (e.g., AE) is in the best interest of the subject

[0413] All attempts should be made to obtain imaging studies at the time of treatment discontinuation or the EOT visit to assess radiographic progression. For subjects with an increasing PSA value in the absence of radiographic or clinical progression, the study drug is continued. Although serial PSA measurements were performed in this study, progression or change in PSA value is not used as the sole indicator of disease progression or treatment discontinuation. If a subject discontinues the study drug but does not revoke consent for follow-up, scheduled assessments should continue according to the follow-up phase in the time and event schedule.

[0414] Overview

[0415] Analysis Population

[0416] The clinical trial exemplified herein was designed to enroll approximately 1,000 patients. Radiographic progression-free survival was tested first. If it was statistically significant, its α was recycled to overall survival based on a fallback method. A Type I error of 5% overall was planned. 368 imaging progression-free survival events were needed to provide at least 85% power to detect a hazard ratio of 0.67, with a two-tailed significance level of 0.005. For the final overall survival analysis, 410 deaths were needed to provide approximately 80% power to detect a hazard ratio of 0.75, with a two-tailed significance level of 0.045. The overall survival analysis incorporated a group sequential design with an α spending function, which was calculated as the Wang-Tsiatis power boundary with a shape parameter of 0.2. Two interim analyses for overall survival were planned. It was estimated that the first interim analysis would include approximately 50% of the total events required for overall survival at the time of the initial analysis of radiographic progression-free survival. Assuming an overall two-tailed significance level of 0.045, the α level for the interim analysis for overall survival was 0.009. Subgroup analyses were pre-specified to assess the consistency of treatment effects. If the dual primary endpoints were statistically significant, secondary endpoints were evaluated in the following hierarchical order, each with an overall two-sided significance level of α = 0.05: 1) time to cytotoxic chemotherapy, 2) time to pain progression, 3) time to long-term opioid use, 4) time to skeletal-related events. Descriptive statistics were used to summarize demographic and baseline characteristics. The primary statistical method for comparing time-to-event endpoints was a stratified log-rank test according to stratification factors. The Kaplan-Meier product-limit method and the Cox proportional hazards model were used to estimate time-to-event variables and determine hazard ratios and associated confidence intervals.

[0417] Sample Size Determination

[0418] The main analysis population is the intention-to-treat (ITT) population, which includes all randomized subjects. The ITT population is used to analyze subject demographics and efficacy. The safety population includes all subjects who received at least 1 dose of the study drug.

[0419] Efficacy Analysis

[0420] The overall type I error for the study was planned at 5%. The study utilized co-primary endpoints of rPFS and OS, where the significance level assigned to the rPFS endpoint was 0.005 and the significance level assigned to the OS was 0.045. The study was considered successful if at least one of the co-primary endpoints was statistically significant.

[0421] If radiographic progression-free survival was statistically significant, the α-level for radiographic progression-free survival was recycled to overall survival using a fallback method. It was estimated that approximately 50% (205 events) of the total events required for the overall survival analysis would be observed in the initial analysis of radiographic progression-free survival. Assuming an overall two-sided significance level of 0.045, the α-level for the interim analysis of overall survival was 0.009. Additional subgroup analyses of patients with low-volume or high-volume disease were permitted in the overall survival analysis without α-consumption. If the co-primary endpoints of overall survival and radiographic progression-free survival were statistically significant, the secondary endpoints were evaluated in the following hierarchical order, each 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 long-term opioid use, 4) time to skeletal-related events. Descriptive statistics were used to summarize demographic and baseline characteristics. The Kaplan-Meier product-limit method and the Cox proportional hazards model were used to estimate time to event variables and to determine hazard ratios and associated confidence intervals. For the radiographic progression-free analysis, patients without evidence of radiographic progression or death or those who withdrew from the study or received a new subsequent anticancer therapy with unrecorded disease progression were censored at the date of the last tumor assessment, and patients without post-baseline tumor assessments were censored at the date of randomization.

[0422] It is estimated that at a two-sided significance level of 0.005, approximately 368 rPFS events are required to provide at least 85% power to detect a hazard ratio (HR) of 0.67 (median rPFS of 20 months in the control group [ADT] vs. 30 months in the treatment group of apalutamide plus ADT). The study will also provide sufficient power (approximately 80%) to detect an HR of 0.75 for the co-primary endpoint of OS based on a hypothesized median OS of 44 months in the control group (ADT). Approximately 410 death events are required to detect the hypothesized HR at a two-sided significance level of 0.045, with a registration duration of approximately 30 months (approximately 1,000 subjects). The total study duration is approximately 54 months to obtain 410 deaths.

[0423] Interim Analysis

[0424] The Kaplan-Meier product-limit method and the Cox proportional hazards model were used to estimate time to event variables and obtain the HR along with the associated confidence intervals.

[0425] Population PK and PD Analysis

[0426] For the co-primary OS endpoint, two interim analyses are planned for the study after approximately 60% (about 246 events) and approximately 75% (about 308 events) of the total number of required (410) events have been observed. The time of the first interim analysis for OS may coincide with the primary analysis of rPFS. However, if the number of death events required for the OS efficacy interim analysis necessitates a delay in the rPFS endpoint analysis, this analysis may be conducted at a different time. No interim analysis is planned for the rPFS endpoint.

[0427] Leuprolide PK Analysis

[0428] Population PK analysis of apalutamide plasma concentration-time data will be performed using a nonlinear mixed-effects model. If sufficient data are available, the relationships between exposure to apalutamide and the active metabolite (JNJ-56142060) and efficacy measures and AEs may also be analyzed.

[0429] Biomarker Analysis

[0430] Descriptive statistics for leuprolide PK data will be summarized by treatment group (apalutamide or placebo) and dose of leuprolide acetate. When leuprolide is administered alone or in combination with apalutamide, statistical analysis will be performed to compare leuprolide concentrations. The percentage of subjects with testosterone levels < 50 ng / dL will be descriptively summarized by treatment group.

[0431] Safety Analysis

[0432] Appropriate statistical methods (such as analysis of variance [ANOVA], classification, or survival models) can be used according to the endpoint to evaluate the association of biomarkers with clinical response or time to event endpoints.

[0433] Results

[0434] The safety parameters to be evaluated are the incidence and intensity of treatment-emergent AEs, clinically significant changes detected on physical examination of the subjects, vital sign measurements, and clinical laboratory results. The reasons for exposure to the study drug and discontinuation of study treatment will be tabulated.

[0435] Overview

[0436] Patients

[0437] Five hundred and twenty-five (525) patients were randomly assigned to the apalutamide plus ADT group, and 527 patients were randomly assigned to the placebo plus ADT group. The median age was 68 years; 8% had prior treatment for local disease; 11% had prior docetaxel; 63% had high-volume disease, and 37% had low-volume disease. At the first interim analysis, at a median follow-up of 22.7 months, apalutamide significantly prolonged radiographic progression-free survival (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.39 to 0.60; P < 0.0001), reducing the risk of radiographic progression or death by 52%. 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 rate of grade 3 / 4 adverse events did not differ between the apalutamide group and the placebo group. The independent data monitoring committee recommended unblinding to allow patients receiving placebo to cross over to receive apalutamide. Adding apalutamide to ADT significantly prolonged overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer and had a side effect profile that did not differ from that of the placebo plus ADT group.

[0438] Figure 1

[0439] Five hundred and twenty-five (525) patients were randomly assigned to the apalutamide group, and 527 patients were randomly assigned to the placebo group ( Figure 1)。At the cutoff of the first pre-specified 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 received was 23 for the apalutamide group and 19 for the placebo group (range 1 to 37 in each group). The median treatment duration was 20.5 months for the apalutamide group and 18.3 months for the placebo group. 66% of patients in the apalutamide group and 46% of patients in the placebo group remained on treatment at the clinical cutoff. A total of 45 patients across the two groups withdrew consent for study treatment. The survival and secondary endpoints were followed for these patients so that their data were not missing. A total of 39 patients either lost follow-up or withdrew from further data collection; the information was not otherwise captured in Table 2: Demographic and Baseline Disease Characteristics this.

[0440] Demographics and baseline disease characteristics were well balanced (Table 2). Patients developed de novo metastatic castration-sensitive prostate cancer or recurrent metastatic disease after initial diagnosis of local disease; most patients had de novo metastatic disease. Prior therapies for prostate cancer are listed in Table 3.

[0441] Table 3: Prior Prostate Cancer Therapies

[0442]

[0443]

[0444]

[0445] ECOG PS, Eastern Cooperative Oncology Group performance status; FACT-P, Functional Assessment of Cancer Therapy - Prostate;

[0446] PSA, prostate-specific antigen.

[0447] *Twenty-seven patients (46.6%) in the apalutamide group and 22 patients (40.0%) in the placebo group were N1 at diagnosis.

[0448] Scores range from 0 to 10, where lower scores indicate lower levels of pain intensity; a change of 2 is the least important difference. 1

[0449] Scores range from 0 to 156, where higher scores indicate more favorable health-related quality of life. A change of 6 to 10 points in the total FACT-P score is the least important difference.

[0450] Prior therapies for prostate cancer are listed in Table 3.

[0451] Dual Primary Endpoints

[0452]

[0453] Radiographic Progression-Free Survival and Overall Survival

[0454] Figure 2A

[0455] Three hundred and sixty-five radiographic progression events were observed (134 in the apalutamide group and 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 prolonged 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 ( Figure 2B ). In this final analysis of radiographic progression-free survival, the median was not reached in the apalutamide group and was 22.1 months in the placebo group. The effect of apalutamide on radiographic progression-free survival was consistently favorable in the subgroups analyzed ( Figure 3A ), including in prior docetaxel use and disease volume. Independent central review further confirmed the investigators' assessment of radiographic progression (concordance rate, 85%).

[0456] Treatment with apalutamide significantly prolonged overall survival (the 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 to 0.89; P = 0.0053), with a 33% reduction in the risk of death ( Figure 3B ). The treatment effect of apalutamide on overall survival was consistently superior to placebo, and the effect of apalutamide did not differ based on disease volume ( Secondary Endpoints ).

[0457] Figure 4

[0458] The time to cytotoxic chemotherapy was significantly prolonged with apalutamide compared with placebo (Table 4, Table 4. Pre-Specified Secondary and Exploratory Efficacy Endpoints ). The time to pain progression was tested based on a preplanned hierarchical testing sequence, and because it did not reach statistical significance, no formal testing was done for additional secondary endpoints.

[0459] Other Clinically Relevant Endpoints .

[0460]

[0461]

[0462] NE, not estimable.

[0463] *The worst pain using the BPI-SF (Item 3) was reported by the patient for pain progression. The score ranged from 0 to 10, where a lower score indicated a lower level of pain intensity; a change of 2 was the least important difference.

[0464] The secondary endpoints were tested in a pre-planned hierarchical sequence. When it was determined that apalutamide did not significantly prolong the time to pain progression, the additional secondary endpoints were not formally tested.

[0465] Skeletal-related events were defined as the occurrence of symptomatic pathologic fracture, spinal cord compression, bone radiation, or bone surgery.

[0466] Figure 5

[0467] The median time to PSA progression was more favorable in the apalutamide group compared to the placebo group ( Figure 6 , Table 4), and PSA reached undetectable levels (PSA < 0.2 ng / mL) in 68% and 29% of the patients in the apalutamide and placebo groups, respectively. Eighty-seven patients in the apalutamide group and 190 patients in the placebo group received subsequent treatment for prostate cancer (the first therapy described in Table 5). The median second progression-free survival was prolonged in the apalutamide group compared to the placebo group (Table 4; Figure 7 ). There were few events between the groups, and there was no difference in the time to symptomatic local progression (Table 4). Analysis of the change from baseline in FACT-P using a mixed-effects repeated measures model showed that health-related quality of life was maintained and there was no difference between the groups ( Table 5: First Subsequent Systemic Prostate Cancer Therapy ).

[0468] Safety

[0469]

[0470]

[0471] *Possible reasons for discontinuation were disease progression, adverse events, patient withdrawal, death, physician decision, and protocol violation.

[0472] Included docetaxel, abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T.

[0473] Some patients were unblinded after discontinuation and before the first subsequent therapy to allow enrollment in subsequent clinical trials.

[0474] § It includes diethylstilbestrol, flutamide, and cyproterone acetate.

[0475] ** It includes etoposide, paclitaxel, estramustine, carboplatin, and cisplatin.

[0476] *** It includes zoledronic acid, clodronate, prednisolone, and prednisone.

[0477] Table 6. Treatment-Emergent Adverse Events

[0478] Table 6 shows the most common treatment-emergent adverse events. There were no differences in the frequencies 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) between the groups. Most treatment discontinuations were the result of progressive disease (99 [19%] in the apalutamide group; 227 [43%] in the placebo; Table 5). Adverse events led to discontinuation in 42 (8.0%) patients in the apalutamide group and 28 (5.3%) patients in the placebo group (Table 7). Ten (1.9%) and 16 (3.0%) patients in the apalutamide and placebo groups, respectively, died due to adverse events (Table 8). Rash of any grade was more common in patients treated with apalutamide compared with placebo (8.5% and 27.1%, respectively; Table 6), and the most common event considered related to 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 grade 1 or 2. Ischemic heart disease was reported in 4.4% and 1.5% of patients in the apalutamide and placebo groups, respectively; ischemic events led to the death of two patients in each group.

[0479] Table 7: Treatment-Emergent Adverse Events Leading to Treatment Discontinuation, Dose Reduction, and Administration Interruption 。

[0480]

[0481]

[0482] Values are numbers (%).

[0483] * Rash is a grouping term that includes rash, butterfly rash, erythematous rash, exfoliative rash, follicular rash, generalized rash, macule, maculopapule, papule, papulovesicle, prurigo, pustule, genital rash, vesicle, skin exfoliation, exfoliative dermatitis, skin reaction, systemic lupus erythematosus, toxic skin rash, oral ulcer, drug rash, conjunctivitis, erythema multiforme, stomatitis, and urticaria.

[0484] Fracture is a grouping term that includes acetabular fracture, ankle fracture, clavicle fracture, femoral neck fracture, femoral fracture, fibular fracture, foot fracture, forearm fracture, fracture, ischial fracture, fracture pain, hand fracture, hip fracture, lower limb fracture, patellar fracture, radial fracture, rib fracture, skull fracture, vertebral compression fracture, spinal fracture, sternal fracture, thoracic fracture, tibial fracture, traumatic fracture, ulnar fracture, upper limb fracture, and wrist fracture.

[0485] Hypothyroidism is a grouping term that includes autoimmune thyroiditis, elevated blood thyroid stimulating hormone, and hypothyroidism.

[0486] § Epilepsy is a grouping term that includes epilepsy and tongue biting.

[0487] Table 8: Causes of Death Reported by Investigators in the Safety Population Study

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495] Table 9: Estimates of Subdistribution Hazard Ratios of the Apalutamide Group Versus the Placebo Group

[0496]

[0497]

[0498] A post hoc analysis considering competing death risks was performed based on the Fine and Gray models (Table 9). Fine JP, Gray RJ, J Am Stat Assoc, 1999, Vol. 94, pp. 496 - 509. Estimates of the subdistribution hazard ratio of the apalutamide group relative to the placebo group are shown, along with the corresponding 95% confidence limits and the P value from the Wald Chi - Square test. The results of this post hoc analysis support and confirm the results of the pre - planned analysis.

[0499] Rash Management

[0500]

[0501] Discussion

[0502] Rashes associated with apalutamide are generally described as generalized rashes or maculopapular eruptions. Treatment-emergent rashes were reported in 27.1% of patients in the apalutamide group, compared with 8.5% of patients in the placebo group. Grade 3 rashes were reported after treatment with apalutamide (6.3%) and placebo (0.6%). Stevens-Johnson syndrome or toxic epidermal necrolysis was not reported. Rashes led to treatment discontinuation, dose reduction, and interruption of dosing in 12 (2.3%), 28 (5.3%), and 44 (8.4%) patients in the apalutamide group and 1 (0.2%), 4 (0.8%), and 5 (0.9%) patients in the placebo group, respectively. Rashes of 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 rashes, treatment included topical corticosteroids, oral antihistamines, systemic corticosteroids, drug interruption, and dose reduction. The median time to rash onset was 81 days in the apalutamide group and 141 days in the placebo group.

[0503] Apalutamide Formulations

[0504] In this phase 3 study of men with metastatic castration-sensitive prostate cancer (mCSPC), apalutamide plus ADT significantly prolonged overall survival and radiographic progression-free survival compared with placebo plus ADT. There was no difference in the reduction of the risk of death based on disease volume, and the benefit in radiographic progression-free survival was consistently observed in all subgroups analyzed, including patients previously exposed to docetaxel. A longer survival was observed in the apalutamide group even though a higher proportion of patients in the placebo group who discontinued treatment received subsequent life-prolonging prostate cancer therapies (64 [38%] of 170 patients in the apalutamide group and 165 [61%] of 271 patients in the placebo group; Table 5). Based on the results of the first interim analysis from this program, the Independent Data Monitoring Committee recommended unblinding to allow patients receiving placebo to cross over to receive apalutamide.

[0505] Secondary and exploratory endpoints, including time to cytotoxic chemotherapy and time to second progression-free survival, also favored apalutamide treatment. Apalutamide plus ADT also led to a higher proportion of patients achieving undetectable PSA levels and a delay in time to PSA progression compared with placebo plus ADT. In this illustrative study, initial treatment with apalutamide in patients with metastatic castration-sensitive prostate cancer led to improved clinical outcomes.

[0506] The intent of the trial was to enroll a broad group of patients with metastatic castration-sensitive prostate cancer, which led to relatively small numbers in some patient subgroups. For example, while all patients acknowledged the survival benefit of taking docetaxel during informed consent, only 11% had received docetaxel previously before study enrollment. This may reflect perceived patient adaptation to docetaxel as well as differences in patient selection or care approaches. However, the consistency of the clinical benefit of apalutamide across all subgroups was convincing.

[0507] The rates of high-grade and serious adverse events did not differ between the apalutamide and placebo groups. The rates of discontinuation due to adverse events were low in both groups. Adverse events generally conformed to the known safety profile of apalutamide. Rash associated with treatment with apalutamide was common and was generally managed with antihistamines and topical corticosteroids, dose interruption, and dose reduction. Hypothyroidism was mild to moderate, monitored by thyroid-stimulating hormone, and managed with levothyroxine. Health-related quality of life was also maintained and did not differ between groups, supporting the tolerability of apalutamide plus ADT.

[0508] In summary, in an illustrative study of patients with metastatic castration-sensitive prostate cancer (including those with high-volume and low-volume disease, those who had previously received docetaxel, and those who had previously received treatment for local disease) and patients with newly diagnosed or existing comorbidities, adding apalutamide to ADT significantly prolonged overall survival and delayed disease progression, with a safety profile that did not differ significantly from placebo plus ADT and maintained health-related quality of life.

[0509] Packaging

[0510] The apalutamide tablets provided for this study contained 60 mg of apalutamide. Their manufacture and supply were the responsibility of the sponsor.

[0511] The placebo was provided as a tablet formulation and was matched in size, color, and shape to keep the study blinded.

[0512] Example 2: Final FDA-Approved Pharmaceutical Product Label

[0513] The 60-mg apalutamide tablets were packaged in 120-tablet strength, 160-cc high-density polyethylene (HDPE) bottles with child-resistant caps.

[0514] Full Prescribing Information

[0515] The FDA approved the following drug product label for ERLEADA TM (apalutamide) on September 17, 2019 TMIt is a drug listed in the reference of apalutamide.

[0516]

[0517]

[0518] Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

[0519] 1. Indications and Usage

[0520] ERLEADA is indicated for the treatment of patients with the following diseases:

[0521] · Metastatic castration-sensitive prostate cancer (mCSPC)

[0522] · Non-metastatic castration-resistant prostate cancer (nmCRPC)

[0523] 2 Dosage and Administration

[0524] 2.1 Recommended Dosage

[0525] The recommended dosage of ERLEADA is 240 mg (four 60 mg tablets), administered orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food.

[0526] Patients should also receive a gonadotropin-releasing hormone (GnRH) analogue concomitantly, or should have had a bilateral orchiectomy.

[0527] 2.2 Dosage Adjustment

[0528] If a patient experiences toxicity greater than or equal to grade 3 or a side effect that is not tolerable, hold dosing until the symptoms improve to less than or equal to grade 1 or baseline, then resume (if necessary) at the same dose or a reduced dose (180 mg or 120 mg).

[0529] 3 Dosage Form and Strength

[0530] Tablets (60 mg): Pale yellow to grayish-green, oval, film-coated tablets with a concave pattern "AR60" on one side.

[0531] 4 Contraindications

[0532] None.

[0533] 5 Warnings and Precautions

[0534] 5.1 Ischemic Cardiovascular Events

[0535] Ischemic cardiovascular events, including events resulting in death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors such as hypertension, diabetes, or dyslipidemia. Consider withholding ERLEADA for Grade 3 and 4 events.

[0536] In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 3% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 (0.5%) patients treated with ERLEADA and 2 (0.2%) patients treated with placebo died from ischemic cardiovascular events. 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.

[0537] 5.2 Fractures

[0538] Fractures occurred in patients receiving ERLEADA. Evaluate a patient's fracture risk. Monitor and manage patients at risk of fracture according to established treatment guidelines and consider use of bone-targeted agents.

[0539] In a randomized study (SPARTAN) of patients with non-metastatic castration-resistant prostate cancer, fractures occurred in 12% of patients treated with ERLEADA and 7% of patients treated with placebo. Grade 3 to 4 fractures occurred in 3% of patients treated with ERLEADA and 1% of patients treated with placebo. For patients treated with ERLEADA, the median time to onset of fracture was 314 days (range: 20 to 953 days). Routine bone density assessments and treatment of osteoporosis with bone-targeted agents were not performed in the SPARTAN study.

[0540] In a randomized study (TITAN) of patients with metastatic castration-sensitive prostate cancer, fractures occurred in 9% of patients treated with ERLEADA and 6% of patients treated with placebo. Grade 3 - 4 fractures were similar in both groups at 2%. For patients treated with ERLEADA, the median time to onset of fracture was 56 days (range: 2 to 111 days). Routine bone density assessments and treatment of osteoporosis with bone-targeted agents were not performed in the TITAN study.

[0541] 5.3 Falls

[0542] Falls occur in patients receiving ERLEADA, and the frequency increases in the elderly [see Use in Specific Populations (8.5)]. Evaluate the patient's risk of falling.

[0543] In the randomized study (SPARTAN), 16% of patients treated with ERLEADA had a fall compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizures.

[0544] 5.4 Seizures

[0545] Seizures occur in patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop seizures during treatment. It is unknown whether antiseizure medications will prevent seizures when using ERLEADA. Inform patients of the risk of developing seizures while receiving ERLEADA and the risk of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

[0546] In two randomized studies (SPARTAN and TITAN), five (0.4%) patients treated with ERLEADA and one (0.1%) patient treated with placebo had seizures. Seizures occurred 159 to 650 days after the start of ERLEADA. Patients with a history of seizures, seizure precipitating factors, or receiving medications known to lower the seizure threshold or induce seizures were excluded. There is no clinical experience with re-administering ERLEADA to patients with seizures.

[0547] 5.5 Embryo-Fetal Toxicity

[0548] The safety and efficacy of ERLEADA have not been established in females. Based on the mechanism of action of ERLEADA, ERLEADA can cause fetal harm and miscarriage when administered to pregnant females [see Clinical Pharmacology (12.1)]. Males with female partners of reproductive potential are advised to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)].

[0549] 6 Adverse Reactions

[0550] The following adverse reactions are discussed in more detail in other subsections of the label: subsection

[0551] · Ischemic cardiovascular events [see Warnings and Precautions (5.1)].

[0552] · Fractures [see Warnings and Precautions (5.2)].

[0553] · Falls [see Warnings and Precautions (5.3)].

[0554] · Epilepsy [See Warnings and Precautions (5.4)].

[0555] 6.1 Clinical Trial Experience

[0556] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to those observed in the clinical trials of another drug and may not reflect the rates observed in practice.

[0557] The most common adverse reactions (≥10%) that occurred more frequently (≥2%, compared to placebo) in patients treated with ERLEADA in randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, joint pain, rash, decreased appetite, falls, weight loss, hypertension, hot flashes, diarrhea, and fractures.

[0558] Table 1: Adverse Reactions in TITAN (mCSPC)

[0559] TITAN: A randomized (1:1), double-blind, placebo-controlled, multi-center clinical study enrolled patients with mCSPC. In this study, patients received placebo or ERLEADA at a dose of 240 mg / day. All patients in the TITAN study received concomitant gonadotropin-releasing hormone (GnRH) analogs or had prior bilateral orchiectomy. The median duration of exposure for patients receiving ERLEADA was 20 months (range: 0 to 34 months), and the median duration of exposure for patients receiving placebo was 18 months (range: 0.1 to 34 months).

[0560] Ten (2%) patients treated with ERLEADA died from adverse reactions. The causes of death were ischemic cardiovascular events (n = 3), acute kidney injury (n = 2), cardiorespiratory arrest (n = 1), sudden cardiac death (n = 1), respiratory failure (n = 1), cerebrovascular event (n = 1), and perforated colonic ulcer (n = 1). ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly rash (2%). Adverse reactions that led to dose interruption or reduction of ERLEADA occurred in 23% of patients: the most frequent adverse reactions (>1%) were rash, fatigue, and hypertension. Serious adverse reactions occurred in 20% of patients treated with ERLEADA and 20% of patients receiving placebo.

[0561] Table 1 shows that in TITAN, adverse reactions occurred in ≥10% of the ERLEADA group, and the absolute increase in frequency was ≥2% compared to the placebo group. Table 2 shows that laboratory abnormalities occurred in ≥15% of patients and were more frequent (>5%) in the ERLEADA group compared to the placebo group.

[0562] Table 2: Laboratory Abnormalities Occurring in ≥15% of Patients Treated With ERLEADA in TITAN (mCSPC) and Occurring

[0563]

[0564] 1 Including fatigue and weakness

[0565] 2 Including rash, maculopapular rash, generalized rash, urticaria, pruritic rash, macule, conjunctivitis, erythema multiforme, papular rash, skin exfoliation, genital rash, erythema, stomatitis, drug rash, oral ulcer, pustular rash, blister, papule, pemphigus, skin erosion, dermatitis and vesicular rash

[0566] 3 According to the Common Terminology Criteria for Adverse Events (CTCAE), the highest severity of these events was grade 3

[0567] Additional adverse reactions of interest that occurred in 2% but less than 10% of patients treated with ERLEADA included dysentery (9% vs. 6% in patients treated with placebo), muscle spasm (3% vs. 2% in patients treated with placebo), dysgeusia (3% vs. 1% in patients treated with placebo), and hypothyroidism (4% vs. 1% in patients treated with placebo).

[0568] At a Rate Higher Than Placebo (Between-Group Difference in All Grades > 5%) Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

[0569]

[0570] 1 does not reflect fasting value

[0571] Table 3: Adverse Reactions in SPARTAN (nmCRPC)

[0572] SPARTAN: A randomized (2:1), double-blind, placebo-controlled, multi-center clinical study enrolled patients with nmCRPC. In this study, patients received placebo or ERLEADA at a dose of 240 mg / day. All patients in the SPARTAN study received concomitant gonadotropin-releasing hormone (GnRH) analog or underwent bilateral orchiectomy. The median duration of exposure for patients receiving ERLEADA was 16.9 months (range: 0.1 to 42 months), and the median duration of exposure for patients receiving placebo was 11.2 months (range: 0.1 to 37 months).

[0573] Eight (1%) patients treated with ERLEADA died from adverse reactions. The causes of death were infection (n = 4), myocardial infarction (n = 3), and intracerebral hemorrhage (n = 1). One (0.3%) patient treated with placebo died from a cardiorespiratory arrest (n = 1) adverse reaction, and ERLEADA was discontinued due to adverse reactions in 11% of patients, the most common reason being rash (3%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 33% of patients: the most common adverse reactions (>1%) were rash, dysentery, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of patients treated with ERLEADA and 23% of patients receiving placebo. The most frequent serious adverse reactions (>2%) were fractures (3%) in the ERLEADA group and urinary retention (4%) in the placebo group.

[0574] Table 3 shows that adverse reactions occurred in ≥10% of the ERLEADA group in SPARTAN, and the absolute increase in frequency was ≥2% compared to the placebo group. Table 4 shows that laboratory abnormalities occurred in ≥15% of patients and were more frequent (>5%) in the ERLEADA group compared to the placebo group.

[0575] Rash

[0576]

[0577] 1 Including fatigue and weakness

[0578] 2 Including rash, maculopapular rash, generalized rash, urticaria, pruritic rash, macule, conjunctivitis, erythema multiforme, papular rash, skin exfoliation, genital rash, erythema, stomatitis, drug eruption, oral ulcer, pustular rash, blister, papule, pemphigus, skin erosion, and vesicular rash

[0579] 3 Including rib fracture, lumbar fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture, humeral fracture, thoracic fracture, upper limb fracture, sacral fracture, hand fracture, pubic fracture, acetabular fracture, ankle fracture, compression fracture, costochondral fracture, facial bone fracture, lower limb fracture, osteoporotic fracture, wrist fracture, avulsion fracture, fibular fracture, coccygeal fracture, pelvic fracture, radial fracture, sternal fracture, stress fracture, traumatic fracture, cervical fracture, femoral neck fracture, and tibial fracture

[0580] 4 According to the Common Terminology Criteria for Adverse Events (CTCAE), the highest severity of these events was grade 3

[0581] 5Including anorexia, decreased appetite, early satiety, and anorexia nervosa

[0582] 6 Including peripheral edema, generalized edema, edema, genital edema, penile edema, peripheral swelling, scrotal edema, lymphedema, swelling, and local edema

[0583] Among patients treated with ERLEADA, additional clinically significant adverse reactions occurring in 2% or more included hypothyroidism (8.1% vs. 2% in patients treated with placebo), pruritus (6.2% vs. 2% in patients treated with placebo), and heart failure (2.2% vs. 1% in patients treated with placebo).

[0584] Table 4: Laboratory abnormalities occurred in ≥15% of patients treated with ERLEADA in SPARTAN (nmCRPC) and the incidence was higher than that of placebo (inter-group difference for all grades >5%)

[0585]

[0586] 1 Do not reflect fasting values

[0587] Hypothyroidism

[0588] In pooled data from two randomized, placebo-controlled clinical studies, the rash associated with ERLEADA was most commonly described as macular or maculopapular. Rash adverse reactions were reported in 26% of patients treated with ERLEADA and 8% of patients treated with placebo. Grade 3 rash (defined as covering >30% of the body surface area [BSA]) was reported in 6% of patients treated with ERLEADA and 0.5% of patients treated with placebo.

[0589] The rash began at a median of 83 days of ERLEADA treatment. The rash resolved in 78% of patients within a median of 78 days after the rash onset. Oral antihistamines and topical corticosteroids were commonly used to manage the rash, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Among patients with dose interruption, 59% of patients experienced recurrence of the rash upon re-introduction of ERLEADA.

[0590] Strong CYP2C8 or CYP3A4 Inhibitors

[0591] In pooled data from two randomized, placebo-controlled clinical studies, based on assessments of thyroid-stimulating hormone (TSH) every 4 months, hypothyroidism occurred in 8% of patients treated with ERLEADA and 2% of patients treated with placebo. TSH elevation occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The onset median was at the first scheduled assessment. There were no grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 5% of patients treated with ERLEADA. Thyroid replacement therapy should be initiated or the dose adjusted when there are clinical indications [see Drug Interactions (7.2)].

[0592] 7 Drug Interactions

[0593] 7.1 Effects of Other Drugs on ERLEADA

[0594] CYP3A4, CYP2C9, CYP2C19, and UGT Substrates

[0595] Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is expected to increase the steady-state exposure of the active moiety (the sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl-apalutamide). No initial dose adjustment is required, but the ERLEADA dose should be reduced based on tolerability [see Dosage and Administration (2.2)]. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect apalutamide exposure.

[0596] 7.2 Effects of ERLEADA on Other Drugs

[0597] P-gp, BCRP, or OATP1B1 Substrates

[0598] ERLEADA is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9. Co-administration of ERLEADA with drugs that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 may result in reduced exposure to these drugs. Replacement of these drugs is recommended if possible, and loss of activity should be evaluated if the drugs are continued. Co-administration of ERLEADA with drugs that are substrates for uridine diphosphate-glucuronosyltransferase (UGT) may result in reduced exposure. If a UGT substrate must be co-administered with ERLEADA, caution should be exercised and loss of activity should be evaluated [see Clinical Pharmacology (12.3)].

[0599] Risk Summary

[0600] Clinically, apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1). At steady state, apalutamide reduces plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP / OATP1B1 substrate). ERLEADA is used concomitantly with drugs that are substrates of P-gp. BCRP or OATP1B1 can result in reduced exposure to these drugs. Caution is warranted if it is a substrate of P-gp. If the drug is continued, BCRP or OATP1B1 must be co-administered with ERLEADA and loss of activity evaluated [see Clinical Pharmacology (12.3)].

[0601] 8 Use in Specific Populations

[0602] 8.1 Pregnancy

[0603] Risk Summary

[0604] The safety and efficacy of ERLEADA have not been established in females. Based on the mechanism of action of ERLEADA, ERLEADA can cause fetal harm and miscarriage [see Clinical Pharmacology (12.1)]. There are no human data on the use of ERLEADA in pregnant women. ERLEADA is not indicated for use in females and, therefore, animal embryo-fetal developmental toxicology studies with apalutamide were not conducted.

[0605] 8.2 Lactation

[0606] Contraceptive Measures

[0607] The safety and efficacy of ERLEADA have not been established in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

[0608] 8.3 Females and Males with Reproductive Potential

[0609] Infertility

[0610] Males

[0611] Based on the mechanism of action and findings in animal reproductive studies, male patients with female partners of reproductive potential are advised to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. [See Use in Specific Populations (8.1)].

[0612] Cardiac Electrophysiology

[0613] Males

[0614] Based on animal studies, ERLEADA may impair fertility in males with reproductive potential [see Nonclinical Toxicology (13.1)].

[0615] 8.4 Pediatric Use

[0616] The safety and effectiveness of ERLEADA in pediatric patients have not been established.

[0617] 8.5 Geriatric Use

[0618] Of the 1327 patients who received ERLEADA in clinical studies, 19% were less than 65 years of age, 41% were 65 to 74 years of age, and 40% were 75 years of age and older.

[0619] No overall difference in effectiveness was observed between geriatric and younger patients.

[0620] Among patients treated with ERLEADA (n = 1073), 3-4 grade adverse reactions occurred in 39% of patients less than 65 years of age, 41% of patients 65 - 74 years of age, and 49% of patients 75 years of age or older. Among patients receiving ERLEADA and androgen deprivation therapy, the frequency of falls was increased in the elderly, occurring in 8% of patients less than 65 years of age, 10% of patients 65 - 74 years of age, and 19% of patients 75 years of age or older.

[0621] 10 Overdose

[0622] There is no known specific antidote for apalutamide overdose. In the event of overdose, discontinue ERLEADA and institute general supportive measures until clinical toxicity abates or resolves.

[0623] 11 Description

[0624] The active ingredient of ERLEADA, apalutamide, is an androgen receptor inhibitor. The chemical name is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide. Apalutamide is a white to pale yellow powder. Apalutamide is practically insoluble in aqueous media over a wide range of pH values.

[0625] The molecular weight is 477.44 and the molecular formula is C 21 H 15 F4N5O2S. The structural formula is

[0626]

[0627] ERLEADA (apalutamide) is provided as a film-coated tablet for oral administration containing 60 mg of apalutamide. The inactive ingredients of the tablet core are: colloidal anhydrous silica, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and siliconized microcrystalline cellulose.

[0628] The finished tablet has a commercially available film coating containing the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

[0629] 12 Clinical Pharmacology

[0630] 12.1 Mechanism of Action

[0631] Apalutamide is an androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and blocks AR-mediated transcription. The major metabolite, N-desmethyl apalutamide, is a less potent AR inhibitor and exhibits one-third of the activity of apalutamide in in vitro transcription. Administration of apalutamide results in decreased tumor cell proliferation and increased apoptosis in a murine xenograft model of prostate cancer, leading to a reduction in tumor volume.

[0632] 12.2 Pharmacodynamics

[0633] Absorption

[0634] The effect of apalutamide 240 mg once daily on QTc interval was evaluated in an open-label, non-controlled, multi-center, single-group dedicated QT study in 45 patients with CRPC. The maximum mean change in QTcF from baseline was 12.4 ms (two-sided 90% upper CI: 16.0 ms). Exposure-QT analysis showed a concentration-dependent increase in QTcF for apalutamide and its active metabolite.

[0635] 12.3 Pharmacokinetics

[0636] Unless otherwise specified, apalutamide pharmacokinetic parameters are expressed as mean [standard deviation (SD)]. Apalutamide C max and the area under the concentration curve (AUC) increase proportionally after once-daily repeated dosing from 30 mg to 480 mg (0.125 to 2 times the recommended dose). After administration of the recommended dose, apalutamide steady state is achieved after 4 weeks, and the mean accumulation ratio is approximately 5-fold. At steady state, apalutamide C maxwas 6.0 mcg / mL (1.7), and the AUC was 100 mcg-h / mL (32). The daily fluctuation of apalutamide plasma concentration was low, with an average peak-to-trough ratio of 1.63. An increase in apparent clearance (CL / F) was observed upon repeated dosing, which may be due to the induction of apalutamide's own metabolism. The autoinduction effect may reach its maximum at the recommended dose, as the exposure of apalutamide in the dose range of 30 mg to 480 mg is dose-proportional.

[0637] At steady state after the recommended dose, the major active metabolite N-desmethyl apalutamide C max was 5.9 mcg / mL (1.0) and the AUC was 124 mcg-h / mL (23). N-desmethyl apalutamide is characterized by a flat concentration-time profile at steady state, with an average peak-to-trough ratio of 1.27. After repeated-dose administration, the mean AUC metabolite / parent drug ratio of N-desmethyl apalutamide was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic characteristics, N-desmethyl apalutamide is likely to contribute to the clinical activity of apalutamide.

[0638] Distribution

[0639] The mean absolute oral bioavailability was approximately 100%. The median time to reach the plasma peak concentration (max) was 2 hours (range: 1 to 5 hours).

[0640] Effect of food

[0641] Administration of apalutamide to healthy subjects with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) under fasting conditions did not result in clinically relevant changes in C max and AUC. The median time to reach t max was delayed by approximately 2 hours after eating.

[0642] Elimination

[0643] The mean apparent volume of distribution of apalutamide at steady state was approximately 276 L.

[0644] 96% of apalutamide and 95% of N-desmethyl apalutamide were bound to plasma proteins, without concentration dependence.

[0645] Specific Populations

[0646] The CL / F of apalutamide after a single dose was 1.3 L / h and may increase to 2.0 L / h at steady state after once-daily dosing due to CYP3A4 autoinduction. At steady state, the mean effective half-life of apalutamide in patients was approximately 3 days.

[0647] Metabolism

[0648] Metabolism is the major route for the elimination of apalutamide. Apalutamide is mainly metabolized by CYP2C8 and CYP3A4 to form the active metabolite N-desmethyl apalutamide. The contributions of CYP2C8 and CYP3A4 to the metabolism of apalutamide were estimated to be 58% and 13% after single-dose administration, but changed to 40% and 37% respectively at steady state.

[0649] After a single oral administration of 240 mg of radiolabeled apalutamide, apalutamide accounted for 45% of the total AUC and N-desmethyl apalutamide accounted for 44% of the total AUC.

[0650] Excretion

[0651] Up to 70 days after a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of the dose as unchanged apalutamide and 2.7% of the dose as N-desmethyl apalutamide), and 24% of the dose was recovered in feces (1.5% of the dose as unchanged apalutamide and 2% of the dose as N-desmethyl apalutamide).

[0652] Drug Interactions

[0653] No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed based on age (18 - 94 years), race (Black, non-Japanese Asian, Japanese), mild to moderate (eGFR 30 - 89 mL / min / 1.73 m2 estimated by the Modification of Diet in Renal Disease [MDRD] formula) renal impairment, or mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment.

[0654] The effects of severe renal impairment or end-stage renal disease (eGFR ≤ 29 mL / min / 1.73 m2, MDRD) or severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of apalutamide are unknown.

[0655] ​

[0656] Effect of other drugs on ERLEADA

[0657] Strong CYP2C8 inhibitors

[0658] After co-administration of ERLEADA as a single 240 mg dose with gemfibrozil (a strong CYP2C8 inhibitor), the Cmax of apalutamide max decreased by 21%, while the AUC increased by 68%. Gemfibrozil is predicted to decrease the Cmax of steady-state apalutamide maxIncreased by 32% and the AUC increased by 44%. For the active moiety (sum of unbound apalutamide plus efficacy-modulated unbound N-desmethyl apalutamide), predicted steady-state C max Increased by 19% and the AUC increased by 23%.

[0659] Strong CYP3A4 inhibitor

[0660] After co-administering ERLEADA as a single 240 mg dose with itraconazole (a strong CYP3A4 inhibitor), the C of apalutamide max Decreased by 22%, while the AUC was similar. Predicted that ketoconazole (a strong CYP3A4 inhibitor) increased the AUC of single-dose apalutamide by 24%, but had no effect on C max No effect, predicted that ketoconazole increased the steady-state apalutamide C max Increased by 38% and the AUC increased by 51%. For the active moiety, predicted steady-state C max Increased by 23% and the AUC increased by 28%.

[0661] CYP3A4 / CYP2C8 inducer

[0662] Predicted that rifampicin (a strong CYP3A4 and moderate CYP2C8 inducer) decreased the steady-state apalutamide C max By 25% and decreased the AUC by 34%. For the active moiety, predicted steady-state C max Decreased by 15% and the AUC decreased by 19%.

[0663] Acid reducer

[0664] Apalutamide is not ionizable under relevant physiological pH conditions, so acid reducing agents (such as proton pump inhibitors, H2 receptor antagonists, antacids) are not expected to affect the solubility and bioavailability of apalutamide.

[0665] Drugs affecting transporters

[0666] In vitro, apalutamide and N-desmethyl apalutamide are substrates of P-gp, but not substrates of BCRP, OATPIB1 and OATP1B3. Since apalutamide is completely absorbed after oral administration and P-gp does not limit the absorption of apalutamide, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.

[0667] Effect of ERLEADA on other drugs

[0668] CYP substrate

[0669] In vitro studies have shown that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations.

[0670] Co-administration of ERLEADA with a single oral dose of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (a CYP3A4 substrate), an 85% decrease in the AUC of omeprazole (a CYP2C19 substrate), and a 46% decrease in the AUC of S-warfarin (a CYP2C9 substrate). ERLEADA did not cause clinically significant changes when exposed to CYP2C8 substrates.

[0671] P-gp, BCRP, and OATP1B1 substrates

[0672] Co-administration of ERLEADA with a single oral dose of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and a 41% decrease in the AUC of rosuvastatin (a BCRP / OATPIB1 substrate), but had no effect on C max No effect.

[0673] UGT substrates

[0674] Apalutamide can induce UGT. Co-administration of ERLEADA with drugs that are UGT substrates can result in reduced exposure to these drugs.

[0675] OCT2, OAT1, OAT3, and MATES substrates

[0676] In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion transporter (MATE), but do not inhibit organic anion transporter 1. It is predicted that apalutamide will not cause clinically significant changes when exposed to OAT3 substrates.

[0677] GnRH analogs

[0678] In mCSPC subjects receiving leuprolide acetate (a GnRH analog) co-administered with apalutamide, PK data showed that apalutamide had no significant effect on the steady-state exposure of leuprolide.

[0679] 13 Nonclinical Toxicology

[0680] 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0681] 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 (Ames) assay and was not genotoxic in the in vitro chromosomal aberration assay or in the in vivo rat bone marrow micronucleus test or in the in vivo rat comet assay.

[0682] In repeated-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate and seminal vesicles, azoospermia / oligospermia, tubular degeneration and / or hyperplasia or hypertrophy in the reproductive system were observed at ≥25 mg / kg / day in rats (1.4 times human exposure based on AUC) and at ≥2.5 mg / kg / day in dogs (0.9 times human exposure based on AUC).

[0683] In a fertility study in male rats, after 4 weeks of dosing at ≥25 mg / kg / day (0.8 times human exposure based on AUC), decreased sperm concentration and motility, increased abnormal sperm morphology, decreased mating and fertility rates, and decreased weights of the accessory sex glands and epididymis were observed (when paired with untreated females). After 4 weeks of administration at 150 mg / kg / day (5.7 times human exposure based on AUC), a decrease in the number of live fetuses was observed due to increased pre- and / or post-implantation losses. The effects on male rats were reversible 8 weeks after the last apalutamide administration.

[0684] 14 Clinical studies

[0685] The efficacy and safety of ERLEADA were demonstrated in two randomized placebo-controlled clinical trials.

[0686] TITAN (NCT02489318): Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

[0687] TITAN was a randomized, double-blind, placebo-controlled, multinational clinical trial in which 1052 patients with mCSPC were randomly assigned (1:1) to receive ERLEADA orally at a dose of 240 mg once daily (N = 525) or placebo once daily (N = 527). All patients in the TITAN trial received concomitant GnRH analogue or had prior bilateral orchiectomy. Patients were stratified according to Gleason score at diagnosis, prior use of docetaxel, and world regions. Patients with both high-volume and low-volume mCSPC were eligible to participate in the study. High-volume disease was defined as metastases involving the viscera with 1 bone lesion or the presence of 4 or more bone lesions. At least 1 bone lesion had to be in a bony structure outside the spine and pelvic bones.

[0688] The following patient demographics and baseline disease characteristics were balanced between treatment groups. The median age was 68 years (range 43 - 94 years), and 23% of patients were 75 years or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three (63%) of the patients had high-volume disease and 37% had low-volume disease. Sixteen (16%) of the patients had previously undergone prostate surgery, radiotherapy, or both. The majority of patients had a Gleason score of 8 or higher (67%). Sixty-eight (68%) of the patients had previously received antiandrogen (bicalutamide, flutamide, or nilutamide) therapy. At study entry, all patients except those in the placebo group had an "Eastern Cooperative Oncology Group Performance Status (ECOG PS)" score of 0 or 1.

[0689] The primary efficacy outcome measures of the study were overall survival (OS) and radiographic progression-free survival (PFS). Radiographic progression-free survival was based on investigator assessment and was defined as the time from randomization to radiographic disease progression or death. Radiographic disease progression was defined by identifying 2 or more new bone lesions and / or soft tissue disease progression on a bone scan (Prostate Cancer Working Group 2 criteria).

[0690] A statistically significant improvement in OS and rPFS was demonstrated in patients randomized to receive ERLEADA compared to patients randomized to receive placebo. The results for OS were based on a pre-specified interim efficacy analysis. The efficacy results for TITAN are summarized in Table 5 and Figure 1 and Figure 2.

[0691] Table 5: Summary of Efficacy Results - Intention-to-Treat mCSPC Population (TITAN)

[0692]

[0693]

[0694] a The interim analysis was based on 50% of the number of events planned for the final analysis, with an alpha of 0.01 allocated.

[0695] b Hazard ratios were from a stratified proportional hazards model, with hazard ratio < 1 favoring ERLEADA

[0696] c p-values were from a log-rank test stratified by Gleason score at diagnosis (≤7 vs. >7), region (NA / EU vs. other countries and regions), and prior use of docetaxel (yes vs. no)

[0697] dNE = Not Estimable

[0698] Consistent improvements in rPFS were observed in the following patient subgroups: disease volume (high vs low), prior docetaxel use (yes or no), and Gleason score at diagnosis (≤7 vs >7).

[0699] Consistent improvements in OS were observed in the following patient subgroups: disease volume (high vs low) and Gleason score at diagnosis (≤7 vs >7).

[0700] Treatment with ERLEADA significantly delayed the initiation of cytotoxic chemotherapy in a statistical sense (HR = 0.39, 95% CI (0.27, 0.56); p < 0.0001).

[0701] Figure 1 : Kaplan-Meier plot of overall survival (OS); intention-to-treat mCSPC population (TITAN)

[0702]

[0703] Figure 2: Kaplan-Meier Plot of Radiographic Progression-Free Survival (rPFS); Intention-to-Treat mCSPC Population (TITAN)

[0704]

[0705] SPARTAN (NCT01946204): Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

[0706] SPARTAN was a multicenter, double-blind, randomized (2:1), placebo-controlled clinical trial in which 1207 patients with nmCRPC were randomly assigned (2:1) to receive ERLEADA orally at a dose of 240 mg once daily (N = 806) or placebo once daily (N = 401). All patients in the SPARTAN trial received concomitant GnRH analog or had undergone bilateral orchiectomy. Patients were stratified by prostate-specific antigen (PSA) doubling time (PSADT), use of bone-protective agents, and local disease. Patients were required to have a PSADT ≤10 months and non-metastatic disease confirmed by blinded independent central review (BICR). PSA results were blinded and not used for treatment discontinuation. Patients randomly assigned to either group discontinued treatment due to radiologic disease progression confirmed by BICR, progression limited to local areas, initiation of new treatment, unacceptable toxicity, or withdrawal.

[0707] The following patient demographics and baseline disease characteristics were balanced between treatment groups. The median age was 74 years (range 48 - 97 years), and 26% of patients were 80 years or older. The racial distribution was 66% white, 12% Asian, and 6% black. Seventy-seven (77%) of patients in both treatment groups had previously undergone surgical or radiation therapy for the prostate. Most patients had a Gleason score of 7 or higher (78%). Fifteen (15%) of patients had 2 cm pelvic lymph nodes at study entry. Seventy-three (73%) of patients had previously received antiandrogen therapy; 69% had received bicalutamide, and 10% had received flutamide. At study entry, all patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1. Among patients who discontinued study treatment (placebo group N = 279, ERLEADA group N = 314), a greater proportion of patients treated with placebo received subsequent therapy (80%) compared to patients treated with ERLEADA (56%). Overall, local-only progression occurred in 2% of patients.

[0708] The primary efficacy outcome measure of the study was metastasis-free survival (MFS), which was defined as the time from randomization to the first evidence of distant metastasis confirmed by BICR, where distant metastasis was defined as a new lesion or soft tissue lesion or enlarged lymph node above the iliac bifurcation, or death from any cause, whichever occurred first. Additional efficacy endpoints were time to metastasis (TTM), progression-free survival (PFS) (which also included local progression), time to symptomatic progression, and overall survival (OS).

[0709] A statistically significant improvement in MFS was demonstrated in patients randomized to receive ERLEADA compared to patients randomized to receive placebo. Consistent results were observed in patient subgroups that included PSADT (≤6 months or >6 months), use of prior bone protectors (yes or no), and local disease (N0 or N1). Statistically significant improvements in TTM, PFS, and time to symptomatic progression supported the primary efficacy outcome. Overall survival (OS) data were immature at the time of the final MFS analysis (24% of the required number of events). The efficacy results for MFS, TTM, and PFS from SPARTAN are summarized in Figure 3 and Table 6.

[0710] Figure 3: Kaplan-Meier Metastasis-Free Survival (MFS) Curve in SPARTAN (nmCRPC)

[0711]

[0712] Table 6: Efficacy Results Evaluated by BICR (SPARTAN)

[0713]

[0714] 1 All analyses were stratified by PSA doubling time, bone protective agent use, and local disease status.

[0715] NE = Not Estimable

[0716] 16 How to Supply / Store and Handle

[0717] ERLEADA (apalutamide) 60 mg film-coated tablets are oval tablets that are slightly yellow to grayish green, with an indented pattern "AR 60" on one side. ERLEADA 60 mg tablets are supplied in bottles of 120. Each bottle contains a silica gel desiccant.

[0718] NDC number 59676-600-12

[0719] Storage and Handling

[0720] Store at 20°C to 25°C (68°F to 77°F): excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0721] Store in the original packaging. Do not discard the desiccant. Protect from light and moisture.

[0722] 17 Patient Counseling Information

[0723] Advise the patient to read the FDA-approved patient labeling (Patient Information).

[0724] Ischemic Cardiovascular Events

[0725] · Inform the patient that ERLEADA is associated with ischemic cardiovascular events. If any symptoms suggestive of a cardiovascular event occur, advise the patient to seek immediate medical attention [see Warnings and Precautions (5.1)].

[0726] Falls and Fractures

[0727] · Inform the patient that ERLEADA is associated with an increased incidence of falls and fractures [see Warnings and Precautions (5.2, 5.3)].

[0728] Seizures

[0729] · Inform the patient that ERLEADA is associated with an increased risk of seizures. Discuss conditions that can precipitate seizures and medications that may lower the seizure threshold, and inform the patient of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. If the patient has a seizure, inform the patient to contact their healthcare provider immediately [see Warnings and Precautions (5.4)].

[0730] Rash

[0731] · Inform patients that ERLEADA is associated with rash and inform their healthcare provider if the patient develops a rash [see Adverse Reactions (6.1)].

[0732] Dose and Administration

[0733] · Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analogue therapy that they need to maintain this therapy during treatment with ERLEADA.

[0734] · Instruct patients to take their dose at the same time each day (once daily). ERLEADA may be taken with or without food. Each tablet should be swallowed whole.

[0735] · Inform patients that in the event of a missed daily dose of ERLEADA, they should take their normal dose as soon as possible on the same day and resume their normal schedule the next day. Patients should not take an extra tablet to make up for a missed dose [see Dosage and Administration (2.1)].

[0736] Embryo-Fetal Toxicity

[0737] · Inform patients that ERLEADA may be harmful to a developing fetus. Male patients with female partners of childbearing potential are advised to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. Male patients are advised to use a condom when having sexual intercourse with a pregnant woman [see Warnings and Precautions (5.5)].

[0738] Infertility

[0739] · Inform male patients that ERLEADA may impair fertility and that they should not donate sperm during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.3)].

[0740] Manufactured by:

[0741] Janssen Ortho LLC

[0742] Gurabo, PR 00778

[0743] Manufactured for:

[0744] Janssen Products, LP

[0745] Horsham, PA 19044

[0746] Janssen Pharmaceutical Companies

[0747]

[0748]

[0749]

[0750] The patient information has been approved by the US Food and Drug Administration. Revision date: September 2019

[0751] The examples and embodiments described herein are for illustrative purposes only and will suggest to those skilled in the art various modifications or variations that are included within the spirit and scope of this application and the appended claims.

Claims

1. Use of a combination of an antiandrogen and at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist in the manufacture of a medicament for the treatment of metastatic castration-sensitive prostate cancer in male humans, said treatment comprising administering, or consisting essentially of administering, a therapeutically effective amount of an antiandrogen in combination with at least one GnRH agonist or antagonist to a male human having metastatic castration-sensitive prostate cancer, wherein the antiandrogen is: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, and wherein, relative to the overall survival rate of the population of male humans having metastatic castration-sensitive prostate cancer, administering the antiandrogen in combination with at least one GnRH agonist or antagonist prolongs the overall survival of the male human, the population having been administered a placebo in combination with at least one GnRH agonist or antagonist, or relative to the progression-free survival rate of the population of male humans having metastatic castration-sensitive prostate cancer, administering the antiandrogen in combination with at least one GnRH agonist or antagonist prolongs the progression-free survival of the male human, the population having been administered a placebo in combination with at least one GnRH agonist or antagonist.

2. Use according to claim 1, wherein the male human has received at least one prior therapy for the treatment of cancer, wherein the prior therapy for the treatment of cancer is radiotherapy, surgical intervention therapy or docetaxel therapy.

3. Use according to claim 1 or 2, wherein the male human is untreated.

4. Use according to claim 1 or 2, wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered daily to the male human.

5. Use according to claim 1 or 2, wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human.

6. Use according to claim 1 or 2, wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human on a continuous daily dosing schedule.

7. Use according to claim 1 or 2, wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of from 30 mg / day to 480 mg / day.

8. Use according to claim 1 or 2, wherein 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 orally administered to the male human at a dose of 180 mg / day to 480 mg / day.

9. Use according to claim 1 or 2, wherein 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 orally administered to the male human at the following doses: (a) 30 mg / day; (b) 60 mg / day; (c) 90 mg / day; (d) 120 mg / day; or (d) 240 mg / day.

10. Use according to claim 1 or 2, wherein 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 orally administered to the male human at a dose of 240 mg / day.

11. Use according to claim 10, wherein if the male human experiences toxicity of grade 3 or higher or intolerable side effects, administration 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 suspended until the symptoms of toxicity of grade 3 or higher improve to grade 1 or lower or the initial level; and daily oral administration 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 resumed at a dose of 240 mg, 180 mg or 120 mg.

12. Use according to claim 1, wherein the treatment comprises (a) administering a daily oral 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 at a dose of 240 mg; (b) if the male human experiences toxicity of grade 3 or higher or intolerable side effects, administration 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 suspended until the symptoms of toxicity of grade 3 or higher improve to grade 1 or lower or the initial level; and daily oral administration 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 resumed at a dose of 240 mg, 180 mg or 120 mg.

13. Use according to claim 1 or 2, wherein the antiandrogen and the at least one GnRH agonist or antagonist are provided in a form suitable for co - administration to a patient.

14. Use according to claim 1 or 2, wherein co - administration of the antiandrogen with the at least one GnRH agonist or antagonist increases overall survival and reduces the risk of death by 33%, or increases progression - free survival and reduces the risk of radiographic progression or death by 52%.

15. Use according to claim 1, wherein the at least one GnRH agonist or antagonist is or comprises leuprorelin, buserelin, nafarelin, histrelin, goserelin, deslorelin, degarelix, ozerelix, ABT - 620 (elagolix), TAK - 385 (relugolix), EP - 100, KLH - 2109 or triptorelin.

16. Use according to claim 1 or 2, wherein 4 - [7 - (6 - cyano - 5 - trifluoromethylpyridin - 3 - yl)-8 - oxo - 6 - thia - 5,7 - diazaspiro[3.4]oct - 5 - yl]-2 - fluoro - N - methylbenzamide is not co - administered with the following drugs: (a) A drug that is a strong CYP2C8 or CYP3A4 inhibitor; (b) A drug that is mainly metabolized by CYP3A4, CYP2C19 or CYP2C9; (c) A drug that is a UDP - glucuronosyltransferase substrate; or (d) A drug that is a substrate of P - glycoprotein, breast cancer resistance protein or organic anion - transporting polypeptide 1B1.

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