ANTIANDROGENS FOR THE TREATMENT OF CASTRATION-SENSITIVE METASTATIC PROSTATE CANCER.

Abstract

This description describes methods for treating metastatic castration-sensitive prostate cancer with antiandrogens, including, but not limited to, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5.7-diazaspiro[3.4]oct-5-yl]-2-fluoro-5 N-methylbenzamide.

Description

This application claims the benefit of US provisional patent application no. US provisional patent application no. 62 / 901,694 filed on September 17, 2019; 62 / 836,920, filed April 22, 2019; US provisional patent application no. 62 / 833,371 filed April 12, 2019; US provisional patent application no. 62 / 822,312 filed March 22, 2019; 62 / 803,096, filed February 8, 2019; and US provisional patent application no. 62 / 798,836 filed January 30, 2019; each of which is incorporated herein by reference in their families. TECHNICAL FIELD Described herein are methods for treating metastatic castration-sensitive prostate cancer with antiandrogens, including, but not limited to, 4-[7-(6-cyano5-trifluoromethylpyridine- 3-¡l)-8-oxo-6-thioxo-5,7-d¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzam¡de. BACKGROUND OF THE INVENTION Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer mortality in men, accounting for 14% (903,500) of all new cancer cases and 6% (258,400) of all deaths by cancer in men worldwide. The course of prostate cancer from diagnosis to death is best categorized as a series of clinical stages based on the extent of disease, hormonal status, and the absence or presence of detectable metastases: localized disease, increased levels of specific antigen of prostate (PSA) after radiotherapy or surgery without detectable metastases, and clinical metastases in the castrated or non-castrated stage. Although surgery, radiation, or a combination of both may be curative for patients with localized disease, a significant proportion of these patients present with recurrent disease, as evidenced by elevated PSA levels, which may lead to the development of of metastases, especially in the high-risk group - a transition to the lethal stage of the disease. Based on current guidelines, androgen deprivation therapy (ADT) with or without docetaxel is considered the appropriate active controller therapy for patients with hormone-sensitive metastatic prostate cancer. However, there is a clear unmet medical need zq LAnn / ίζηζ / Ε / γίΛΐ for alternative treatment options in metastatic castration-sensitive prostate cancer (mCSPC). Treatments that can delay disease progression and associated morbidities would be of significant clinical benefit in this patient population. The methods described address these and other important needs. BRIEF DESCRIPTION OF THE INVENTION Disclosed herein are methods for treating metastatic castration-sensitive prostate cancer in a human male, comprising, consisting of, essentially consisting of administering a therapeutically effective amount of an antiandrogen to a human male with metastatic prostate cancer castration sensitive. In these methods, the antiandrogen can be: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazasp¡ro[3.4]oct-5-¡l ]-2-fluoro-N-methylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazole d¡n-l-¡l)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo6-thioxo-5,7-d¡azasp¡ ro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)lH-pyrazol-l-yl] propan-2-¡l}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. In some embodiments, administration of the antiandrogen provides an increase in overall survival of male humans relative to the overall survival rate of a comparative population of male humans with castration-sensitive metastatic prostate cancer, such a comparative population has been administered a placebo in combination with an androgen deprivation therapy. In other modalities, the comparative population has not received treatment. In additional modalities, administration of the antiandrogen provides an increase in progression-free survival of male humans relative to the progression-free survival rate of a comparative population of male humans with castration-sensitive metastatic prostate cancer, said comparative population being you have been given a placebo in combination with androgen deprivation therapy. In other modalities, the comparative population has not received treatment. In some embodiments, the male human has received at least one prior cancer treatment therapy prior to administration of the antiandrogen, wherein the prior cancer treatment therapy is radiation, surgical intervention, or docetaxel therapy. In some embodiments, the male human has no prior treatment. In some modalities, the antiandrogen is 4-[7-(6-dano-5-tr¡f1uorometh¡lp¡ndin-3-¡l)-8oxo-6-thioxo-5,7-d¡azasp¡ro[3.4 ]oct-5-yl]-2-fluoro-N-methylbenzamide. In additional modalities, generally the antiandrogen and more specifically 4-[7-(6-cyano-5-tnfluoromethylpyridin-3-¡l)-8-oxo-6thioxo-5,7-d¡ Azaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered daily to the male human. In other additional modalities, generally the antiandrogen and more specifically 4-[7 zq LRnn / ίζηζ / Ε / γίΛΐ (6-c¡ano-5-tr¡fluoromet¡lp¡rid¡n-3-¡l)-8- oxo-6-thioxo-5,7-diazasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide is administered orally to the male human. In some modalities, generally the antiandrogen and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-d¡azaspiro[3.4 ]oct-5-yl]2-fluoro-N-methylbenzamide is administered orally to the male human on a continuous daily dosing schedule. In additional modalities, generally the antiandrogen and more specifically 4-[7-(6cyano-5-tr¡fluorometh¡lp¡r¡d¡n-3-¡l)-8-oxo-6-thioxo-5, 7-d¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamida is administered orally to the male human at a dose of about 30 mg per day to about 480 mg per day. In other additional modalities, generally the antiandrogen and more specifically 4-[7-(6-cyano-5-tr¡fluoromet¡lpir¡d¡n-3-¡l)-8-oxo-6-th¡oxo -5,7-d¡azaspiro[3.4]oct-5-¡l]-2fluoro-N-methylbenzamide is orally administered to the male human at a dose of about 180 mg per day to about 480 mg per day. In certain modalities, generally the antiandrogen and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-¡l] -2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of: (a) approximately 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In some modalities, generally the antiandrogen and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin3-¡l)-8-oxo-6-thioxo-5,7-diazasp¡ro[3.4]oct-5- il]-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of approximately 240 mg per day. In some modalities, the dose of generally the antiandrogen and specifically 4-[7-(6-cyano-5-trifluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6thioxo-5, 7-d¡azasp¡ro[3.4]oct-5-yl]-2-fluoro-N-methylbenzam¡de is reduced to 180 mg per day or 120 mg per day if the male human experiences greater or equal toxicity than grade 3 toxicity. In certain modalities, generally the antiandrogen and specifically 4-[7-(6cyano-5-tr¡fluoromethylpyridin-3-¡l)-8-oxo-6-thioxo-5,7 -diazasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide is not co-administered with: (a) a drug that is a strong inhibitor of CYP2C8 or CYP3A4; (b) a drug that is primarily metabolized by CYP3A4, CYP2C19, or CYP2C9; (c) a medicament that is a substrate of UDP-glucuronosyl transferase (UGT); or (d) a drug that is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1). in English). In some modalities, generally the antiandrogen and more specifically 4-[7-(6dano-5-tr¡fluoromet¡lp¡r¡d¡n-3-¡l)-8-oxo-6-t¡oxo-5, 7-d¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-met¡lbenzam¡de is administered in combination with androgen deprivation therapy. In other modalities, generally the antiandrogen and more specifically 4-[7-(6-dano-5-tnfluoromethylp¡r¡d¡n-3-yl)-8-oxo-6-thioxo-5,7diazaspiro [3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide is administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist. In still other embodiments, the at least one GnRH agonist or antagonist is or comprises leuprolide, zq LRnn / ίζηζ / Ε / γίΛΐ buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK- 385 (relugolix), EP-100, KLH-2109, or triptorelin. In certain modalities, generally the antiandrogen and more specifically 4-[7-(6-cyano-5-trifluoromethylpyridin-3-¡l)-8-oxo-6-thioxo-5,7-d¡azaspiro[3.4]oct- 5-yl]-2fluoro-N-methylbenzamide is used in combination with bilateral orchiectomy. In some modalities, the antiandrogen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)5,5-dimethyl-4-oxo-2-thioxoimidazole din-l-l)-2-fluoro-N-methylbenzamide. In other embodiments, 4-(3(4-cyano-3-(tnfluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazol¡din-l-¡l)-2-fluoro- N-methylbenzamide is administered orally to the male human at a dose of approximately 160 mg per day. In some embodiments, the antiandrogen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]8-oxo-6-thioxo-5,7-d¡azaspiro[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-1-1]propan-2-1}-5-( l-hydroxyethyl)-lH-pyrazole-3-carboxamide (darolutamide). In additional embodiments, N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(lhydroxyethyl)- 1H-pyrazole-3-carboxamide is orally administered to the male human at a dose of 600 mg twice daily. In additional embodiments, N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lHpyrazol-l-¡l]propan-2-¡l}-5-(l-hidrox¡et 11)-1H-pyrazole-3-carboxamide is orally administered to the male human at a dose of 600 mg twice daily with food. Also described herein are methods for the treatment of metastatic castration-sensitive prostate cancer in male humans essentially consisting of administering a therapeutically effective amount of an antiandrogen to a male human with metastatic castration-sensitive prostate cancer, in where the antiandrogen is one or more of: 4-[7-(6-cyano-5-tr¡f¡uoromet¡lp¡r¡d¡ntrifluorometh¡lp¡r¡d¡n-3-yl)- 8-oxo-6-thioxo-5,7diazasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide, 4-(3-(4-cyano-3-(trifluorometh ¡l)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazol¡din-l-¡l)-2-fluoro-N-methylbenzamide, 4-[7-[4- cyano-3-(trifluoromethyl)phenyl]-8-oxo6-thioxo-5,7-d¡azaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)lH-pyrazol-l-¡l]propan-2-¡l}-5-(l-hidrox¡et¡l)-lH-p Irazole-3-carboxamide. Also described herein are methods for treating metastatic castration-sensitive prostate cancer in a male human, the methods comprising: (a) determining whether the male human has metastatic castration-sensitive prostate cancer; and (b) administering an antiandrogen to a male human in a therapeutically effective amount to treat metastatic castration-responsive prostate cancer, wherein the antiandrogen is: 4-[7-(6-cyano-5tnfluoromethylpyridin- 3-¡l)-8-oxo-6-thioxo-5,7-d¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzam¡de, 4- (3-(4cyano-3-(trifluoromethyl)phenyl)-5,5-d¡methyl-4-oxo-2-thioxoimidazol¡din-l-¡l )-2-fluoro-N-methylbenzamide, 4-[7[4-cyano-3-(tnfluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-d ¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzam¡de, or N{(2S)-l-[3-(3-chloro-4-cyanophen¡ l)-1H-pyrazole-1-11]propan-2-11}-5-(1-hydrox11)-1H-pyrazole-3-carboxamide. LRnn / ί7Π7 / Ε / ΥΙΛΙ A method of treating metastatic castration-sensitive prostate cancer comprising administering an approved drug product comprising apalutamide to a male human with metastatic castration-sensitive prostate cancer in an amount that is described on a drug product label for said pharmacological product. In some embodiments, the approved drug product comprising apalutamide is an ANDA drug product, a new drug application supplemental drug product, or a 505(b)(2) drug product. In some modalities, the method is clinically proven to be safe and / or effective. Also described herein are pharmaceutical products comprising an amount of apalutamide clinically proven to be safe and clinically proven to be effective, wherein the drug product is packaged and wherein the package includes a label that (a) identifies apalutamide as an entity regulatory-approved chemical, and (b) mandates the use of apalutamide in the treatment of castration-sensitive prostate cancer. Further disclosed herein is a method of selling an approved drug product comprising apalutamide, said method comprising selling such drug product, wherein a drug product label for a reference numbered drug for such drug product includes instructions for treating cancer castration-sensitive prostate. Further described herein are methods of offering for sale an approved drug product comprising apalutamide, said method comprising offering for sale such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating castration-sensitive prostate cancer. In some embodiments, the drug product is an ANDA drug product, a new drug application supplemental drug product, or a 505(b)(2) drug product. BRIEF DESCRIPTION OF THE FIGURES The abstract, as well as the following detailed description, is further understood when read in conjunction with the accompanying figures. For the purpose of illustrating the described methods, the figures show illustrative embodiments of the methods; however, the methods are not limited to the specific modalities described. In the figures: FIG 1 is a schematic of the apalutamide phase III clinical trial study design. ADT = androgen deprivation therapy. Figures 2A through 2B illustrate Kaplan-Meier estimates of radiographic progression-free survival (Figure 2A) and forest plot of radiographic progression-free survival by reference patient characteristics (Figure 2B). Analyzes were performed using a Mantel-Cox zo LAnn / ίζηζ / Ε / γίΛΐ test with stratification by Gleason score at diagnosis (<7 vs. >7), region (North America and European Union vs. all other countries). , and previous treatment with docetaxel (yes vs. no). Figures 3A to 3B illustrate the Kaplan-Meier estimate of overall survival (Figure 3A) and the forest plot of overall survival by reference patient characteristics (Figure 3B). Analyzes were performed using a Mantel-Cox test with stratification by Gleason score on diagnosis (<7 vs. >7), region (North America and European Union vs. all other countries), and prior docetaxel treatment ( yes vs. no). Figure 4 illustrates the Kaplan-Meier estimate of time to cytotoxic chemotherapy. Analyzes were performed using a Mantel-Cox test with stratification by Gleason score on diagnosis (<7 vs. >7), region (North America and European Union vs. all other countries), and prior docetaxel treatment ( yes vs. no). Figure 5 illustrates a Kaplan-Meier estimate of time to PSA progression. Time to PSA progression was the time from the date of randomization to the date of PSA progression, based on prostate cancer Workgroup 2 criteria. Analyzes were performed using a Mantel-Cox test with stratification by Gleason score on diagnosis (<7 vs. >7), region (North America and European Union vs. all other countries), and prior docetaxel treatment ( yes vs. no). Figure 6 shows the Kaplan-Meier calculation of time to second progression-free survival. Second progression-free survival was the time from the date of randomization to the first occurrence of investigator-determined disease progression (PSA progression, imaging progression, or clinical progression) while the patient was receiving a first subsequent therapy. for prostate cancer or death due to any cause, whichever comes first. Analyzes were performed using a MantelCox test with stratification by Gleason score on diagnosis (<7 vs. >7), region (North America and EU vs. all other countries), and prior docetaxel treatment (yes vs. . No). Figure 7 shows the repeated measures mixed-effects analyzes for the mean change from baseline in the FACT-P total score. Error bars are standard errors of the mean. Raw FACT-P scores range from 0 to 156, with higher scores indicating a more favorable health-related quality of life; a change of 6 to 10 points in the total FACT-P score would be the minimally important difference. However, this figure presents mean changes in total scores compared to baseline rather than raw total scores. FACT-P, Functional Assessment of Prostate Cancer Therapy. zq LRnn / ίζηζ / Ε / γίΛΐ DETAILED DESCRIPTION OF THE INVENTION It will be understood that certain features of the invention which, for clarity, are described herein in the context of separate embodiments, may also be provided combined in a single embodiment. That is, unless clearly incompatible or specifically excluded, each individual modality is considered to be combinable with any other modality, and that combination is considered another modality. Conversely, various features of the invention which are described, for brevity, in the context of a single embodiment may furthermore be provided separately or in any sub-combination. Finally, although a modality can be described as part of a series of stages or part of a more general structure, each of said stages can also be considered as an independent modality on its own, combinable with others. The transitional terms comprising, consisting essentially of, and consisting of are intended to connote their generality in accepted meanings in patent language; that is, (i) comprising, being synonymous with, including, containing, or characterized by, inclusive or open-ended and does not exclude additional unenumerated steps or elements of the method; (ii) consisting of excludes any element, step, or ingredient not specified in the claim; and (i¡¡) consisting essentially of limiting the scope of a claim to specified steps or materials and those that do not materially affect the basic and novel feature(s) of the claimed invention. More specifically, the basic and novel features relate to the ability of the method to provide at least one of the benefits described herein, including, but not limited to, the ability to improve male human population survival in relation to the survival of the comparative male human population described elsewhere in the present disclosure. Modalities described in terms of the phrase it comprises (or its equivalent) further provide as modalities those which are independently described in terms of consisting of and essentially consisting of. When a value is expressed as an approximation through the use of the descriptor approximately, it will be understood that the particular value forms another modality. Generally, the use of the term approximately indicates approximations that may vary depending on the desired properties that are intended to be obtained by the described subject matter and should be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of course. In some cases, the number of significant figures used for a particular value can be a non-limiting method of determining the scope of the word approximately. In other cases, the gradations used in a series of values ​​can be used to determine the predicted interval available for the term approximately for each zq LAnn / ίζηζ / Ε / γίΛΐ value. When present, all intervals are inclusive and combinable. That is, references to values ​​indicated in ranges include all values ​​within that range. Unless otherwise specified, the term approximately means a variance of ±10% of the associated value, but additional modalities include those where the variance may be ±5%, ±15%, ±20%, ±25%, or ± 50%. It will be understood that certain features of the invention which, for clarity, are described herein in the context of separate embodiments, may also be provided combined in a single embodiment. That is, unless clearly incompatible or specifically excluded, each individual modality is considered to be combinable with any other modality, and that combination is considered another modality. Conversely, various features of the invention which are described, for brevity, in the context of a single embodiment may furthermore be provided separately or in any sub-combination. Finally, although a modality can be described as part of a series of stages or part of a more general structure, each of said stages can be considered as an independent modality on its own, combinable with others. When presenting a list, unless otherwise stated, it should be understood that each individual element of that list, and each combination of that list, is a separate modality. For example, a list of modalities that appears as A, B, or C, should be interpreted as including the modalities, A, B, C, A or B, A or C, B or C, or A, B or C. . The present invention may be more readily understood by reference to the following description taken in connection with the accompanying figures and examples, all of which form a part of this description. It is to be understood that this invention is not limited to the specific products, methods, conditions, or parameters described or shown herein, and that the terminology used in the present description is for the purpose of describing particular embodiments by way of example only and is not intended to limit any claimed invention. Similarly, unless otherwise specifically stated, any description as to a possible mechanism or mode of action or reason for enhancement is intended to be illustrative only, and the invention herein is not to be limited by correctness or incorrectness of such suggested mechanism or mode of action or reason for improvement. Throughout this text, it is recognized that the descriptions refer to various compounds, compositions, and methods of using such compounds and compositions. That is, where the description describes or claims a feature or modality associated with a composition or a method of using a composition, it is appreciated that such description or claim is intended to extend these features or modality to modalities in each of these contexts (i.e., compositions and methods of use). The androgen receptor (AR) is a member of the nuclear and steroid receptor superfamily. Within this large family of proteins, only five vertebrate steroid receptors are known and they include the androgen receptor, the estrogen receptor, the progesterone zq LRnn / ίζηζ / Ε / γίΛΐ receptor, the glucocorticoid receptor, and the progesterone receptor. of mineralocorticoids. AR is a soluble protein that functions as an intracellular transcriptional factor. AR function is regulated by the binding of androgens, which initiate sequential conformational changes of the receptor that affect receptor-protein interactions and receptor-DNA interactions. AR is expressed primarily in androgen target tissues, such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest level of expression observed in the prostate, adrenal gland, and the epididymis. The AR can be activated by the binding of endogenous androgens, which include testosterone and 5-dihydrotestosterone (5a-DHT). The androgen receptor (AR), located at Xql 1-12, is a 110 kD nuclear receptor that, upon activation by androgens, mediates the transcription of growth-modulating target genes. and the differentiation of the epithelial cells of the prostate. Similar to the other steroid receptors, unbound AR is located primarily in the cytoplasm and associates with a heat shock protein (HSP) complex through interactions with the ligand-binding domain. Upon agonist binding, the AR undergoes a series of conformational changes: heat shock proteins dissociate from the AR, and the transformed AR is dimerized, phosphorylated, and translocated to the nucleus, which is mediated by the localization signal. nuclear. The translocated receptor then binds to the androgen response element (ARE), which is characterized by two 5'-TGTTCT-3' mid-site six nucleotide consensus sequences separated by three random nucleotides and is located in the promoter region or enhancer of RA target genes. Recruitment of other coregulators of transcription (including coactivators and corepressors) and transcriptional machinery further ensures transactivation of AR-regulated gene expression. All of these processes are initiated by ligand-induced conformational changes in the ligand-binding domain. AR signaling is crucial for the development and maintenance of the male reproductive organs, including the prostate gland, since genetic males with AR loss-of-function mutations and genetically engineered mice with AR defects do not develop prostates or prostate cancer. This dependence of prostate cells on AR signaling continues even after neoplastic transformation. Androgen depletion (such as the use of GnRH agonists) continues to be the mainstay of prostate cancer treatment. However, androgen reduction is usually effective for a limited duration and prostate cancer evolves to regain the ability to grow despite low levels of circulating androgens. Castration-resistant prostate cancer (CRPC) is a lethal phenotype and almost all patients will die of prostate cancer. Interestingly, while a small minority of CRPCs avoid the requirement for AR signaling, the vast majority of CRPCs, although often referred to as androgen-independent prostate cancer or hormone-refractory prostate cancer, retain their lineage dependence on the RA signaling. zq LRnn / ίζηζ / Ε / γίΛΐ Prostate cancer is the second most common cause of cancer death in men in the United States, and approximately one in six American men will be diagnosed with the disease in their lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men who present with recurrent disease, which usually manifests first as a rise in plasma prostate-specific antigen (PSA) followed by spread to distant sites. Because prostate cancer cells depend on the androgen receptor (AR) for growth and survival, these men are treated with agents that block testosterone production (eg, GnRH agonists), alone or in combination with antiandrogens (eg, bicalutamide), which antagonize the effect of any residual testosterone in RA. The approach is effective, as evidenced by a reduction in PSA and visible tumor regression (if present) in some patients; however, this is followed by a resurgence as a castration resistant prostate cancer (CRPC) to which most patients will eventually succumb. Recent studies on the molecular basis of CRPC have shown that CRPC continues to be dependent on AR signaling, and that a key mechanism of acquired resistance is an elevated level of AR protein (Nat. Med, 2004, 10, 33-39). AR-targeting agents with activity in castration-resistant or castration-sensitive prostate cancer hold great promise for treating this lethal disease. The course of prostate cancer from diagnosis to death is best categorized as a series of clinical stages based on the extent of disease, hormonal status, and the absence or presence of detectable metastases: localized disease, increased levels of specific antigen prostate cancer (PSA) after radiotherapy or surgery without detectable metastases, and clinical metastases at the castrated or non-castrated stage. Although surgery, radiation, or a combination of both may be curative for patients with localized disease, a significant proportion of these patients present with recurrent disease, as evidenced by elevated PSA levels, which can lead to the development of of metastases, especially in the high-risk group - a transition to the lethal phenotype of the disease. Androgen depletion is the standard treatment with a generally predictable outcome: a decrease in PSA, a period of stability in which the tumor does not proliferate, followed by an increase in PSA and regrowth as in castration-resistant disease. Molecular profiling studies of castration-resistant prostate cancers commonly show increased androgen receptor (AR) expression, which may occur through AR gene amplification or other mechanisms. Antiandrogens are useful for the treatment of prostate cancer during its early phase. However, prostate cancer frequently progresses to a 'hormone refractory' state, in which the disease progresses in the presence of continuous androgen ablation or zq LRnn / ίζηζ / Ε / γίΛΐ antiandrogen therapy. Cases of antiandrogen withdrawal syndrome have also been reported after prolonged antiandrogen therapy. Antiandrogen withdrawal syndrome is commonly observed clinically and is defined in terms of tumor regression or symptomatic relief observed after cessation of antiandrogen therapy. AR mutations that can cause receptor promiscuity and the ability of these antiandrogens to exhibit agonist activity could, at least partially, explain this phenomenon. For example, hydroxyflutamide and bicalutamide act as AR agonists in T877A and W741L / W741C AR mutants, respectively. If prostate cancer cells rendered resistant to castration by AR overexpression appear, certain antiandrogen compounds, such as bicalutamide, have been shown to have a mixed antagonist / agonist profile (Science, May 8, 2009;324 (5928): 787-90). This agonist activity helps explain a clinical observation, termed antiandrogen withdrawal syndrome, whereby approximately 30% of men who show growth on AR antagonists experience a decrease in serum PSA when therapy is discontinued (J Clin Oncol , 1993. Oncol, 1993. 11(8): pp. 1566-72). Prostate Cancer Stages In the early stages of prostate cancer, the cancer is located in the prostate. In these early stages, treatment typically includes surgical removal of the prostate or radiation therapy to the prostate, or observation alone without active intervention therapy in some patients. In the initial stages where prostate cancer is localized and requires intervention, surgery or radiotherapy are curative by eradicating cancer cells. About 30% of the time these procedures fail, and the prostate cancer continues to progress, typically as evidenced by a rising PSA level. Men whose prostate cancers have progressed after these initial treatment strategies are said to have recurrent or advanced prostate cancer. Because prostate cancer cells depend on the androgen receptor (AR) for growth and survival, these men are treated with agents that block testosterone production (eg, GnRH agonists), alone or in combination with antiandrogens (eg, bicalutamide), which antagonize the effect of any residual testosterone in RA. These treatments reduce serum testosterone to levels typical of castration, which generally delays the progression of the disease for a period of time. The approach is effective, as shown by a reduction in PSA and regression of visible tumors in some patients. Eventually, however, this is followed by a resurgence called castration-resistant prostate cancer (CRPC), to which most patients eventually succumb. Castration-resistant prostate cancer (CRPC) is classified as non-metastatic or metastatic, depending on whether or not the prostate cancer has metastasized to other parts of the body. zq LRnn / ίζηζ / Ε / γίΛΐ Estimates from European country-specific registries indicate that approximately 15% to 30% of men diagnosed with prostate cancer had metastatic castration-sensitive prostate cancer (IM) (mCSPC). See, p. eg Flamand V, et al., Prog Uro / . 2008;18:53-59. In the US, patients with mCSPC account for approximately 4% of all prostate cancer diagnoses. Cetin K, et al. Urology 2010;75:1396-1405. This disparity may result from differences in the use of PSA screening in different geographies. Schróder FH, et a / , Eur Uro!. 2012;62:745-752. However, the percentage of men in the US who have mCSPC may increase because there now appears to be a decline in PSA screening after the United States Preventive Services Task Force (USPSTF) ) published their recommendation against PSA selection in 2012. Drazer MW, etal, J Clin. Oncol 2015;33:2416 2423; Lin K, et al. Agency for Healthcare Research and Quality, 2011;no. 12-05160-EF-l. Since prostate cancer cells depend on AR signaling for their proliferation and survival, the standard treatment for patients with mCSPC disease is androgen deprivation therapy (ADT). Androgen deprivation therapy is defined as medical castration (ie, gonadotropin-releasing hormone [GnRHa; agonist or antagonist] analogue) or surgical castration (ie, bilateral orchiectomy). To prevent tumor flare in patients with obvious metastases, a short course of first-generation antiandrogen therapy can be used to reduce the flare in testosterone with initiation of a GnRH agonist. antiandroaens As used herein, the term antiandrogen carries a generally accepted meaning and can refer to a group of hormone receptor antagonist compounds that are capable of preventing or inhibiting the biological effects of androgens in normally responsive tissues in the body. . In some embodiments, an antiandrogen is a small molecule. In some embodiments, an antiandrogen is an AR antagonist. In some modalities, an antiandrogen is a complete antagonist of the AR. In some embodiments, an antiandrogen is a first generation antiandrogen. In some embodiments, an antiandrogen is a second generation antiandrogen. As used herein, the terms AR antagonist and AR inhibitor are used interchangeably herein, and refer to an agent that inhibits or reduces at least one activity of an AR polypeptide. Illustrative AR activities include, but are not limited to, coactivator binding, DNA binding, ligand binding, or nuclear translocation. As used herein, a complete antagonist refers to an antagonist that, at an effective concentration, essentially completely inhibits an activity of an AR polypeptide. As used herein, a partial antagonist refers to a ZQ LRnn / Lznz / Ε / ΥΙΛΙ antagonist which is capable of inhibiting an activity of an AR polypeptide, but which, even at the highest concentration is not a complete antagonist. By essentially completely is meant 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 greater inhibition of the activity of an AR polypeptide. As used herein, the term "first generation antiandrogen" refers to an agent that exhibits antagonistic activity against a wild-type AR polypeptide. However, first-generation antiandrogens differ from second-generation antiandrogens in that first-generation antiandrogens can potentially act as agonists in castration-resistant prostate cancers (CRPCs). Examples of first generation antiandrogens include, but are not limited to, flutamide, nilutamide, and bicalutamide. As used herein, the term "second generation antiandrogen" refers to an agent that exhibits full antagonistic activity against a wild-type AR polypeptide. Second-generation antiandrogens differ from first-generation antiandrogens in that second-generation antiandrogens act as full antagonists in cells expressing high levels of the AR, such as in castration-resistant prostate cancers (CRPC). Illustrative second-generation antiandrogens include 4-[7-(6-cyano-5-tr¡fluorometh¡lp¡r¡d¡n-3-¡l)-8-oxo-6-th¡oxo-5 ,7-D¡azaspiro[3,4]oct-5-¡l]-2fluoro-N-methylbenzamide (also known as apalutamide or JNJ-56021927; CAS No. 956104-40-8); 4-(3-(4-cyano-3-(t¡fluoromethyl)phenyl)-5,5-d¡methyl-4-oxo-2-th¡oxo¡m¡dazol¡d¡ n-l-¡l)-2fluoro-N-methylbenzamide (also known as MDV3100 or enzalutamide; CAS No.: 91508733-1), 4-[7-[4-cyano-3-(trifluoromethyl) phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (RD162; CAS No. 915087-27-3 ) and N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazoll-¡l]propan-2-¡l}-5-(l-hydroxy¡et¡ 1)-1H-pyrazole-3-carboxamide (also known as darolutamide). In some embodiments, a second generation antiandrogen binds to an AR polypeptide at or near the AR polypeptide ligand binding site. zq LRnn / ίζηζ / Ε / γίΛΐ 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazasp¡ro[3.4 ]oct-5-¡l]-2-fluoro-N-methylbenzamide (apalutamide) zQLRnn / Lznz / E / Yi 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxomidazolin-l- ¡l)-2-fluoro-N-methylbenzamide (enzalutamide) 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazasp¡ro[3.4]oct-5- ¡l]-2-fluoroO-Nmethylbenzamide (RD162) N-{(2S)-l-[3-(3-chloro-4~cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl)-lHpyrazole-3-carboxamide (darolutamide). In some embodiments, an antiandrogen contemplated in the methods described herein inhibits AR nuclear translocation, such as darolutamide, DNA binding to androgen response elements, and coactivator recruitment. In some embodiments, an antiandrogen contemplated in the methods described herein does not exhibit agonist activity in AR-overexpressing prostate cancer cells. Apalutamide is a second-generation antiandrogen that binds directly to the ligand-binding domain of the AR, preventing nuclear translocation, binding of the AR to DNA, and modulation of AR target genes, thereby inhibiting tumor growth. and promoting apoptosis. Apalutamide binds with higher affinity to AR than bicalutamide and induces partial or complete tumor regression in bicalutamide-resistant, hormone-sensitive non-castrated human xenograft models (Clegg et al. Cancer Res. Mar 15, 2012 72 ; 1494). Apalutamide lacks the partial agonist activity seen with bicalutamide in the setting of AR overexpression. Darolutamide, BAY1841788 or ODM-201, is an AR antagonist that includes two diastereomers - ORM-16497 and ORM-16555. The chemical name is N-{(2S)-l-[3-(3-chloro-4c¡anofen¡l)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-h¡drox¡ et¡l)-lH-pyrazole-3-carboxamide. It has activity against AR mutants known to confer resistance to other second-generation antiandrogens. Darolutamide binds to AR with high affinity, and prevents subsequent androgen-induced nuclear translocation of AR and transcription of the AR target gene. Matsubara, N., Mukai, H., Hosono, A. et al. Cancer Chemother Pharmacol (2017) 80: 1063. some terms The terms used in the present description carry a commonly accepted meaning, but for the avoidance of doubt, some of the definitions are provided in the present description. The term cancer, as used herein, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, to metastasize (spread). The term prostate cancer, as used herein, refers to a histologically or cytologically confirmed adenocarcinoma of the prostate. The term androgen-reducing therapy (ADT) refers to the reduction of androgen levels in a prostate cancer patient to castrated levels of testosterone (<50 ng / dl). Such treatments may include orchiectomy or the use of gonadotropin-releasing hormone agonists or antagonists. ADT includes surgical castration (orchiectomy) ZQ LRnn / Lznz / Ε / ΥΙΛΙ and / or administration of luteinizing hormone-releasing hormone (LHRH) / gonadotropin-releasing hormone agonists or antagonists to a human. Examples of the GnRH agonist or antagonist are or comprise leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP100, KLH-2109 or triptorelin. In certain embodiments, examples of GnRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin palmoate. The term locally advanced prostate cancer refers to prostate cancer in which all active cancer cells appear to be confined to the prostate and associated or neighboring organs (eg, gallbladder, seminal gland, bladder neck, and rectal wall). ). The term high-risk localized prostate cancer refers to locally advanced prostate cancer that has a probability of developing metastasis or recurrent disease after primary therapy for curative purposes. In some modalities, high risk of developing metastases 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, or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months or < 1 month. In some modalities, high risk of developing metastases is defined as a prostate-specific antigen doubling time (PSADT) < 10 months. In some modalities, high risk of developing metastases is defined by having a high Gleason score or bulky tumor. For the avoidance of doubt, the terms castration-sensitive prostate cancer and hormone-sensitive prostate cancer are equivalent and are used interchangeably. The terms castration-sensitive prostate cancer and hormone-sensitive prostate cancer refer to cancer that responds to androgen deprivation therapy (ADT) either as localized disease, biochemical relapse, or in a metastatic setting. The term castration-sensitive metastatic prostate cancer refers to cancer that has spread (metastasized) to other areas of the body, e.g. eg, to bone, lymph nodes, or other parts of the body in a man, and that responds to androgen deprivation therapy (ADT). The term nonmetastatic castration-sensitive prostate cancer refers to cancer that has not spread (metastasized) in a male, and that is responsive to androgen-reducing therapy (ADT). In some modalities, nonmetastatic castration-sensitive prostate cancer is evaluated by bone scans and computed tomography (CT) or magnetic resonance imaging (MRI) scans.

[0089] The term CRPC as used herein refers to castration resistant prostate cancer. CRPC is prostate cancer that continues to grow despite suppression of the male hormones that fuel the growth of prostate cancer cells. zq LRnn / ίζηζ / Ε / γίΛΐ The term "metastatic castration resistant prostate cancer" refers to castration resistant prostate cancer that has metastasized to other parts of the human body. Metastatic castration sensitive prostate cancer (SCPS), refers to prostate cancer that is still responsive to testosterone suppression therapy. The term NM-CRPC, as used herein, refers to non-metastatic castration resistant prostate cancer. In some modalities, NM-CRPC is evaluated with a bone scan and computed tomography (CT) or magnetic resonance imaging (MRI). The term "metastatic castration-resistant prostate cancer not previously treated with chemotherapy" refers to metastatic castration-resistant prostate cancer that has not been previously treated with a chemotherapeutic agent. The term metastatic castration-resistant prostate cancer post-abiraterone acetate-prednisone treatment refers to metastatic castration-resistant prostate cancer that has already been treated with abiraterone acetate. The term high-risk NM-CRPC refers to the probability that a man with NMCRPC will develop metastases. In some modalities, high risk of developing metastases 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, or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months or < 1 month. In some modalities, high risk of developing metastases is defined as a prostate-specific antigen doubling time (PSADT) < 10 months. In some modalities, high risk of developing metastases is defined as having local-regional recurrence (eg, primary tumor bed, bladder neck, anastomotic site, pelvic lymph nodes). The terms ''co-administration or the like'', as used herein, encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration. , at the same time or at different times. The term pharmaceutical combination, as used in the present description, means a product that results from the mixture 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 ingredients, eg, apalutamide and a coagent, are simultaneously administered to a patient both in the form of a single unit or single dosage form. The term "non-fixed combination" means that the active ingredients, for example, apalutamide and a coagent, are administered to a patient as separate units or separate dosage forms, simultaneously, together, or sequentially without specific intervention time limits, where the administration provides zq LRnn / ίζηζ / Ε / γίΛΐ safe and effective levels of the two active ingredients in the human body. The latter also applies to cocktail therapy, eg the administration of three or more active ingredients. The term FDHT-PET refers to 18F16P-fluoro-5a-dihydrotestosterone positron emission tomography, and is a technique that uses a dihydrotestosterone-based tracer and allows a visual assessment of ligand binding to the androgen receptor in a patient. It can be used to assess the pharmacodynamics of an androgen receptor-directed therapy. The term "continuous daily dosing schedule" refers to the administration of a particular therapeutic agent without any drug discontinuation of the particular therapeutic agent. In some embodiments, the continuous daily dosing schedule for a particular therapeutic agent comprises daily administration of a particular therapeutic agent at approximately the same time each day. The terms treat and treatment refer to the treatment of a patient suffering from a pathological condition and refers to an effect that alleviates the condition by killing cancer cells, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in progress rate, a stop in progress rate, a condition buff, and a condition cure. In addition, treatment is included as a prophylactic measure (ie, prophylaxis). Unless otherwise specified, the terms treat, and treatment refer to all of the described effects, but in other embodiments, the terms may also refer to any one of the described effects, or the exclusion of at least an effect. The term metastasis-free survival or MFS refers to the percentage of subjects in a study who have survived without the cancer spreading for a defined period of time or death. The MFS is usually reported as the time from the start of study enrollment, randomization, or treatment. The MFS is reported for an individual or a study population. In the setting of CRPC treatment with an antiandrogen, an increase in metastasis-free survival is the additional time seen without cancer spread or death, whichever comes first, compared with placebo treatment. In some modalities, the increase in metastasis-free survival is approximately 1 month, approximately 2 months, zq LRnn / ίζηζ / Ε / γίΛΐ approximately 3 months, approximately 4 months, approximately 5 months, approximately 7 months, approximately 8 months , approximately 10 months, approximately 11 months, approximately 14 months, approximately 17 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 13 months, approximately 16 months, approximately 19 months, approximately 20 months, or greater than 20 months . In some modalities, administration of a safe and effective amount of an antiandrogen provides an increase in metastasis-free survival of a male human, optionally, wherein the increase in metastasis-free survival is relative to the median survival rate of a female. population of male humans with non-metastatic castration-resistant prostate cancer, which population has been treated with a placebo. In some modalities, metastasis-free survival refers to the time from randomization to the time of first evidence of BICR-confirmed bone or soft tissue metastases due to any cause, whichever comes first. The term time to metastasis is the time from randomization to the time of analysis showing the first evidence of radiographically detectable bone or soft tissue metastases confirmed by BICR. In some modalities, administration of a safe and effective amount of an antiandrogen provides enhanced antitumor activity as measured by time to metastasis (TMT). The term radiographic progression-free survival is the time from randomization to the first imaging-based documentation of progressive disease or death, whichever came first. A subject is considered to have radiographic progressive disease if the subject has progression of soft tissue lesions as measured by computed tomography or magnetic resonance imaging or a new lesion on bone scan. The term progression-free survival is based on RECIST vl.l and is defined as follows: For subjects with at least one measurable lesion, progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions using the smallest sum in the study as the reference (this includes the reference sum if it is the smallest in the study). In addition to the 20% relative increase, the sum must also demonstrate an absolute increase of at least 5mm. Furthermore, the appearance of one or more new lesions is also considered progression. For subjects with only one non-measurable disease seen on CT or MRI evaluations, unequivocal progression (representative of change in overall disease state) or the appearance of one or more new lesions was considered progression. For new bone lesions detected on bone scans, a second imaging modality (eg, CT or MRI) is required to confirm progression. In some modalities, administration of a safe and effective amount of an antiandrogen provides enhanced antitumor activity as measured by progression-free survival rate. The term prostate cancer-specific survival is defined as the time from randomization to the date of death attributed to prostate cancer. The term PFS2 means the time from the initial randomization of the study to the second progression of the disease or death from any cause. The term time to symptomatic progression is defined as the time from randomization to documentation on the CRF of any of the following (whichever occurs first): (1) development of a skeletal related event (SRE, for its zq LRnn / ίζηζ / Ε / γίΛΐ English): pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to bone; (2) progression of pain or worsening of disease-related symptoms requiring initiation of a new systemic anticancer therapy; or (3) development of clinically significant symptoms due to locoregional tumor progression requiring surgical intervention or radiation therapy. In some modalities, administration of a safe and effective amount of an antiandrogen provides enhanced antitumor activity as measured by time to symptomatic progression. The term time to pain progression is defined as the time from randomization to pain progression (average 2-point increase from baseline in the worst Abbreviated Pain Intensity Questionnaire [BPI] pain intensity -SF] observed at two consecutive assessments >3 weeks apart, with an average worst pain score of >4 in patients who have not had opioid tapering or chronic opioid initiation, whichever comes first). The worst pain from the BPI-SF (item 3) is used for the endpoint of time to pain progression. Scores range from 0 to 10, with lower scores representing lower levels of pain intensity; the minimally important difference was a change of 2. The term time to skeletal related event (SRE) is defined as the time from the date of randomization to the date of the first observation of an SRE (symptomatic pathologic fracture, spinal cord compression, radiation to the bone or surgery to the bone). The term time to chronic opioid use is defined as the time from the date of randomization to the first date of confirmed chronic opioid use. Chronic opioid use was defined as opioid analgesic administration for >3 weeks for oral formulations or >7 days for non-oral formulations. For patients already receiving opioids at study entry, chronic opioid use was defined as a >30% increase in total daily dose of opioid analgesics lasting >3 weeks for oral formulations or >7 days for oral formulations. not oral. Administration of opioid analgesics as needed (eg, non-fixed or scheduled dosing) or prolonged use of opioids for treatment other than the patient's prostate cancer did not require discontinuation of study treatment. The term time to local symptomatic progression is defined as the time from the date of randomization to the date of local symptomatic progression, whichever comes first. Examples of symptomatic local progression include, but are not limited to, urethral obstruction or bladder outlet obstruction. zq LRnn / ίζηζ / Ε / γίΛΐ The term time to ECOG PS grade deterioration is defined as the time from the date of randomization to the first date of deterioration in ECOG PS grade (defined as worsening of ECOG PS grade by at least 1 point). . The term overall survival is defined as the time from randomization to the date of death due to any cause. Survival data for subjects who are alive at the time of analysis were to be censored at the last known date they were alive. In addition, for subjects with no survival after baseline data, the data had to be censored at the date of randomization; in the case of subjects who cannot be followed or who withdraw their consent, the data is redacted as of the last known date alive. In some modalities, administration of a safe and effective amount of an antiandrogen provides enhanced antitumor activity as measured by overall survival. The term time to cytotoxic chemotherapy is defined as the time from randomization to documentation of a new cytotoxic chemotherapy. The term progression-free survival with first subsequent treatment (PFS2) is defined as the time from randomization to investigator-assessed disease progression (PSA, radiographic, symptomatic, or any combination) during the first subsequent anticancer therapy or death (any cause) before the start of the second subsequent anti-cancer treatment, whichever came first. The term time to PSA progression is defined as the time from randomization to the date of PSA progression based on prostate cancer Workgroup 2 criteria. Scher HI, et al. J Clin Oncol 2008;26:1148-1159. The term time to second progression-free survival is defined as the time from randomization to the first occurrence of investigator-determined disease progression (PSA progression, imaging progression, or clinical progression) while the patient was receiving a first subsequent therapy for prostate cancer or death due to any cause, whichever comes first. Progression data for subjects with no documented progression after subsequent therapy are censored at the last known date without progression or the date of death. In some modalities, administration of a safe and effective amount of an antiandrogen provides improved antitumor activity such as progression-free survival with the first subsequent therapy. Prostate-specific antigen response and time to PSA progression are assessed at the time of the primary MFS analysis according to the Prostate Cancer Working Group (PCWG2) criteria. PSA progression time is calculated as the time from randomization to when the criteria for PSA progression according to PCWG2 are met. zq LRnn / ίζηζ / Ε / γίΛΐ The term placebo, as used in the present description, means administration of a pharmaceutical composition that does not include a second generation antiandrogen. In the setting of treatment for metastatic castration-sensitive prostate cancer, men receiving an antiandrogen or placebo will need to continue to maintain castrated testosterone levels either by co-administration of a GnRH agonist / antagonist or orchiectomy. The term survival benefit as used herein means an increase in patient survival from the time of randomization in the trial of the administered drug until death. In some modalities, the survival benefit is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30 , about 35, about 40, about 45, about 50, about 55, about 60, about 80, about 100 months or greater than 100 months. The term delay in symptoms related to disease progression, as used herein, means an increased time to develop symptoms such as pain, urinary obstruction, and quality of life considerations from the time of randomization in the trial of the drug administered. The term 'randomization', referring to a clinical trial, refers to the time at which the patient is confirmed as eligible for the clinical trial and is assigned a treatment arm. The terms kit and item of manufacture are used synonymously. The terms subject and patient and human are used interchangeably. Routes of administration of pharmaceutical compositions The therapeutic agents described herein are administered in any suitable manner or suitable formulation. Suitable routes of administration of therapeutic agents include, but are not limited to, oral and parenteral (eg, intravenous, subcutaneous, intramuscular). All formulations are in doses suitable for administration to a human. An overview of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference for disclosure. Studies looking at safety also seek to identify any potential adverse effects that may result from exposure to the drug. Efficacy is frequently measured zq LRnn / ίζηζ / Ε / γίΛΐ by determining whether an active drug ingredient demonstrates a health benefit over placebo or another intervention when tested in an appropriate setting, such as a strictly controlled clinical trial. Unless otherwise specified, the terms effective amount or therapeutically effective amount, as used herein, refer to an amount of an antiandrogen that is administered to treat the underlying disease or condition including stopping or slowing down the progression of the disease or condition. The term acceptable with respect to a formulation, composition or ingredient, as used herein, means that the beneficial effects of that formulation, composition or ingredient on the general health of the male human being treated substantially outweigh its detrimental effects, to the extent that they exist. In some embodiments, the antiandrogen is present in a solid oral dosage form. In some embodiments, the antiandrogen is formulated as an oral dosage form, an oral unit dosage form, or a solid dosage form (eg, a capsule, tablet, or pill). In some embodiments, for example, the antiandrogen is formulated as a tablet. In some modalities, the antiandrogen is 4-[7-(6-cyano-5-tr¡fluorometh¡lp¡r¡d¡n-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[ 3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide. In some modalities, the antiandrogen is 4-(3(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo¡ midazol¡din-l-¡l)-2-fluoro-N-methylbenzamide. In some embodiments, the antiandrogen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-1]-2 -fluoro-N-methylbenzamide. In some embodiments, the antiandrogen is N{(2S)-l-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-l-yl]propan-2-yl}- 5-(l-h¡drox¡et¡l)-lH-pyrazole-3-carboxamide. Formulations may further comprise two or more of these materials in combinations. Solid oral dosage forms containing the antiandrogen can be provided as soft gelatin capsules as described in US Pat. WO2014113260 and CN104857157, each of which is incorporated herein by reference, or as tablets as described in patent nos. WO2016090098, WO2016090101, WO2016090105 and WO2014043208, each of which is incorporated herein by reference. Suitable techniques for preparing solid oral dosage forms of the present invention are described in Remington's Pharmaceutical Sciences, 18th Edition, edited by AR. Gennaro, 1990, Chapter 89, and in Remington - The Science, and Practice of Pharmacy, 21st Edition, 2005, Chapter 45. 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 approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, or 240 mg of the antiandrogen per unit dosage form or an amount in a range limited by two of these values. zq LRnn / ίζηζ / Ε / γίΛΐ To prepare the pharmaceutical compositions of this invention, the active drug ingredient is thoroughly mixed with a pharmaceutical carrier in accordance with conventional pharmaceutical techniques for preparing compounds, and said carrier may take various forms depending on the form of preparation desired for administration. (eg, oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and Pharmaceutical Society of Great Britain. In solid oral preparations, such as dry powders for reconstitution or inhalation, granules, capsules, caplets, gelcaps, pills, and tablets (each including immediate-release, timed-release, and sustained-release formulations), the carriers and additives Suitable agents include, but are not limited to, diluents, granulating agents, lubricants, binders, glidants, disintegrating agents, and the like. Due to their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated with sugar, gelatin, film, or enteric coated, using standard techniques. Preferably these compositions are in unit dosage form such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosol or liquid sprays, drops or suppositories for oral, intranasal administration. , sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler, or other means of inhalation or insufflation. These formulations were manufactured by conventional formulation techniques. To prepare solid pharmaceutical compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, with conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, release agents and glidants. Suitable diluents include, but are not limited to, starch (i.e., corn, wheat, or potato starch, which can be hydrolyzed), lactose (granulated, spray-dried, or anhydrous), sucrose, sucrose-based diluents. (icing sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, from about 0.1 to 0.2 weight percent corn starch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e., AVICEL microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like. Suitable binders and adhesives include, but are not limited to, gum acacia, guar gum, gum tragacanth, sucrose, gelatin, glucose, starch, and zq LRnn / ίζηζ / Ε / γίΛΐ cellulosic materials (i.e., methylcellulose, sodium carboxymethylcellulose , ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethyl cellulose (i.e. TYLOSE available from Hoechst Celanese], polyethylene glycol, polysaccharides, bentonites, polyvinylpyrrolidone, polymethacrylates, and pregelatinized starch) and the like Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (silicate of aluminum and magnesium), celluloses (such as crosslinked sodium carboxymethyl cellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar gum, locust bean gum, karaya, pectin and tragacanth), crosslinked polyvinylpyrrolidone and the like. Suitable lubricants and anti-seizes include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc, waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax-4000, carbowax-6000 , sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, and the like. Suitable glidants include, but are not limited to, talc, corn starch, silica (i.e., CAB-O-SIL silica available from Cabot, SYLOID silica available from W.R. Grace / Davison, and AEROSIL silica available from Degussa) and the like. similar. Sweeteners and flavorings may be added to the chewable solid dosage forms to improve the palatability of the oral dosage form. In addition, dyes and coatings may be added or applied to the solid dosage form to facilitate drug identification or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide a precise appropriate dose of the pharmaceutical active with a therapeutic release profile. One aspect of the invention is a solid dispersion comprising the antiandrogen. Various techniques exist for preparing the solid dispersions of the invention including melt extrusion (eg hot melt extrusion), spray drying and solution evaporation, in particular hot melt extrusion and spray drying. aspersion; spray drying is preferred. One aspect of the invention is a particle consisting of a solid dispersion as described in the present description. In one aspect of the invention, the particles described in the present description can be obtained, in particular are obtained, by means of spray-drying a mixture generally comprising the antiandrogen and more specifically RNA-509 and HPMCAS in a solvent. appropriate. In one aspect, the particles can be obtained, in particular are obtained, by means of melt extrusion. HPMCAS or Hydroxypropyl Methylcellulose Acetate Succinate or Hypromellose Acetate Succinate (CAS number 71138-97-1) is a mixture of acetic acid and hydroxypropylmethylcellulose monosuccinic acid esters (IUPAC name: cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate). Different differentiated grades are available based on the degree / ratio of zq LRnn / ίζηζ / Ε / γίΛΐ substitution (acetyl content, succinoyl content) and particle size (micronized and granular). In one aspect of the invention, the HPMCAS in the RNA-509 dispersions is HPMCAS LG (granular grade) or HPMCAS LF (micronized grade) (Shin-Etsu Chemical Co., Ltd), in particular HPMCAS LG. Suitable binders for use in the pharmaceutical compositions provided herein include, but are not limited to, starches, cellulose, and their derivatives (eg, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose , hydroxypropyl methylcellulose), polyvinyl-1 pyrrolidone, and mixtures thereof. Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is typically present at about 50 to about 99 percent by weight of the pharmaceutical composition or dosage form. Disintegrants can be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate on storage, while those containing too little may not disintegrate at a desired rate or under desired conditions. Therefore, a sufficient amount of disintegrant that is neither too much nor too little to impair the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based on the type of formulation and is easily discernible to those skilled in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent disintegrant, specifically from about 1 to about 5 weight percent disintegrant. Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, other celluloses, gums, and mixtures of these. Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, polyethylene glycol, other glycols, stearic acid, lauryl sulfate. sodium stearyl fumarate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil ), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Lubricants are typically used in an amount of less than about 1 percent by weight of the pharmaceutical compositions or dosage forms into which they are incorporated. zq LRnn / ίζηζ / Ε / γίΛΐ Compressed tablet formulations can optionally be film coated to provide color, light protection and / or taste masking. Tablets can also be coated to modulate the initiation and / or rate of release in the gastrointestinal tract, to optimize or maximize the patient's biological exposure to the API. Hard capsule formulations can be produced by filling a mixture or granulation of apalutamide or enzalutamide in shells consisting of, for example, gelatin or hypromellose. Soft gel capsule formulations can be produced. Pharmaceutical compositions intended for oral use can be prepared from the solid dispersion formulations and mixed materials described above according to the methods described herein and other methods known in the art for the manufacture of pharmaceutical compositions. These compositions may further contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically acceptable and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, granulating and disintegrating agents, binding agents, glidants, lubricating agents and antioxidants, for example propyl gallate, butylated hydroxyanisole and butylated hydroxytoluene. The tablets may be uncoated or may be film-coated to modify their appearance or may be coated with a functional coating to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained action over a longer period. Compositions for oral use may additionally be presented as capsules (eg hard gelatin), wherein the active ingredient is mixed with an inert solid diluent, eg calcium carbonate, calcium phosphate or starch, or as soft gelatin capsules, wherein the active ingredient is mixed with liquids or semi-solids, eg peanut oil, liquid paraffin, fractionated glycerides, surfactants or olive oil. The aqueous suspensions contain the active materials in admixture with suitable excipients for the manufacture of aqueous suspensions. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. In certain embodiments of the invention, the pharmaceutical compositions of the invention include a diluent, disintegrant, salt, lubricant, glidant, and film coating system, at 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 zq LRnn / ίζηζ / Ε / γίΛΐ about 4%w / w, from about 0 %w / w, from approximately 0%w / w to approximately 2%w / w and from approximately 1%w / w to approximately 5%w / w respectively, or from approximately 18%w / w to approximately 40%w / w, from approximately 7%w / w to approximately 15%w / w, from approximately 7%w / w to approximately 18%w / w, from approximately 1.0%w / w to approximately 3.0%, from approximately 0.1%w / w to approximately 1.0%w / w, and from about 2.0%w / w to about 4.0%w / w, respectively. In certain embodiments, the solid dispersion formulations are mixed with a diluent, one or more disintegrating agents, lubricants, and glidants. An exemplary mixed composition or oral dosage form includes mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silica, sodium stearyl fumarate, and magnesium stearate. 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 of these. The combination of salts and disintegrants is present at a concentration of from about 5% w / w to about 35% w / w of the final pharmaceutical composition. In certain embodiments, the inactive ingredients of the core tablet are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropylmethylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. In other embodiments, tablets are finished with a film coating consisting of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. In other embodiments, a single unit dosage of the pharmaceutical composition comprises, consists of, or consists essentially of about 60 mg of apalutamide. In some embodiments, multiple doses of the single unit dosage pharmaceutical composition comprising, consisting of, or consisting essentially of about 60 mg of apalutamide, eg, 4 single or multiple unit dosage forms are administered to the human. The total daily dose of apalutamide may be approximately 240 mg per day. In some embodiments, a single unit dosage of the pharmaceutical composition comprises, consists of, or consists essentially of about 40 mg of enzalutamide. In some embodiments, multiple doses of the single unit dosage pharmaceutical composition are administered comprising, consisting of, or consisting essentially of about 40 mg of enzalutamide, e.g. eg, 4 single or multiple unit dosage forms, to human. The total daily dose of enzalutamide may be approximately 160 mg per day. In still other embodiments, a single unit dosage of the pharmaceutical composition comprises, consists of, or consists essentially of about 300 mg of darolutamide. In some embodiments, multiple doses of the zq LRnn / ίζηζ / Ε / γίΛΐ pharmaceutical composition are administered in a single unit dosage comprising, consisting of, or consisting essentially of about 300 mg of darolutamide, e.g. eg, 2 single or multiple unit dosage forms, to human. The total daily dose of darolutamide may be approximately 600 mg twice daily. The total daily dose of darolutamide may be approximately 1200 mg per day. All formulations for oral administration are in a dosage form suitable for such administration. Dosage methods and treatment regimens In one aspect described herein are methods of treating metastatic castration-sensitive prostate cancer in a male human, comprising, consisting of, or consisting essentially of administering a therapeutically effective amount of an antiandrogen to a male human with metastatic castration-sensitive prostate cancer, wherein the antiandrogen is at least one of: 4-[7-(6-cyano-5-trifluorometh¡lp¡r¡d¡n-3-¡l)-8 -oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide, 4-(3-(4-cyano-3-(tr¡ fluoromethyl)phenyl)-5,5-dimethyl-4-oxo2-thioxoimdazol¡d¡n-l-¡l)-2-fluoro-N-methylbenzamide, 4-[7- [4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo5,7-diazaspiro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide, or N- {(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l¡l]propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole -3-carboxamide. In the following description, methods for treating metastatic castration-sensitive prostate cancer may alternatively be mentioned as methods for treating a male human having metastatic castration-sensitive prostate cancer. For the sake of brevity, each of the possible alternatives is not broken down, but each of them is considered separately as if they had a complete description. Also described herein are methods for the treatment of metastatic castration-sensitive prostate cancer in male humans essentially consisting of administering a therapeutically effective amount of an antiandrogen to a male human with metastatic castration-sensitive prostate cancer, in where the antiandrogen is one or more of: 4-[7-(6-cyano-5-tnf¡uoromet¡lp¡nd¡ntr¡fluoromet¡lp¡nd¡n-3-yl)-8-oxo- 6-thioxo-5,7diazaspiro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl )-5,5-d¡methyl-4oxo-2-thioxo¡m¡dazol¡din-l-¡l)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano- 3-(trifluoromethyl)phenyl]-8-oxo6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide or N -{(2S)-l-[3-(3-chloro-4-cyanophen¡l)lH-pyrazole-l-¡l]propan-2-¡l}-5-(l-hidrox¡et¡l) -1H-p¡razole-3-carboxamide. In another aspect described herein, administration of the antiandrogen provides an increase in overall survival of male humans relative to the overall survival rate of a comparative population of male humans with metastatic castration-sensitive prostate cancer, at said comparative population has been given a placebo in combination with an androgen deprivation therapy, the placebo has ZQ LRnn / Lznz / Ε / ΥΙΛΙ been administered before or during antiandrogen administration. In other modalities, the comparative population has not received treatment. In another aspect described herein, administration of the antiandrogen provides an increase in overall survival of male humans relative to the overall survival rate of a comparative population of male humans with metastatic castration-sensitive prostate cancer, at said Comparative population has been administered an androgen deprivation therapy. In certain embodiments, administration of the antiandrogen provides an increase in overall survival of male humans relative to the overall survival rate of a comparative population of male humans with castration-sensitive metastatic prostate cancer, said comparative population having received no treatment. . In certain embodiments, administration of the antiandrogen provides an increase in overall survival of male humans relative to the overall survival rate of a comparative population of male humans with castration-sensitive metastatic prostate cancer, such a comparative population has been administered a first-generation antiandrogen, with or without androgen deprivation therapy. In some modalities, the population to which the antiandrogen is administered and the comparator population were pretreated with the same or a similar pretreatment regimen. In additional modalities, administration of the antiandrogen provides an increase in progression-free survival of male humans relative to the progression-free survival rate of a comparative population of male humans with castration-sensitive metastatic prostate cancer, said comparative population being you have been given a placebo in combination with androgen deprivation therapy. In another aspect described herein, administration of the antiandrogen provides an increase in progression-free survival of male humans relative to the progression-free survival rate of a comparative population of male humans with metastatic castration-sensitive prostate cancer, said comparative population has previously been administered an androgen deprivation therapy. In certain modalities, administration of the antiandrogen provides an increase in progression-free survival of male humans relative to the progression-free survival rate of a comparative population of male humans with castration-sensitive metastatic prostate cancer, such a comparative population has not previously received treatment. In certain embodiments, administration of the antiandrogen provides an increase in progression-free survival of male humans relative to the rate of progression-free survival of a comparative population of male humans with castration-sensitive metastatic prostate cancer, said comparative population being you have previously been given a first-generation antiandrogen, with or without androgen deprivation therapy. Again, in preferred zq LRnn / ίζηζ / Ε / γίΛΐ modalities, the population to which the antiandrogen is administered and the comparator population have previously undergone the same or a similar prior treatment regimen. In one aspect, methods of treating metastatic castration-sensitive prostate cancer comprising, consisting of, or essentially consisting of administering a safe and effective amount of an antiandrogen to a male human with a prostate cancer are disclosed herein. metastatic castration-sensitive, where the antiandrogen is administered orally. In some modalities, the antiandrogen is administered daily. In some modalities, the antiandrogen is administered twice daily. In some modalities, the antiandrogen is administered three times daily. In some modalities, the antiandrogen is administered four times daily. In some modalities, the antiandrogen is administered every other day. In some modalities, the antiandrogen is administered weekly. In some modalities, the antiandrogen is administered twice a week. In some modalities, the antiandrogen is administered every other week. In some embodiments, the antiandrogen is administered orally on a continuous daily dosing schedule. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at suitable intervals, for example, as two, three, four or more sub-doses per day. In some modalities, the antiandrogen is conveniently presented in divided doses that are administered simultaneously (or for a short period of time) once daily. In some embodiments, the antiandrogen is conveniently presented in divided doses that are administered in equal parts twice daily. In some modalities, the antiandrogen is conveniently presented in divided doses that are administered in equal parts three times daily. In some modalities, the antiandrogen is conveniently presented in divided doses that are administered in equal parts four times daily. In certain embodiments, the desired dose may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fractional unit dosages over the course of the day such that the total amount of antiandrogen delivered by the Fractional unit dosages over the course of the day provide the total daily dosages. In additional modalities, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 is administered daily -fluoro-N-methylbenzamide) to the male human. In other additional modalities, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 is administered orally ]oct-5-¡l]-2-fluoro-N-methylbenzamide) to the male human. In some embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro- N-methylbenzamide orally to the human male on a continuous daily dosing schedule. In additional modalities, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide is administered daily to male human. In ZQ LRnn / Lznz / Ε / ΥΙΛΙ other additional modalities, 4-(3-(4-cyano-3-(tr¡fluoromet¡l)feniI)-5,5-d¡met¡l-4- oxo-2tioxo¡m¡dazol¡d¡n-l-¡l)-2-fluoro-N-methylbenzam¡de orally to the male human. In some modalities, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazole is administered d¡n-l-¡l)2-fluoro-N-methylbenzamide orally to the human male on a continuous daily dosing schedule. In other modalities, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro is administered -N-methylbenzamida daily to the human male. In other additional modalities, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7diazaspiro[3.4]oct-5-¡ is administered l]-2-fluoro-N-methylbenzamide orally to the human male. In some modalities, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct- is administered 5-¡l]2-fluoro-N-methylbenzamide orally to the human male on a continuous daily dosing schedule. In other modalities, N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-lyl]propan-2-yl}-5-(l-hydroxyl) is administered et¡l)-lH-p¡razol-3-carboxam¡dida daily to the human male. In additional other modalities, N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-l-yl]propan-2-yl}5-(l-hydroxyethyl) is administered -1H-p¡razole-3-carboxam¡de orally to the male human. In some embodiments, N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl) is administered -lHpyrazole-3-carboxamide orally to the human male on a continuous daily dosing schedule. In some embodiments, the antiandrogen is a second generation antiandrogen. In certain embodiments, the antiandrogen is enzalutamide, apalutamide, RD-162, or darolutamide. In some modalities, the antiandrogen is apalutamide. In some modalities, the antiandrogen is enzalutamide. In some modalities, the antiandrogen is RD-162. In some modalities, the antiandrogen is darolutamide. Generally, the doses of antiandrogen used for the treatment of the diseases or conditions in humans described herein are typically in the range of 10 mg to 1000 mg per day. In some embodiments, the antiandrogen is orally administered to the human at a dose of from about 30 mg per day to about 1200 mg per day. In some embodiments, the antiandrogen is orally administered to the human at a dose of about 30 mg per day to about 600 mg per day. In some embodiments, the antiandrogen is orally administered to the human at a dose of about 30 mg per day, about 60 mg per day, about 90 mg per day, about 120 mg per day, about 160 mg per day, about 180 mg approximately 240 mg per day, approximately 300 mg per day, approximately 390 mg per day, approximately 480 mg per day, approximately 600 mg per day, approximately 780 mg per day, approximately 960 mg per day, or approximately 1200 mg per day . In certain embodiments, doses of the antiandrogen used for treatment of the diseases or conditions in humans described herein may have a zq LRnn / ίζηζ / Ε / γίΛΐ range of 30 to 40 mg / day, 40 to 50 mg / day, 50 to 60 mg / day, 60 to 70 mg / day, 70 to 80 mg / day, 80 to 90 mg / day, 90 to 100 mg / day, 100 to 120 mg / day, 120 to 140 mg / day , 140 to 160 mg / day, 160 to 180 mg / day, 180 to 200 mg / day, 200 to 220 mg / day, 220 to 240 mg / day, 240 to 260 mg / day, 260 to 280 mg / day, 280 to 300 mg / day, 300 to 320 mg / day, 320 to 340 mg / day, 340 to 360 mg / day, 360 to 380 mg / day, 380 to 400 mg / day, 400 to 420 mg / day, 420 at 440 mg / day, 440 to 460 mg / day, 460 to 480 mg / day, or any range defined by two or more of these ranges, or any individual value quoted in these ranges. In some embodiments, the doses of the antiandrogen used for the treatment of the diseases or conditions in humans described herein may range from 0.3 to 0.4 mg / kg / day, 0.4 to 0.5 mg / kg / day, 0.5 to 0.6 mg / kg / day, 0.6 to 0.7 mg / kg / day, 0.7 to 0.8 mg / kg / day, 0.8 to 0.9 mg / kg / day, 0.9 to 1 mg / kg / day, 1 to 1.2 mg / kg / day, 1.2 to 1.4 mg / kg / day, 1.4 to 1.6 mg / kg / day, 1.6 to 1.8 mg / kg / day, 1.8 to 2 mg / kg / day, 2 to 2.2 mg / kg / day, 2.2 to 2.4 mg / kg / day, 2.4 to 2.6 mg / kg / day, 2.6 to 2.8 mg / kg / day, 2.8 to 3.0 mg / kg / day, 3.0 to 3.2 mg / kg / day, 3.2 to 3.4 mg / kg / day , 3.4 to 3.6 mg / kg / day, 3.6 to 3.8 mg / kg / day, 3.8 to 4.0 mg / kg / day, 4.0 to 4.2 mg / kg / day, 4.2 to 4.4 mg / kg / day, 4.4 to 4.6 mg / kg / day, 4.6 to 4.8 mg / kg / day, or any range defined by two or more of these ranges, or any individual value quoted in these ranges. In additional modalities, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2- is administered fluoro-N-methylbenzamide orally to the male human at a dose of about 30 mg per day to about 480 mg per day. In other additional modalities, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct5-¡l]- is administered 2-Fluoro-N-methylbenzamide orally to the male human at a dose of about 180 mg per day to about 480 mg per day. In certain modalities, 4-[7-(6-cyano5-tnfluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6-thioxo-5,7-diazasp¡ro[3.4]oct- is administered 5-l]-2-fluoro-N-methylbenzamide orally to the male human at a dose of: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In some modalities, 4-[7-(6-cyano-5t¡fluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6-t¡oxo-5,7-diazasp¡ro[ is administered 3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide orally to the male human at a dose of approximately 240 mg per day. In some modalities, the dose of 4-[7-(6-cyano-5-tr¡fluoromethylp¡ridin-3-¡l)-8-oxo-6thioxo-5,7-d¡azasp¡ro[3.4 ]oct-5-¡l]-2-fluoro-N-methylbenzam¡de is reduced to 180 mg per day if the human male experiences toxicity greater than or equal to Grade 3 toxicity. Alternatively, or in addition, the Original dosage may be maintained until toxicity symptoms improve to less than or equal to Grade 1 toxicity; thereafter, the dosage can be reduced as indicated herein or resumed at the original dosage with continuous monitoring. In some modalities, the dose of 4-[7-(6-cyano-5-tr¡fluorometh¡lp¡r¡din-3-¡l)-8-oxo-6-thioxo-5,7diazaspiro [3.4]oct-5-¡l]-2-fluoro-N-meth¡lbenzam¡da is reduced to 180 mg per day if the human male zq LRnn / ίζηζ / Ε / γίΛΐ experiences an intolerable side effect. In some modalities, the dose of 4-[7-(6-cyano-5t¡fluoromethylpyrid¡n-3-¡l)-8-oxo-6-thioxo-5,7-d¡azasp¡ro[3.4 ]oct-5-¡l]-2-fluoro-N-methylbenzam¡de is reduced to 120 mg per day if the male human experiences toxicity greater than or equal to Grade 3 toxicity. Alternatively, or in addition to the original dosage May be maintained until toxicity symptoms improve to toxicity less than or equal to Grade 1 toxicity; thereafter, the dosage can be reduced as indicated herein or resumed at the original dosage with continuous monitoring. In some modalities, the dose of 4-[7-(6-cyano-5t¡fluoromethylpyrid¡n-3-¡l)-8-oxo-6-thioxo-5,7-d¡azasp¡ro[3.4 ]oct-5-¡l]-2-fluoro-N-methylbenzam¡de is reduced to 120 mg per day if the male human experiences an intolerable side effect. In some modalities, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4oxo-2-thioxoimidazolidin-l-il)- is administered 2-fluoro-N-methylbenzamide orally at a dose of approximately 160 mg per day. In some modalities, more than 160 mg per day of enzalutamide is administered. In some modalities, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6thioxo-5,7-diazasp¡ro[3.4]oct-5-¡l is administered ]-2-fluoro-N-methylbenzamide orally to the human male at a dose of about 30 mg per day to about 480 mg per day. In other additional modalities, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5yl]- is administered. 2-Fluoro-N-methylbenzamide orally to the male human at a dose of about 180 mg per day to about 480 mg per day. In certain modalities, 4-[7-[4cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazasp¡ro[3.4]oct- 5-1]-2-fluoro-N-methylbenzamide orally to the male human at a dose of: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In some modalities, 44-[7-[4cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-d¡azasp¡ro[3.4] is administered oct-5-1]-2-fluoro-N-methylbenzamide orally to the human male at a dose of approximately 240 mg per day. In some embodiments, N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-¡l]propan-2¡l}-5-(l-h¡ droxyet¡l)-lH-pyrazole-3-carboxamide is administered orally at a dose of approximately 1200 mg per day. In some modalities, more than 1200 mg per day of N-{(2S)-1-[3-(3-chloro4-cyanophenyl)-1H-pyrazol-1-1]propan- 2-¡l}-5-(l-hydroxyet¡l)-1H-p¡razole-3-carboxamide. In certain modalities where no improvement in the disease state or condition in the human is observed, the daily dose of the antiandrogen is increased. In some modalities, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In some modalities, a three times daily dosing schedule is used to increase the amount of the antiandrogen that is administered. In some embodiments, the amount of antiandrogen administered to the human varies depending on factors such as, but not limited to, condition and severity of the disease zq LRnn / ίζηζ / Ε / γίΛΐ or condition, and identity (eg, weight) of the human, and the particular additional therapeutic agents being administered (if applicable). In some embodiments, the male human received at least one prior cancer treatment therapy, wherein the prior cancer treatment therapy is radiation, surgical intervention, or docetaxel therapy. In some embodiments, the male human has no prior treatment. In some modalities, the antiandrogen is administered in combination with androgen deprivation therapy. In additional embodiments, the antiandrogen is administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist. In still other embodiments, the at least one GnRH agonist or antagonist is or comprises leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100 , KLH-2109 or triptorelin. Clinicians may prescribe GnRH agonists in accordance with instructions, recommendations, and practices. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is leuprolide. In some modalities, leuprolide is administered as a depot injection at a dose of approximately 7.5 mg every 4 weeks or 22.5 mg every 3 months or approximately 30 mg every 4 months or approximately 45 mg every 6 months. In some embodiments, leuprolide is administered in about 0.01 mg to about 200 mg of leuprolide over a period of about 3 days to about 12 months, preferably about 3.6 mg of leuprolide over a period of about 3 days to about 12 months. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is buserelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is naferelin. 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 about 50 mg of histrelin acetate in a 12-month period of histrelin acetate or about 50 pg per day of histrelin acetate. In some embodiments, the GnRH agonist or antagonist is goserelin. In some modalities, goserelin is administered as a subcutaneous implant at a dose of approximately 3.6 mg every 4 weeks or approximately 10.8 mg every 12 weeks. In some embodiments, goserelin is administered in about 0.01 mg to about 20 mg of goserelin over a period of about 28 days to about 3 months, preferably about 3.6 mg 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 modalities, degarelix is ​​administered as a subcutaneous injection at a dose of approximately zq LRnn / ίζηζ / Ε / γίΛΐ 240 mg followed by approximately 80 mg given every 4 weeks. In some embodiments, the GnRH agonist or antagonist is ozarelix. In some embodiments, the GnRH agonist or antagonist is ozarelix. In some embodiments, the GnRH agonist or antagonist is ABT-620 (elagolix). In some embodiments, the GnRH agonist or antagonist is TAK-385 (relugolix). In some embodiments, the GnRH agonist or antagonist is EP-100. In some embodiments, the GnRH agonist or antagonist is KLH-2109. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is triptorelin. In some embodiments, triptorelin is administered in about 0.01 mg to about 20 mg of triptorelin over a period of about 1 month, preferably about 3.75 mg of triptorelin over a 1-month period. In certain modalities, the antiandrogen is used in combination with bilateral orchiectomy. In certain modalities, the antiandrogen is administered after bilateral orchiectomy. In other additional modalities, 4-[7-(6-cyano-5-tr¡fluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6thioxo-5,7-d¡azasp¡ ro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is not co-administered with. (a) a drug that is a strong inhibitor of CYP2C8 or CYP3A4; (b) a drug that is primarily metabolized by CYP3A4, CYP2C19, or CYP2C9; (c) a medicament that is a substrate of UDPglucuronosyl transferase (UGT); or (d) a drug that is a substrate of P-glycoprotein, BCRP, or OATP1B1. In certain embodiments, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7diazaspiro[3.4] oct-5-¡l]-2-fluoro-N-methylbenzamide is not co-administered with a drug that is a strong inhibitor of CYP2C8 or CYP3A4. In certain embodiments, 4-[7-(6-cyano-5-trifluorometh¡lp¡rid¡n-3-¡l)8-oxo-6-thioxo-5,7-d¡azasp¡ro[ 3.4]oct-5-¡l]-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-trifluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6-thioxo-5,7-d¡azasp ¡ro[3.4]oct-5-¡l]-2-fluoro-N-methylbenzamide is not co-administered with a drug that is a substrate of UDP-glucuronosyl transferase (UGT); or (d) a drug that is a substrate of P-glycoprotein, BCRP, or OATP1B1. A non-limiting example of a strong CYP2C8 inhibitor is gemfibrozil. Non-limiting examples of strong CYP3A4 inhibitors include boceprevir, aprepitant, clarithromycin, conivaptan, grapefruit juice, indinavir, lopinavir, itraconazole, mibefradil, ketoconazole, nefazodone, ritonavir, posaconazole, nelfinavir, saquinavir, conivaptan, telaprevir, boceprevir, telithromycin, clarithromycin, voriconazole, clotrimazole, diltiazem, erythromycin, fluconazole, verapamil, and troleandomycin. Non-limiting examples of moderate to strong CYP3A4 inducers include avasimibe, St. John's wort, carbamazepine, efavirenz, phenytoin, etravirine, bosentan, nafcillin, rifampin, modafinil, rifabutin, and barbiturates. A non-limiting example of a drug that is primarily metabolized by CYP3A4 is midazolam. A non-limiting example of a drug primarily metabolized zq LRnn / ίζηζ / Ε / γίΛΐ by CYP2C19 is omeprazole. A non-limiting example of a drug that is primarily metabolized by CYP2C9 is S-warfarin. A non-limiting example of a drug that is a P-glycoprotein substrate is fexofenadine. A non-limiting example of a drug that is a BCRP substrate is rosuvastatin. A non-limiting example of a drug that is a substrate of OATP1B1 is rosuvastatin. In another aspect, methods of treating metastatic castration-sensitive prostate cancer in a male human are provided herein, comprising, consisting of, or consisting essentially of: (a) determining whether the male human has metastatic castration-sensitive prostate cancer to castration; and (b) administering an antiandrogen to a male human in a therapeutically effective amount for the treatment of metastatic castration-sensitive prostate cancer, wherein the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3- yl)-8-oxo-6-thioxo5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl )phenyl)-5,5dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4 -cyano-3(t¡fluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-d¡azaspiro[3.4]oct-5-yl]-2-fluoro-N-met ¡lbenzamide or N-{(2S)l-[3-(3-chloro-4-cyanophenyl)-1H-p¡razol-l-yl]propan-2-¡l}-5-(l-hydrox ¡et¡l)-lH-p¡razole-3-carboxamide. Treatment methods involving an approved drug product The present disclosure further provides a method of treating metastatic castration-sensitive prostate cancer in a male human comprising administering a drug product comprising apalutamide to a male human with metastatic castration-sensitive prostate cancer in an amount described on a drug product label for said drug product. In some embodiments, the approved drug product comprising apalutamide is an ANDA drug product, a new drug application supplemental drug product, or a 505(b)(2) drug product. In certain modalities, the method is clinically proven to be safe and / or effective. In certain modalities, the method is clinically proven to be safe. In certain modalities, the method is clinically proven to be effective. The term, drug product or approved drug product is a product containing an active drug ingredient that has been approved for marketing for at least one indication by a governmental authority, for example, the Food and Drug Administration or similar authority in other countries. Similarly, drug product label or label refers to information provided to a patient that provides relevant information regarding the zq LRnn / ίζηζ / Ε / γίΛΐ drug. This information includes, without limitation, one or more of the drug description, clinical pharmacology, indications (uses for the drug product), contraindication (who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and elderly patients, how the drug is supplied, patient safety information, or any combination of these. In certain embodiments, the drug product label or label provides an instruction for use in a patient with metastatic castration-sensitive prostate cancer. In other embodiments, the label or drug product label identifies apalutamide as a regulatory approved chemical entity. In additional other modalities, the label comprises data for superior efficacy in improving radiographic progression-free survival or overall survival relative to placebo. In yet other embodiments, the label instructs a patient or physician to administer apalutamide if the patient has metastatic castration-sensitive prostate cancer. The term Reference Listed Drug (RLD) is a drug product against which new generic versions are compared to show that they are bioequivalent. 1 / ^21 CFR 314.3(b)). It is also a medicinal product whose marketing has been authorized by a Member State of the European Union or the Commission on the basis of a completed file, that is, with the presentation of quality preclinical and clinical data in accordance with articles 8(3 ), 10a, 10b or 10c of Directive 2001 / 83 / EC and to which the marketing authorization application for a generic / hybrid medical product refers, through demonstration of bioequivalence, usually through the presentation of bioavailability studies suitable. In the United States, a company seeking approval to market a generic equivalent must refer to the RLD in its abbreviated new drug application (ANDA). For example, an ANDA applicant relies on the FDA's conclusion that a previously approved drug, i.e., the RLD, is safe and efficacious, and must demonstrate, among other things, that the proposed generic drug is in certain ways same as RLD. Specifically, with limited exceptions, a drug for which an ANDA is filed must have, among other things, the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and ( with certain allowable differences) labeled than the RLD. The RLD is the listed drug to which the ANDA applicant must compare their proposed ANDA drug and demonstrate that both are the same with respect to active ingredient(s), dosage form, route of administration, concentration, labeling and conditions of use, among other characteristics. In the e-orange book there is a column for RLDs and a column for referenced standards. In the printed version of the orange book, RLDs and reference standards are identified by a specific symbol. In the case of an ANDA based on an approved eligibility petition (an ANDA zq LRnn / ίζηζ / Ε / γίΛΐ petitioned), the reference listed drug is generally the listed drug referenced in the approved eligibility petition . A reference standard is the FDA-selected drug product that an applicant seeking ANDA approval must use to conduct the in vivo bioequivalence study required for approval. Generally, the FDA selects a single reference standard that ANDA applicants must use in live bioequivalence testing. The FDA will normally select the reference listed drug as the reference standard. However, in some cases (eg, when the reference listed drug has been withdrawn from sale and the FDA has determined that it has not been withdrawn for safety or efficacy reasons, and the FDA selects an ANDA as the standard of reference), the reference listed drug and the reference standard may be different. The FDA identifies reference listed drugs on the prescription drug product, over-the-counter (OTC) drug product, and discontinued drug product lists. Listed drugs identified as reference listed drugs represent drug products that an applicant can rely on to apply for ANDA approval. The FDA attempts to periodically update the reference listed drugs identified on the prescription drug product, OTC drug product, and discontinued drug product lists, as appropriate. The FDA also identifies reference standards on the Prescription Drug Product and OTC Drug Product lists. The listed drugs identified as reference standards represent the FDA's best judgment at this time as to the appropriate comparator for conducting the in vivo bioequivalence studies required for approval. In some cases, when the FDA has not designated a listed drug as a reference listed drug; the listed drug can be protected from generic competition. If the FDA has not designated a reference listed drug for a drug product that the applicant intends to duplicate, the potential applicant may ask the FDA to designate a reference listed drug for that drug. FDA may, on its own initiative, select a new reference standard when doing so will help ensure that generic drug applications can be submitted and reviewed, for example, if the currently listed drug selected as the reference standard has been Withdrawn from sale for reasons other than safety and efficacy. In Europe, applicants identify on the application form their generic / hybrid drug product, which is the same as an ANDA or Supplemental NDA (sNDA) drug product, the reference drug product (product name, strength, dosage form, MAH, first authorisation, Member State / Community), which is synonymous with an RLD, as follows: zq LRnn / ίζηζ / Ε / γίΛΐ 1. The medicinal product that is or has been authorized in the European Economic Area (EEA), used as the basis to demonstrate that the data protection period defined in the European pharmaceutical legislation has expired. This reference medicinal product, identified for calculating the expiration of the data protection period, may be for a different strength, dosage form, route of administration or presentation than the generic / hybrid medicinal product. 2. The medicinal product, whose file is cross-referenced in the generic / hybrid application (product name, strength, dosage form, MAH, marketing authorization number). This reference medicinal product may have been authorized through separate procedures and under a different name than the identified reference medicinal product to calculate the expiration of the data protection period. The product information for this reference medicinal product will, in principle, serve as the basis for the claimed product information for the generic / hybrid medicinal product. 3. The medicinal product (product name, strength, dosage form, MAH, Member State of origin) used for the bioequivalence study(s) (where applicable). The different abbreviated approval routes for drug products under the FD&C Act include the abbreviated approval routes described in section 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 23 355(b)(2), respectively). According to the FDA (https: / / www.fda.gov / downloads / Drugs / GuidanceComplianceRegulatoryInformation / Guidances / UCM579751.pdf), the contents of which are incorporated herein by reference), NDAs and ANDAs can be divided into the following four categories: (1) An independent NDA is an application submitted pursuant to section 505(b)(l) and approved pursuant to section 505(c) of the FD&C Act that contains comprehensive reports of safety and efficacy investigations conducted by or to applicants, or for which the applicant has the right of reference or use. (2) A 505(b)(2) application is an NDA filed pursuant to section 505(b)(l) and approved pursuant to section 505(c) of the FD&C Act that contains comprehensive reports of investigations of safety and efficacy, where at least part of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a reference or use right. zq LRnn / ίζηζ / Ε / γίΛΐ (3) An ANDA is an application for a duplicate of a previously approved drug product that was submitted and approved pursuant to section 5050) of the FD&C Act. An ANDA relies on the FDA's conclusion that the previously approved drug product, that is, the Reference Listed Drug (RLD), is safe and efficacious. An ANDA should generally contain information to demonstrate that the proposed generic product (a) is the same as the RLD with respect to active ingredient(s), conditions of use, route of administration, dosage form, resistance and labeling (with certain allowable differences) and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are necessary to establish the safety and efficacy of the proposed product. (4) A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient) and for which the FDA has determined, in response to a petition filed under section 5O50)(2)(C) of the FD&C Act (petition for appropriateness), that studies are not needed to establish the safety and efficacy of the proposed drug product. A scientific premise underlying the Hatch-Waxman amendments is that a drug product approved in an ANDA pursuant to section 5050) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent may be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified on the label. In contrast to an ANDA, a 505(b)(2) application allows for greater flexibility in terms of proposed product characteristics. A 505(b)(2) application will not necessarily be classified as therapeutically equivalent to the listed drug to which it refers once approved. The term "therapeutically equivalent to a reference listed drug" means that the drug product is a generic equivalent, i.e. pharmaceutical equivalents, of the reference listed drug product and as such is classified by the FDA as an AB therapeutic equivalent of the listed drug product whereby actual or potential bioequivalence issues have been resolved with appropriate in vivo and / or in vitro evidence supporting bioequivalence. Pharmaceutical equivalents refers to drug products in dosage forms and routes of administration that contain identical amounts of the identical active drug ingredient to the reference listed drug. ZQ LRnn / Lznz / Ε / ΥΙΛΙ The FDA classifies as therapeutically equivalent products that meet the following general criteria: 1) are approved as safe and effective; (2) are pharmaceutical equivalents in that (a) they contain identical amounts of the same active pharmacological active ingredient in the same dosage form and route of administration, and (b) meet pharmacopoeial or other applicable standards for strength, quality, purity, and identity; (3) are bioequivalent in that (a) they do not present a known or potential bioequivalence problem and meet an acceptable in vitro standard or (b) if they do present a known or potential problem, they are shown to meet an appropriate bioequivalence standard ; (4) are properly labeled; and (5) are manufactured in accordance with current good manufacturing practice standards. The term bioequivalent or bioequivalence is the absence of a significant difference in the rate and extent to which the active ingredient or active entity in pharmaceutical equivalents or pharmaceutical alternatives is available at the site of drug action when administered at the same dose. molar under similar conditions in a suitably designed study. Section 505(j)(8)(B) of the FD&C Act outlines a set of conditions under which a test and a reference listed drug must be considered bioequivalent: the rate and extent of absorption of the [test] drug do not show a significant difference compared to the rate and degree of absorption of the [reference] drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions either in single or multiple doses; o the extent of absorption of the [test] drug does not show a significant difference compared to the extent of absorption of the [reference] drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or in multiple doses and the [reference] drug difference in drug absorption rate is intentional, reflected in the proposed labeling, is not essential for achieving effective drug concentrations in the body in chronic use, and is considered medically insignificant for the drug. Where these above methods are not applicable (eg, for pharmaceuticals that are not intended to be absorbed into the bloodstream), other scientifically valid in vivo or in vitro test methods may be suitable to demonstrate bioequivalence. For example, bioequivalence can sometimes be demonstrated by using an in vitro bioequivalence standard, especially when the in vitro test has been correlated with in vivo bioavailability data. In other situations, bioequivalence can sometimes be demonstrated by clinical trials or comparative pharmacodynamic studies. Further provided herein are pharmaceutical products comprising an amount of apalutamide clinically proven to be safe and clinically proven to be effective, wherein the drug product is packaged and wherein the package includes a label that (a) identifies the apalutamide as an entity regulatory approved chemistry, and (b) zq LRnn / ίζηζ / Ε / γίΛΐ teaches the use of apalutamide in the treatment of metastatic castration-sensitive prostate cancer. In certain modalities, the label provides data to improve radiographic progression-free survival and / or placebo-related overall survival. In certain modalities, the label lists ischemic cardiovascular events, fractures, falls, and seizures as adverse reactions. In certain modalities, the label includes data indicating an increase in ischemic cardiovascular events, fractures, falls, or seizures relative to a standard of care. In certain modalities, the standard of care is the administration of androgen deprivation therapy. As used herein, unless otherwise indicated, the term "safe" means that no undue adverse side effects (such as toxicity, irritation, or allergic response) occur, commensurate with a reasonable benefit / risk ratio when is used as indicated in this invention. Similarly, unless otherwise indicated, the term "efficacious" means that efficacy of the treatment has been demonstrated for the treatment of patients with metastatic castration-sensitive prostate cancer when dosed at a therapeutically effective dose. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In additional embodiments, the methods described herein are safe and effective. In yet other modalities, the therapeutically effective amount of apalutamide is safe. In yet other embodiments, the therapeutically effective amount of apalutamide is effective. In other modalities, the therapeutically effective amount of apalutamide is safe and effective. As used herein, unless otherwise indicated, the term clinically proven (used independently or to modify the terms safe and / or effective) means that the evidence has been demonstrated by a phase III clinical trial or IV that is sufficient to meet US Food and Drug Administration approval standards, or similar study for EMEA marketing authorization. Preferably, an adequately sized, randomized, placebo-controlled, double-blind study is used to clinically test the effects of apalutamide. Most preferably, to clinically test the effects of apalutamide for treating metastatic castration-sensitive prostate cancer, this would be a randomized, placebo-controlled, double-blind study of apalutamide plus androgen deprivation therapy vs. androgen deprivation therapy with patient condition assessed by radiographic progression-free survival or overall survival. For example, evidence can be provided by the clinical trial described in Example 1. As used herein, unless otherwise indicated, the term clinically proven effective means that the efficacy of the treatment has been proven by a Phase III or IV clinical trial to be statistically significant, i.e. not clinical trial results are likely to be by chance with an alpha level less than 0.05 or zq LRnn / ίζηζ / Ε / γίΛΐ clinical efficacy results are sufficient to meet US Food and Drug Administration approval standards USA, or similar study for commercial authorization by ENEA. For example, apalutamide has been clinically proven effective for the treatment of patients with metastatic castration-sensitive prostate cancer when administered orally at a therapeutically effective dose of 240 mg and co-administered with androgen deprivation therapy to improve survival. without radiographic progression and overall survival relative to patients treated with placebo plus androgen deprivation therapy, and as specifically set forth in the examples. As used herein, unless otherwise stated, the term clinically proven safe means that the safety of the treatment has been demonstrated by a phase III or IV clinical trial by analysis of trial data. and the results establish that the treatment is free from undue adverse side effects and commensurate with statistically significant clinical benefit (eg, efficacy) sufficient to meet US Food and Drug Administration approval standards or study similar for trade authorization in Europe, the Middle East and Africa (EMEA). For example, apalutamide has been clinically proven safe for the treatment of patients with metastatic castration-sensitive prostate cancer when administered orally at a therapeutically effective dose of 240 mg and co-administered with androgen deprivation therapy, and as is specifically set forth in the examples. sales methods The present disclosure provides methods for selling an approved drug product comprising apalutamide, the method comprises, consists of, or consists essentially of selling such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions to treat metastatic castration-sensitive prostate cancer. In certain embodiments, the drug product is an ANDA drug product, a new drug application supplemental drug product, or a 505(b)(2) drug product. The terms sell or sell mean to transfer a drug, e.g. eg, a pharmaceutical composition or an oral dosage form, from a seller to a buyer. The present disclosure further provides methods of offering for sale an approved drug product comprising apalutamide, which method comprises, consists of, or consists essentially of offering for sale such a drug product, wherein a drug product label for a drug listed as Reference for such a drug product includes instructions for treating metastatic castration-sensitive prostate cancer. In certain embodiments, the drug product is an ANDA drug product, a new drug application supplemental drug product, or a 505(b)(2) drug product. zq LRnn / ίζηζ / Ε / γίΛΐ The term offer for sale means the proposal of a sale by a seller to a buyer for a drug, e.g. eg, a pharmaceutical composition or an oral dosage form. In another aspect, the present disclosure describes methods of selling apalutamide, said method comprising, consisting of, or consisting essentially of placing apalutamide in the accessory stream wherein said apalutamide includes a package accessory containing instructions for safely and effectively treating the metastatic castration-sensitive prostate cancer using apalutamide. In other additional embodiments, the present description describes methods of offering for the sale of apalutamide, said methods comprise, consist of, or consist essentially of offering to place apalutamide in the current of commerce, wherein said apalutamide includes a package accessory that contains instructions to safely and effectively treat metastatic castration-sensitive prostate cancer using apalutamide. examples These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Example 1: Phase 3 randomized, placebo-controlled, double-blind study of apalutamide plus androaene deprivation therapy (ADT) vs. ADT in subjects with metastatic hormone-sensitive prostate cancer (mCSPC) Goals primary objective To determine whether the addition of apalutamide to androgen deprivation therapy (ADT) provides superior efficacy in improving radiographic progression-free survival (rPFS) or overall survival (OS) for subjects with mCSPC. Secondary objectives • To assess clinically relevant improvements with the addition of apalutamide to ADT including delays in pain progression and opioid use for prostate cancer, skeletal-related events, and the need for cytotoxic chemotherapy; • Characterize the safety of adding apalutamide to ADT for subjects with mCSPC; zq LRnn / ίζηζ / Ε / γίΛΐ • Characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of apalutamide; • To assess the concentration of leuprolide and to assess the PD effect of leuprolide on testosterone concentrations when used alone or in combination with apalutamide; • To assess the efficacy of treatment with the addition of apalutamide to ADT for subpopulations of subjects with low-volume or high-volume mCSPC. Other objectives • To evaluate the predictive exploratory biomarkers of response and resistance to treatment with apalutamide; • Assess relevant patient outcomes including symptoms (ie pain, fatigue, urination) and function (ie physical, emotional, social) and health-related quality of life; • To assess improvements in other clinically relevant endpoints of apalutamide plus ADT compared to ADT alone; • Collect medical resource utilization (MRU) data that can be used in future economic models. Study design The study described in Example 1 was at least partially completed according to the criteria described in the present description and is still ongoing. This was a Phase 3 randomized, double-blind, placebo-controlled, multinational, multicenter study to determine whether subjects with mCSPC benefited from the addition of apalutamide to ADT. Data presented herein as associated with this study reflects the status of this study at the time of this presentation. The study was carried out at 260 centers in 23 countries. Review boards at all participating institutions approved the study, which was carried out in accordance with the current International Conference on Harmonization for Good Clinical Practice and in accordance with the Helsinki Declaration of Principles. All patients provided written informed consent. The sponsor commissioned an independent data oversight committee to monitor safety and efficacy prior to unblinding and to make recommendations for conducting the study. Staff at each site transcribed data from the source documents onto electronic case report forms prepared by the sponsor. Blinding of investigators, patients, study center staff, and the sponsor's study team to the zq LRnn / ίζηζ / Ε / γίΛΐ randomization codes was maintained until study completion, the independent recommendation of the data monitoring committee, or the individual medical necessity of patients. Enrollment of approximately 1000 subjects was planned for this study. Subjects meeting all inclusion criteria and none of the exclusion criteria were stratified by Gleason score at diagnosis (<7 vs. >7), region (North America [NA] and European Union [EU] compared with other countries), and previous use of docetaxel (yes vs. no). Patients were randomized 1:1 to receive apalutamide (240 mg) or matched placebo administered orally once daily, in addition to continuous ADT. Patients were stratified by Gleason score at diagnosis (<7 vs. >7), region (vs. (North America and European Union vs. all other countries), and prior docetaxel treatment (yes vs. no). A screening phase of up to 28 days prior to randomization established study eligibility Subjects will / received treatment in 28-day cycles during the treatment phase until disease progression or the onset of treatment-related toxicity unacceptable or sponsor terminates study If subject has / had radiographic progression without clinical progression and alternative therapy is not initiated / initiated, treatment may continue until clinical progression is observed, subjects should discontinue study drug with progression Documented clinical evidence based on protocol-specified criteria.Following study drug discontinuation, subjects will have an end-of-treatment visit within 30 days of the last dose of study drug. During the follow-up phase, data collection (every 4 months) will include survival, additional data on secondary endpoints, date, and type of disease progression (radiographic, PSA, clinical, or a combination) at the first subsequent therapy to prostate cancer, and subsequent therapy for prostate cancer. Data collection at follow-up will continue until the subject dies, withdraws consent, is not found at follow-up, or the sponsor terminates the study. Measures of the Brief Pain Intensity Questionnaire (BPI SF), the Brief Fatigue Questionnaire (BFI), and the Patient Report Outcome (PRO) ) EQ-5D-5L will also continue in the follow-up phase for up to 12 months after treatment discontinuation. In the event of a positive study result in any of the interim analyzes or in the final analysis, all subjects in the treatment phase will have the opportunity to enroll in an open-label extension phase, allowing subjects to receive the active drug (apalutamide) for approximately 3 years. Subjects were / will be monitored for safety from the signing of the informed consent until 30 days after the last dose of study drug. Adverse events (AEs) including adverse laboratory events will be scored and summarized using the National Cancer Institute zq LRnn / ίζηζ / Ε / γίΛΐ common terminology criteria for adverse events (NCI-CTCAE; Version 4.03). Dose modifications will be made according to the dose modification rules described in the protocol. A diagram of the study design is provided in Figure 1. Study population Each potential subject met all of the following criteria to be enrolled in the study. Patient Eligibility Overview Eligible patients were required to have a documented adenocarcinoma of the prostate and distant metastatic disease documented by a lesion >1 on bone scan, with or without visceral or lymph node involvement. All patients had an Eastern Cooperative Oncology Group performance status (a 5-point scale, with higher numbers reflecting greater disability) of 0 or 1. Patients were castration-sensitive (ie, patients who not receiving ADT at the time of progression). Prior treatment for prostate cancer limited to prior docetaxel use (maximum six cycles, no evidence of progression on treatment or prior to randomization), ADT of <6 months for metastatic castration-sensitive prostate cancer or <3 years total duration for localized prostate cancer, a course of radiation or surgical therapy for symptoms associated with metastatic disease, and other localized treatments (eg, radiation therapy, prostatectomy) completed >1 year prior to randomization . Patients who received a gonadotropin-releasing hormone agonist <28 days prior to randomization were required to take a first-generation antiandrogen (ie, biclutamide, flutamide, or nilutamide) for >14 days prior to randomization. The antiandrogen had to be discontinued prior to randomization. Patients with severe angina, myocardial infarction, congestive heart failure, venous / arterial thromboembolic events, history of predisposition to seizures, or recent ventricular arrhythmias were excluded. Inclusion criteria • Subject must be male >18 years of age (or the legal age of consent in the jurisdiction in which the study is conducted); • Investigator-confirmed diagnosis of adenocarcinoma of the prostate; • distant metastatic disease documented by >1 bone lesions on technetium-99m (99mTc) bone scan, with or without visceral or lymph node involvement. Subjects with a single bone lesion should have confirmation of bone metastases by computed tomography (CT) or magnetic resonance imaging (MRI); ZQ LRnn / Lznz / Ε / ΥΙΛΙ • All patients have an Eastern Cooperative Oncology Group (ECOG) PS grade of 0 or 1; • Androgen deprivation therapy (ie, medical or surgical castration) must have started >14 days prior to randomization. Subjects starting a GnRH agonist <28 days prior to randomization will be required to take a first-generation antiandrogen for >14 days prior to randomization. The antiandrogen must be discontinued prior to randomization; • Subjects were castration sensitive and subjects receiving docetaxel treatment must meet the following criteria: to. They received a maximum of 6 cycles of docetaxel therapy for mCSPC; b. They received the last dose of docetaxel <2 months before randomization; c. The disease maintained a stable or better response to docetaxel, by imaging and PSA assessment by the investigator, prior to randomization; • were able to swallow whole tablets of study drug; • To avoid the risk of drug exposure via ejaculation (even in men with vasectomies), subjects must use a condom during sexual activity while receiving study drug and for 3 months after the last dose of study drug. study. Sperm donation is not allowed while receiving study drug and for 3 months after the last dose of study drug; • Each subject must sign an Informed Consent Form (ICF) indicating that they understand the purpose and procedures of the study, and that they are willing to voluntarily participate in the study. The subject must be willing and able to comply with the prohibitions and restrictions specified in this protocol. • Other allowable pretreatments for mCSPC: to. maximum of 1 course of radiation or surgery with metastatic disease, and other localized treatments completed >1 year prior to randomization; radiation therapy for metastatic lesions must be completed prior to randomization; b. <6 months of ADT prior to randomization for mCSPC or <3 years of total duration for localized prostate; • Allowable prior treatments for localized prostate cancer (all treatments must have been completed >1 year prior to randomization) zq LRnn / ίζηζ / Ε / γίΛΐ to. <3 years total ADT; b. all other forms of prior therapies including radiation therapy, prostatectomy, lymph node dissection, and systemic therapies. Exclusion criteria Any potential subject who met any of the following criteria was excluded from participating in the study: • Pathologic finding consistent with small cell, ductal, or neuroendocrine carcinoma of the prostate; • known brain metastases; • lymph nodes as unique sites of metastases; • visceral metastases (ie liver or lung) as single sites of metastases; • other prior malignancies (except: squamous cell or basal cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in full remission adequately treated) <5 years prior to randomization; • clinical laboratory values ​​during the screening phase: to. hemoglobin <9.0 g / dl; b. neutrophils <1.5 x 109 / 1; c. platelets <100 x 109 / 1; d. total bilirubin >1.5 x upper limit of normal (ULN) [NOTE: In subjects with Gilbert syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is <1.5 x ULN, measure direct and indirect bilirubin subject may be eligible]; and. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN; F. serum creatinine >2.0 x ULN; g. serum albumin >3.0 g / dL • Prior treatment with other next-generation antiandrogens (eg, enzalutamide), CYP17 inhibitors (eg, abiraterone acetate), immunotherapy (eg, sipuleucel-T) , radiopharmaceutical agents or other treatments for prostate cancer except those listed in the inclusion criteria; • Initiation of bisphosphonate or denosumab treatment for management of bone metastases <28 days prior to randomization; zq LRnn / ίζηζ / Ε / γίΛΐ • Medications known to lower the seizure threshold should be discontinued or substituted >28 days prior to randomization; • Administration of other investigational therapeutic agents, blood product support, growth factor support, or invasive surgical procedure (not including surgical castration) <28 days prior to randomization or currently enrolled in an investigational study; • Current or previous treatment with antiepileptic drugs for the treatment of seizures. History of seizures or a condition that may predispose to seizures (including, but not limited to, prior cerebrovascular accident, transient ischemic attack, or loss of consciousness within 1 year prior to randomization; cerebral arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma causing edema or mass effect); • current evidence of any of the following: to. severe / unstable angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant venous or arterial thromboembolic events (eg, pulmonary embolism), or clinically significant ventricular arrhythmias <6 months prior to randomization; b. gastrointestinal disorder affecting absorption; c. active infection requiring systemic therapy such as human immunodeficiency virus (HIV); d. active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to liver dysfunction; • the subject has known allergies, hypersensitivity or intolerance to apalutamide or its excipients. • Any condition or situation that, in the investigator's judgment, would preclude participation in this study. Treatment Assignment Procedures for stratification and randomization Subjects were stratified by Gleason score at diagnosis (<7 vs. >7), region (North America [NA] and European Union [EU] vs. other countries), and prior docetaxel use (Yes vs. No). Subjects were randomly assigned to the active or control group in a 1:1 ratio. Randomization was balanced using randomly permuted blocks. The interactive web response system (IWRS) was assigned a unique treatment code, which determined treatment assignment and matching study drug kits for the subject. The applicant used ZQ LRnn / Lznz / Ε / ΥΙΛΙ your own user ID and personal identification number when contacting the IWRS and then provided with relevant subject details to uniquely identify the subject. dosage v administration Apalutamide administration Apalutamide was administered continuously, but for the purpose of scheduling study assessments and treatment adherence, a treatment cycle is defined as 28 days. Subjects were randomly assigned in a 1:1 ratio to receive apalutamide or matched placebo: • Apalutamide 240 mg (4 tablets of 60 mg); taken orally once daily with or without food or • placebo (4 tablets); it was taken orally once daily with or without food. If a dose of apalutamide (or placebo) was missed, it was skipped and not made up or taken with the subsequent dose the next day. ADT Administration All subjects who did not have surgical castration received and remained on 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 consistent with the prescribing information. Toxicity and management of rash Table 1 summarizes apalutamide / placebo dose modifications for drug-related toxicities. Dose modifications for drug-related eruptions may also be provided. Once the dose was reduced for drug-related toxicities, a dose increase was discussed with the sponsor. Table 1: Dose modification of apalutamide / placebo zq LRnn / ίζηζ / Ε / γίΛΐ Severity Number of apalutamide tablets / placebo Grade 1 or 2 No change or hold until return to baseline >Grade 3 Hold to Grade 1 or baseline, resume at full dose Recurrence >Grade 3 Hold to Grade 1 or reference value; 2-dose reductions are allowed for recurrent treatment-related toxicity (180 mg [3 tablets] and 120 mg [2 tablets]). Discontinue if toxicity persists after 2 dose reductions. First onset of seizures of any grade or grade 4 neurotoxicity Discontinue Note: Unfavorable events are scored according to NCI-CTCAE version 4.03 zq LRnn / ίζηζ / Ε / γίΛΐ If the rash has any component of scaling, mucosal involvement, or pustules, stop dosing with apalutamide / placebo, refer the subject to dermatology for evaluation, and a skin biopsy is recommended (in addition to dose modifications). If the rash is grade 3 or higher, the subject may be asked to consider her consent for documentation by photograph and further evaluation by a dermatologist. Pre-study and concomitant therapy Permitted care support therapies Supportive care medications are allowed following institutional guidelines for use. The following supportive care therapies are considered allowable during the study: • Short intermittent course of opioid analgesics is allowed to control pain; • Surgical interventions and procedures such as transurethral resection of the prostate (TURP) and ureteral stenting for management of complications due to local progression; • Bisphosphonates and denosumab for the management of bone-related metastases should be used according to the market-approved label. Subjects must receive a stable dose of such agents for >28 days prior to randomization or must agree not to initiate such therapy until radiographic progression is documented. Bisphosphonates and denosumab are allowed in doses to prevent osteoporosis; • conventional multivitamins, selenium and soy supplements; • transfusions and hematopoietic growth factors per institutional practice guidelines (Note that blood product support and growth factor support are not allowed in the period <28 days prior to randomization); • Immunoglobulin therapy for non-cancer treatment in accordance with institutional practice guidelines. Prohibited concomitant therapies As a class effect, AR antagonists have been associated with seizures due to an off-target mechanism of action (gamma amino butyric acid [GABAA] chloride channel inhibition). Drugs known to lower the seizure threshold or cause seizures are prohibited, and a representative list follows: • atypical antipsychotics (eg, clozapine, olanzapine, risperidone, ziprasidone); • bupropion; • lithium; • meperidine (pethidine); • phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, thioridazine); • tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine); • aminophylline / theophylline; Other prohibited therapies include the following: • investigative agents; • abiraterone acetate or other CYP17 inhibitor; • other hormonal agents for the treatment of prostate cancer; • other antineoplastic agents; • radiation therapy for new painful lesions of metastatic prostate cancer that were not present on initial images; • 5-a-reductase inhibitors; • chemotherapy • immunotherapy or vaccine therapy for the treatment of cancer; • other antiandrogens (eg, bicalutamide, nilutamide, flutamide, cyproterone acetate, enzalutamide); • Bisphosphonates or denosumab to manage bone metastases unless such therapy is initiated >28 days prior to randomization and subjects have received a stable dose. Bisphosphonate or denosumab is allowed in doses for osteoporosis prophylaxis; • systemic ketoconazole (or other azole drugs such as fluconazole or itraconazole); • diethylstilbestrol (DES) or similar; • other preparations such as pomegranates or pomegranate juice or saw palmetto, which are believed to have endocrine effects on prostate cancer; • radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) or similar analogues such as radium-223 (223Ra); • spironolactone. zq LRnn / ίζηζ / Ε / γίΛΐ Restricted concomitant medications Highlights of the drug interaction are summarized below. • Strong CYP3A4 inducers: The potential for drug-drug interactions with apalutamide has not been clinically proven. Strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort) should be avoided as much as possible; • Apalutamide can also induce CYP3A4; therefore, care should be taken when co-administered with CYP3A4 substrates that have a narrow therapeutic index; • Strong CYP2C8 inhibitors (eg gemfibrozil) should be used cautiously in combination with apalutamide; • Long-term use of systemically administered corticosteroids is not permitted during the study. Short-term (<4 weeks, including taper) and locally administered (eg, inhaled, topical, ophthalmic, and intra-articular) steroid use is permitted if clinically indicated. Efficacy evaluations / endpoints Radiographic progression was / will be assessed by soft tissue lesion by computed tomography (CT) / magnetic resonance imaging (MRI) by Modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or by bone lesion progression on bone scans . Survival data was collected throughout the treatment phase and during the follow-up phase. evaluations Patients were evaluated by Modified Response Endpoint in Solid Tumors version 1.1 using CT or MRI of the chest, abdomen, and pelvis at screening (<6 weeks prior to randomization) and task force criteria. 2 for prostate cancer using bone scans during cycles 3 and 5, and every fourth cycle thereafter. The investigator evaluated progression events. Scans from ~60% of patients were randomly selected for independent central review. Adverse events were assessed monthly and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3. FACT-P assessments were 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 were collected 6 days before cycle 1, after each cycle, at the end of treatment, and every 4 months for up to 1 year after discontinuation. zq LRnn / ίζηζ / Ε / γίΛΐ More specifically, effectiveness evaluations include the following: • Tumor measurements (CT or MRI [abdomen, chest and pelvis], 99mTc bone scans). The same imaging modality for tumor evaluation should be used during the evaluation of an individual subject. Unscheduled evaluation of the tumor and appropriate imaging should be considered if signs or symptoms suggestive of disease progression are noted, including increased pain not otherwise attributed, worsening of PS status grade of ECOG or physical examination findings consistent with disease progression; • scans from approximately 60% of patients were randomly selected for independent central review; • Serum PSA assessments (performed at a central laboratory); • skeletal related event (SRE) is defined as the occurrence of symptomatic pathologic fracture, spinal cord compression, radiation to bone, or surgery to bone; • pain progression is defined as a 2-point increase from baseline in the worst pain intensity observed on the BPI-SF questionnaire (item 3) at 2 consecutive assessments >4 weeks apart; with an average worst pain score >4 in subjects who have not had opioid tapering or chronic opioid initiation, whichever comes first. Patient-Reported Outcomes Patient-reported outcomes include administration of various questionnaires including the Abbreviated Pain Intensity Questionnaire (BPI-SF), Analgesic Use Log, Abbreviated Fatigue Questionnaire (BFI), Functional Assessment of Therapy against cancer (FACT-P) and the EQ-5D-5 L (a standardized measure of health status developed by the EuroQoL Group to provide a simple and generic measure of health for clinical and economic evaluation (EuroQoL Group, 1990) ). Patient-reported outcome questionnaires were collected throughout the study, as well as during the follow-up phase (up to 12 months after discontinuation of treatment) and the open-label extension phase. Response criteria your morale Tumor response was assessed using imaging measurements, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In this study, the RECIST was modified based on the Prostate Cancer Working Group (PCWG2) criteria, which are zq LRnn / ίζηζ / Ε / γίΛΐ specific for this patient population. Prostate-specific antigen measurements were assessed according to the PCWG2 criteria. The investigator assessed the rPFS assessment. Patients in the incorporated study were evaluated for efficacy by Solid Tumor Modified Response Endpoints Version 1.1 and Prostate Cancer Workgroup 2 Criteria. 2 The Prostate Cancer Task Force 2 criteria for progression are as follows: • PSA: first increase >25% from baseline and >2 ng / mL above nadir (confirmed by second value 3 or more weeks later) • Soft tissue lesions: response assessment criteria are followed in solid tumors with warnings or imaging should include a CT scan or MRI at a minimum; centers with relevant experience should use endorectal MRI or transrectal ultrasound or only report changes in lymph nodes that were >2 cm in diameter at baseline or record changes in nodal and visceral soft tissue sites separately o Record complete clearance of disease at any separate site o Confirm favorable change with second scan o Record changes using waterfall chart o Progression at first assessment should be confirmed by second scan >6 weeks later • Bone: >2 new lesions appeared and, for the first reassessment only, a confirmatory scan was performed >6 weeks later, indicating a minimum of >2 new lesions. Valuation criteria Dual primary endpoints Dual primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). zq LRnn / ίζηζ / Ε / γίΛΐ Secondary Endpoints Secondary endpoints were time to cytotoxic chemotherapy, time to pain progression as assessed by the Abbreviated Pain Intensity Questionnaire (BPI-SF; worst pain [item 3] was used for the endpoint time to pain progression; scores range from 0 to 10, with lower scores representing lower levels of pain intensity; a change of 2 was the minimally important difference), time to chronic opioid use , and the time until the event related to the skeleton. Prespecified subgroup analysis was planned based on data from patients with low-volume or high-volume metastatic castration-sensitive prostate cancer, and evaluation of treatment outcomes in these groups was a secondary objective. The definition of high volume disease was as adapted from Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373:737-46 as follows 1) visceral metastases and >1 bone lesion, or 2) >4 bone lesions, with >1 outside the axial skeleton. Low volume disease was defined as the presence of bone lesions that do not meet the definition of high volume disease. Exploratory Endpoints Exploratory endpoints included time to prostate-specific antigen (PSA) progression, second progression-free survival, and time to local symptomatic progression. Time to second progression-free survival was defined as the time from randomization to the first occurrence of investigator-determined disease progression (PSA progression, imaging progression, or clinical progression) while the patient was receiving a first subsequent therapy for prostate cancer or, death due to any cause, whichever comes first. Patient-reported outcomes for health-related quality of life were assessed using the Functional Assessment of Prostate Cancer Therapy Questionnaire (FACT-P). Raw FACT-P scores range from 0 to 156, with higher scores indicating a 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. Population pharmacokinetic assessments Minimal PK samples were / will be collected. Pre-dose blood samples for analysis of apalutamide and active metabolite (JNJ-56142060) concentrations were / will be collected on Day 1 of Cycles 2, 3, 4, 5, and 6. zq LRnn / ίζηζ / Ε / γίΛΐ Leuprolide PK Substudy Optional PK samples were / will be collected from at least 60 consenting subjects (in selected countries) who received or will receive leuprolide acetate as GnRHa at the time of randomization. Samples were collected on Day 1 of Cycles 1, 3, 4, 5, and 6 for analysis of leuprolide and testosterone concentrations. Biomarker Assessments Plasma-based circulating DNA was / will be used to assess for the presence of the F876L androgen receptor (AR) mutation and whole blood or plasma DNA to assess for other markers that may be associated with resistance to apalutamide. Formalin-fixed paraffin-embedded (FFPE) tumor blocks or tumor slides were / will be collected to assess mRNA expression of genes representing AR signaling to compare the biology of high and low volume disease with result and to evaluate the expression of immune markers such as 0X40, GITR and FOXP3. security assessments Safety assessments include AE, vital sign (blood pressure) measurements, physical examinations, ECOG PS, and clinical laboratory tests including, but not limited to, a hematology profile, serum chemistry profile, liver function test and fasting lipid profile. In case of additional safety monitoring, unscheduled laboratory evaluations were / will be performed as needed. Vital signs and performance status of the Grupo Oncologico Cooperativo del Este were assessed at screening and at each scheduled visit during treatment. Safety was continually assessed and adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.3. FACT-P assessments were collected on Day 1 of Cycles 1 through 7, then every other cycle, at the end of treatment, and once every 4 months for up to 1 year after discontinuation. Electrocardiogram (ECG) Electrocardiograms (ECGs) (12 leads) were recorded at screening. Vital signs Body temperature, heart rate, respiratory rate, and blood pressure were recorded at screening. At all other visits, only blood pressure will be measured. zq LRnn / ίζηζ / Ε / γίΛΐ Physical exam The screening physical examination included, at a minimum, the subject's general appearance, height, weight, skin examination, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. During the treatment phase and at the EOT visit, limited symptom-directed physical examination and weight assessment were required. Eastern Cooperative Cancer Group (ECOG) PS When scheduled, ECOG PS assessments as with PRO questionnaires were obtained before any other study procedures planned for the same day. Termination / Withdrawal of Subjects Ending A subject will be considered to have completed the study if they died before the end of the study or have not been lost to follow-up or have not withdrawn consent before the end of the study. discontinuation of apalutamide If a subject's study drug must be discontinued prior to the end of the treatment regimen, this will not mean that the subject has been automatically withdrawn from the study. If the subject has radiographic progression without clinical progression and alternative therapy is not initiated, treatment may continue until clinical progression is observed. All attempts should be made to capture radiographic progression even in subjects who have evidence of clinical progression. However, a subject's study treatment should be discontinued for: • Clinical progression defined as: • Deterioration in ECOG PS grade to grade 3 or higher (related to prostate cancer progression) • Need to initiate any of the following due to tumor progression (even in the absence of radiographic evidence of disease) • Subsequent cancer therapy for metastatic prostate cancer • Radiation therapy for metastatic prostate cancer lesions (palliative radiation to existing lesions at baseline will not be considered clinical progression) • Surgical interventions for complications due to metastatic progression of prostate cancer . zq LRnn / ίζηζ / Ε / γίΛΐ • Chronic need for opioid analgesics: For subjects entering the study not receiving opioids, chronic opioid use is defined as administration of opioid analgesics lasting >3 weeks for oral formulations or >7 days for non-oral formulations. For subjects entering the study having already received opioids, chronic opioid use is defined as a >30% increase in total daily dose of opioid analgesics lasting >3 weeks for oral formulations or >7 days for non-oral formulations. • More than 2 dose level reductions for Grade 3 or greater treatment-related AEs (Table 1) • Seizures for any Grade or Grade 4 neurotoxicity • Subjects who have had their treatment assignment were unblinded for any reason except by IDMC recommendation to unblind the study • Investigator believes that for safety reasons (eg, AE) it is in the best interest of the subject to discontinue study treatment. All attempts should be made to obtain imaging studies at discontinuation of treatment or EOT visit to assess for radiographic progression. Study drug was continued / will continue / is being continued for subjects who have rising PSA values ​​in the absence of radiographic or clinical progression. Although serial PSA measurements were performed in this study, progression or change in PSA values ​​were not used as the sole indicator for disease progression or discontinuation of treatment. If a subject discontinues study drug, but does not withdraw consent for follow-up, scheduled evaluations should continue according to the follow-up phase in the time and event plan. Statistical methods General description The clinical trial exemplified herein was designed to enroll -1000 patients. First, radiographic progression-free survival was tested. If it was statistically significant, its alpha was recycled to overall survival based on the backtracking method. A general type I error of 5% was planned. 368 imaging progression-free survival events were required 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 required to provide “80% power to detect a hazard ratio of 0.75 with a two-tailed significance level of 0.045. The zq LRnn / ίζηζ / Ε / γίΛΐ analysis of overall survival incorporated a cluster sequential design with an output function alpha calculated as Wang-Tsiatis power limits of shape parameter 0.2. Two interim analyzes for overall survival were planned. The first interim analysis was estimated to include ~50% of the total events required for overall survival at the time of the primary analysis for radiographic progression-free survival. The alpha level for the interim analysis for overall survival was 0.009, assuming an overall two-tailed significance level of 0.045. Subgroup analyzes were prespecified to assess the consistency of the treatment effect. If the dual primary endpoints were statistically significant, evaluation of the secondary endpoints was performed 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 chronic opioid use, 4) time to skeletal-related event. Demographic and baseline characteristics were summarized using descriptive statistics. The primary statistical method of comparison for the time-to-event endpoints was the Mantel-Cox test stratified, according to the stratification factors. The KaplanMeier product limit method and the Cox proportional hazards model were used to calculate the time-to-event variables and determine the associated hazard ratios and confidence intervals. Analysis populations The primary analysis population uses the intended-to-treat (ΓΤΤ) population, which includes all randomized subjects. The ITT population was used for analysis of subject willingness and efficacy. The safety population includes all subjects who received at least 1 dose of study drug as per treatment. Determination of sample size An overall type I error of 5% is planned for this study. This study uses the co-primary endpoints of rPFS and OS with a significance level of 0.005 assigned for the rPFS endpoint and 0.045 assigned for OS. The study is considered a success if at least one of the co-primary endpoints is statistically significant. The regression method was used to recycle the alpha level from radiographic progression-free survival to overall survival if radiographic progression-free survival was statistically significant. It was estimated that ~50% (205) of the total events required for the overall survival analysis would have been observed in the primary analysis for radiographic progression-free survival. The alpha level for the interim analysis for overall survival was 0.009, assuming an overall two-tailed significance level of 0.045. An additional subgroup analysis of patients with zq LRnn / ίζηζ / Ε / γίΛΐ low- or high-volume disease was allowed in the overall survival analysis without assigned alpha output. If the dual primary endpoints and radiographic progression-free survival were statistically significant, evaluation of the secondary endpoints was to be performed in the following hierarchical order, each at an overall two-sided significance level of α=0.05: 1) time to initiation of cytotoxic chemotherapy, 2) time to pain progression, 3) time to chronic opioid use, 4) time to skeletal-related event. Demographic and baseline characteristics were summarized using descriptive statistics. The Kaplan-Meier product limit method and Cox proportional hazards model were used to calculate time-to-event variables and determine associated hazard ratios and confidence intervals. For radiographic progression-free analyses, patients without evidence of radiographic progression or death or those who withdrew from the study or received subsequent new anticancer therapy without documented disease progression were censored on the date of last tumor evaluation, and patients with no post-baseline tumor assessment were censored at the date of randomization It is estimated that approximately 368 rPFS events are required to provide at least 85% power in detection for a hazard ratio (HR) of 0.67 (median rPFS of 20 months for the control group [ADT] vs. 30 months for the apalutamide plus ADT treatment group) at a 2-tailed significance level of 0.005. The study will also provide sufficient power (approximately 80%) to detect an HR of 0.75 in the co-primary endpoint of OS based on an assumed median OS of 44 months for the control group (ADT). Approximately 410 death events will be required to detect the putative HR at a 2-tailed significance level of 0.045 with an enrollment duration of approximately 30 months (approximately 1000 subjects). The total duration of the study will be approximately 54 months to obtain 410 deaths. efficacy analysis The Kaplan-Meier product limit method and Cox proportional hazards model were used to calculate the time-to-event variables and to derive the HR along with associated confidence intervals. interim analysis For the co-primary endpoint of OS, 2 interim analyzes are planned for this study after approximately 60% (~246 events) and approximately 75% (~308 events) of the total number of (410) required events have been observed. The time of the first OS interim analysis can occur at the same time as the main rPFS analysis. However, this analysis may be performed at a different time if the number of death events required for one analysis ZQ LRnn / Lznz / Ε / ΥΙΛΙ OS valid provisional would require a long delay in analysis of the rPFS endpoint. No interim analyzes are planned for the rPFS endpoint. PK population and PD analysis Population PK analysis of apalutamide plasma concentration-time data will be performed using non-linear mixed-effects modelling. If sufficient data are available, the exposure ratio of apalutamide and the active metabolite (JNJ-56142060) can also be analyzed to measure efficacy and AE. Leuprolide PK analysis Descriptive statistics of leuprolide PK data will be summarized by treatment group (with apalutamide or placebo) and leuprolide acetate dose. Statistical analysis will be performed to compare leuprolide concentrations when administered alone or in combination with apalutamide. The percentage of subjects with testosterone levels <50 ng / dl will be summarized descriptively by treatment groups. Biomarker analysis Associations of biomarkers with clinical response or time-to-event endpoints can be assessed using appropriate statistical methods (such as analysis of variance [ANOVA], categorical, or survival models), depending on the endpoint. Security analysis Safety parameters to be evaluated are the incidence and severity of treatment-emergent AEs, clinically significant changes in the subject's physical examination findings, vital sign measurements, and clinical laboratory results. Study drug exposure and reasons for discontinuation of study treatment will be tabulated. Results General description Five hundred twenty-five (525) patients were randomized to apalutamide plus ADT and 527 to placebo plus ADT. The median age was 68 years; 8% had prior treatment for localized disease; 11% used docetaxel previously; 63% had high volume and 37% had low volume of disease. In the first interim analysis, with a median follow-up of 22.7 months, apalutamide significantly improved radiographic progression-free survival (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.39 to 0.60; P< 0.0001), with a 52% reduction in the risk of radiographic progression or death. Overall survival was also improved zq LRnn / ίζηζ / Ε / γίΛΐ with apalutamide, with a 33% reduction in risk of death (HR, 0.67; 95% CI, 0.51 to 0.89, P=0.0053). Grade 3 / 4 adverse event rates were not different between the apalutamide and placebo groups. The independent data monitoring committee recommended unblinding to allow patients receiving placebo to switch to apalutamide. The addition of apalutamide to ADT significantly improved overall survival and radiographic progression-free survival for patients with metastatic castration-sensitive prostate cancer and had a side effect profile that did not differ from the placebo plus ADT group. patients Five hundred twenty-five (525) patients were randomized to apalutamide and 527 to placebo (Figure 1). At the close of the first prespecified interim analysis and after 83 and 117 deaths in the apalutamide and placebo groups, respectively, the median follow-up time was 22.7 months. The median number of cycles received was 23 for apalutamide and 19 for placebo (range 1 to 37 in each group). The median duration of treatment was 20.5 months for apalutamide and 18.3 months for placebo. 66% and 46% of patients in the apalutamide and placebo groups, respectively, remained at the clinical limit of treatment. A total of 45 patients from all groups withdrew consent for study treatment. These patients were followed for survival and secondary endpoints, so their data was not lacking. A total of 39 patients were lost to follow-up or withdrew from subsequent data collection; this information is not captured in any other way in Figure 1. Baseline and demographic characteristics of the disease were well balanced (Table 2). Patients had de novo metastatic castration-sensitive prostate cancer or recurrent metastatic disease after initial diagnosis of localized disease; most had de novo metastatic disease. Previous therapies for prostate cancer are listed in Table 3. Table 2: Demographic data and reference characteristics of the disease zq LRnn / ίζηζ / Ε / γίΛΐ Apalutamide (n=525) Placebo (n=527) Age, median - year (range) 69 (45-94) 68 (43-90) Age (years) - no. (%) <65 149 (28.4) 182 (34.5) 65 to 69 136 (25.9) 108 (20.5) 70 to 74 107 (20.4) 124 (23.5) <75 133 (25.3) 113(21.4) Breed - no. (%) White 354 (67.4) 365 (69.3) Asian 119 (22.7) 110(20.9) Black or African American 10(1.9) 9(1.7) American Indian or Alaska Native 6(1.1) 13(2.5) Not reported 11( 2.1) 8(1.5) Other 24 (4.6) 22 (4.2) Multiples 1 (0.2) 0 ECOG PS Score - no. (%) n=525 n=527 0 328 (62.5) 348 (66.0) 1 197 (37.5) 178 (33.8) 2 0 1 (0.2) Gleason score at initial diagnosis, n (%) n=525 n= 527 <7 41 (7.8) 39 (7.4) 7 133 (25.3) 130 (24.7) >7 351 (66.9) 358 (67.9) Tumor, lymph node, metastatic stage at n = 525 n=527 initial diagnosis - no. (%) TO 1 (0.2) 0 IT 41 (7.8) 27 (5.1) Q2 146 (27.8) 110(20.9) Q3 210 (40.0) 225 (42.7) Q4 76 (14.5) 105 (19.9) TX 51 (9.7) 60(11.4) NO 212 (40.4) 216(41.0) NI 199 (37.9) 184 (34.9) NX 114 (21.7) 127 (24.1) MO 85 (16.2) 59(11.2) MI 411 (78.3) 441 (83.7) MX 29(5.5) 27 (5.1) Volume of disease - no. (%) Low 200 (38.1) 192 (36.4) High 325(61.9) 335 (63.6) Extent of disease upon study entry - no. (%) 525 (100.0) 527 (100.0) Bone 289 (55.0) 269 (51.0) Bone only 199 (37.9) 219 (41.6) Lymph node 56 (10.7) 72(13.7) Visceral and bone 47 (9.0) 64(12.1 ) Lung 12(2.3) 13(2.5) Liver 22 (4.2) 27 (5.1) Soft tissue and bone Median time from initial diagnosis 4.1 (0.5-222.9) 4.0 (0.7-341.4) to randomization (range) - month LRnn / Lznz / Ε / ΥΙΛΙ Previous use of docetaxel - no. (%) Yes* No 58(11.0) 467 (89.0) 55 (10.4) 472 (89.6) Median of no. of docetaxel cycles among the 6 6 patients with prior docetaxel Prior therapy for localized prostate cancer - no. (%) Prostatectomy or radiotherapy 94 (17.9) 79 (15.0) Prostatectomy only 26 (5.0) 27 (5.1) Radiotherapy only 47 (9.0) 39 (7.4) Prostatectomy and radiotherapy 21 (4.0) 13(2.5) Median PSA (range ) - pg / l 5.97 (0-2682) 4.02 (0-2229) Median LDH (range) - U / l 178 (88-1248) 179 (85-1514) Median alkaline phosphatase (range) - U / l 98 (26-5193) 94 (32-3892) Median baseline BPI-SF pain score + - no. (%) 198 (37.7) 200 (38.0) 0 (no pain) 195 (37.1) 207 (39.3) 1 to 3 (mild pain) 98 (18.7) 95 (18.0) 4 to 7 (moderate pain) 12 (2.3) 11(2.1) 8 to 10 (acute pain) Median FACT-P total score of 113 113 baseline* ECOG PS, Eastern Cooperative Cancer Group performance status; FACT-P, functional assessment of prostate cancer treatment; PSA, prostate specific antigen * 27 patients (46.6%) in the apalutamide group and 22 patients (40.0%) in the placebo group were Not in the diagnosis. + Scores range from 0 to 10, with lower scores representing lower levels of pain intensity; a change of 2 was the least important difference1* Scores range 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 is the least important difference. Previous therapies for prostate cancer are listed in Table 3. Table 3: Prior prostate cancer therapy Apalutamide (n=525) Placebo (n=527) Prostatectomy or radiotherapy - no. (%) 94 (17.9) 79 (15.0) Prostatectomy only 26 (5.0) 27 (5.1) Radiotherapy only 47 (9.0) 39 (7.4) Prostatectomy and radiotherapy 21 (4.0) 13 (2.5) Hormone therapy - no. (%) 525 (100) 527 (100) First-generation antiandrogen 352 (67.0) 361 (68.5) Gonadotropin-releasing hormone agonist 462 (88.2) 455 (86.3) Gonadotropin-releasing hormone antagonist 56(10.7) 53(10.1) Bilateral orchiectomy 33 (6.3) 40 ( 7.6) Docetaxel - no. (%) 58(11.0) 55 (10.4) Vandetanib - no. (%) 1 (0.2) 0 zq LAnn / ίζηζ / Ε / γίΛΐ Dual primary endpoints Radiographic progression-free survival v overall survival 365 radiographic progression events (134 apalutamide, 231 placebo) were observed. Event-free rates at 24 months were 68% in the apalutamide group and 48% in the placebo group. Treatment with apalutamide significantly improved radiographic progression-free survival (HR, 0.48; 95% CI, 0.39 to 0.60; P<0.0001), with a 52% reduction in the risk of radiographic progression or death (Figure 2A). In this final analysis for radiographic progression-free survival, the median was not reached for apalutamide and 22.1 months for placebo. The effect of apalutamide on radiographic progression-free survival was consistently favorable across subgroups analyzed (Figure 2B), even across prior docetaxel use and disease volume. Independent central review further confirmed the investigators' assessment of radiographic progression (concordance rate, 85%). Treatment with apalutamide significantly improved overall survival (24-month event-free rates 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 3A). The treatment effect on overall survival consistently favored apalutamide over placebo, with no difference in the effect of apalutamide based on volume of disease (Figure 3B). Secondary Endpoints The time to cytotoxic chemotherapy was significantly improved with apalutamide compared with placebo (Table 4, Figure 4). Based on the pre-planned hierarchical test sequence, time to pain progression was tested and, failing to reach statistical significance, no formal testing for other secondary endpoints was performed. Table 4. Secondary and exploratory prespecified efficacy endpoints. zq LRnn / ίζηζ / Ε / γίΛΐ Endpoint Apalutamide (n=525) Placebo (n=527) Hazard Ratio (95° / o CI) p-value, stratified Mantel-Cox test Secondary endpoints Median time to cytotoxic chemotherapy - month NE NE 0.39 (0.270.56) <0.0001 Median time to pain progression* - month NE NE 0.83 (0.65- 1.05) 0.1173+ Median time to chronic opioid use - month NE NE 0.77 (0.54- 1.11) - Median time to skeletal-related events* - month NE NE 0.80 (0.56- 1.15) - Other clinically relevant endpoints Median time to symptomatic progression - month NE NE 1.20 (0.71- 2.02) Median time to symptomatic progression PSA - month NE 12.91 0.26 (0.210.32) Median second progression-free survival - month NE NE 0.66 (0.500.87) NE=not estimable. * The patient using the worst pain BPI-SF (item 3) reported pain progression. Scores range from 0 to 10, with lower scores representing lower levels of pain intensity; the minimally important difference was a change of 2. + Secondary endpoints were tested in a preplanned hierarchical sequence. When it was determined that time to pain progression was not significantly improved with apalutamide, no further secondary endpoints were formally tested. * Skeletal-related events were defined as the occurrence of symptomatic pathologic fracture, spinal cord compression, radiation to bone, or surgery to bone. Other relevant clinical endpoints The median time to PSA progression was more favorable after apalutamide compared with placebo (Figure 5, Table 4), with PSA reaching undetectable levels (PSA <0.2 ng per mL) in 68% and 29%. of patients in the apalutamide and placebo groups respectively. 87 and 190 patients in the apalutamide and placebo groups respectively received subsequent treatment for prostate cancer (first therapies described in Table 5). Median second progression-free survival was improved with apalutamide compared with placebo (Table 4; Figure 6). There were few events and no difference between groups in time to local symptomatic progression (Table 4). Analysis of the change in the FACT-P from baseline using a mixed-effect repeated measures model demonstrated that health-related quality of life was maintained and there was no difference between groups (Figure 7). ZQ LRnn / Lznz / Ε / ΥΙΛΙ Table 5: First subsequent systemic therapy for systemic prostate cancer Apalutamide (n=525) Placebo (n=527) Patients who discontinued treatment for any reason* and remained alive (denominator for first subsequent therapy calculations below)- no. 170 (%) 271 (%) Patients who discontinued treatment due to disease progression - no. (%) 99 (18.9) 227 (43.1) Patients with adverse events as the main reason for discontinuation - no. (%) 39 (7.4) 17 (3.2) Patients with adverse events leading to discontinuation - no. (%) 42 (8.0) 28 (5.3) Patients with subsequent therapy for life-prolonging prostate cancer + - no. (%) 87 (63) 190 (78) Patients receiving systemic therapy for prostate cancer at the data limit * - no. (%) 87 (51.2%) 190 (70.1%) First subsequent therapy Hormone therapy - no. (%) 44 (25.9) 98 (36.2) Abiraterone acetate plus prednisone 21 (12.4) 45 (16.6) Bicalutamide 16 (9.4) 31 (11.4) Enzalutamide 3(1.8) 17 (6.3) Other* 4 (2.4) 5 ( 1.8) Chemotherapy - no. (%) 35 (20.6) 73 (26.9) Docetaxel 29(17.1) 67 (24.7) Cabazitaxel 1 (0.6) 2 (0.7) Other§ 5 (2.9) 4(1.5) Other therapy - no. (%) 8 (4.7) 19 (7.0) Radio-223 2(1.2) 4(1.5) Sipuleucel-T 2(1.2) 5 (1.8) Other** 4 (2.4) 10 (3.7) Possible reasons for discontinuation were disease progression, adverse event, patient withdrawal, death, medical decision, and protocol violation. + Included docetaxel, abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T. *Some patients were unblinded after discontinuation and prior to the first subsequent therapy to allow enrollment in a subsequent clinical trial. § Diethylstilbestrol, flutamide and cyproterone were included. ** Included etoposide, paclitaxel, estramustine, carboplatin, and cisplatin. *** Zoledronic acid, dodronate, prednisolone and prednisone were included. Security Table 6 presents the most common treatment-emerging adverse events. 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) were not different between the groups. Most treatment discontinuations resulted from progressive disease (99 [19%] apalutamide; 227 [43%] placebo; Table 5). Adverse events led to discontinuation in (42 (8.0%) patients in the apalutamide group and 28 (5.3%) in the placebo group (Table 7). Ten (1.9%) and 16 (3.0%) patients in the apalutamide and placebo groups respectively died as a result of an adverse event (Table 8).Rash of any grade was more common among patients treated with apalutamide than placebo (27.1% and 8.5% respectively; Table 6), and the event The most common considered related to apalutamide was rash of any type (6.3%).Hypothyroidism was reported in 6.5% and 1.1% in each group respectively (Table 6), all events were grade 1 or 2. Cardiac disease was reported ischemic events in 4.4% and 1.5% of patients in the apalutamide and placebo groups, respectively; ischemic events led to death in two patients in each group. ZQ LRnn / Lznz / Ε / ΥΙΛΙ Table 6. Treatment-emergent adverse events. Adverse event Apalutamide (n=524) Placebo (n=527) Any adverse event 507 (96.8) 509 (96.6) Grade 3 or 4 adverse event 221 (42.2) 215 (40.8) Any serious adverse event 104 (19.8) 107 ( 20.3) Any adverse event leading to treatment suspension 42 (8.0) 28 (5.3) Adverse event leading to death 10 (1.9) 16 (3.0) Treatment-emergent adverse events reported in >10% of patients or grade >3 in >10 patients in any group All grades Grade >3 All grades Grade >3 Hot flashes 119 (22.7) 0 86 (16.3) 0 Fatigue 103 ( 19.7) 8(1.5) 88 (16.7) 6(1.1) Hypertension 93 (17.7) 44 (8.4) 82 (15.6) 48 (9.1) Back pain 91 (17.4) 12 (2.3) 102 (19.4) 14 (2.7) Arthralgia 91 (17.4) 2 (0.4) 78 (14.8) 5 (0.9) Pain in extremities 64 (12.2) 3 (0.6) 67 (12.7) 5 (0.9) Pruritus 56 (10.7) 1 (0.2) 24 (4.6) 1 (0.2) Weight gain 54 (10.3) 6(1.1) 89 (16.9) 10(1.9) Anemia 48 (9.2) 9(1.7) 71 (13.5) 17 (3.2) Constipation 47 (9.0) 0 57 (10.8) 0 Asthenia 37 (7.1) 10(1.9) 44 (8.3) 3 (0.6) Bone pain 34 (6.5) 6(1.1) 53 (10.1) 9(1.7) Generalized rash 34 (6.5) 14 (2.7) 5 (0.9) 2 (0.4) Blood alkaline phosphatase increased 16(3.1) 2 (0.4) 28 (5.3) 13 (2.5) Urinary retention 13(2.5) 0 19 (3.6) 10(1.9) Adverse events of special interest All grades Grade >3 All grades Grade >3 Eruption* 142 (27.1) 33 (6.3) 45 (8.5) 3 (0.6) Fall 39 (7.4) 4 (0.8) 37 (7.0) 4 (0.8) Fracture+ 33 (6.3) 7( 1.3) 24 (4.6) 4 (0.8) Hypothyroidism* 34 (6.5) 0 6(1.1) 0 Seizure§ 3 (0.6) 1 (0.2) 2 (0.4) 0 ZQ LRnn / Lznz / Ε / ΥΙΛΙ The values ​​are nos. (%). * Rash was a cluster term including rash, rash malar, rash erythematous, rash exfoliating, rash follicular, rash generalized, rash macular, rash maculopapular, papules, rash papular, rash pruritic, rash pustular, rash genital, blister, exfoliation of the skin, 5 exfoliating dermatitis, skin reaction, systemic lupus erythematosus rash, toxic skin rash, mouth ulceration, drug rash, conjunctivitis, erythema multiforme, stomatitis, and urticaria. + Fracture was a cluster term including acetabulum fracture, ankle fracture, clavicle fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, forearm fracture, fracture, fractured ischium, fracture pain, hand fracture, hip fracture, lower extremity fracture, patella fracture, radius fracture, rib fracture, skull fracture, spinal compression fracture, spinal fracture, sternal fracture, thoracic vertebral fracture, tibia fracture , traumatic fracture, ulna fracture, upper extremity fracture and wrist fracture. * Hypothyroidism was a pooled term that included autoimmune thyroiditis, increased blood thyroid-stimulating hormone, and hypothyroidism. § Seizure was a group term that included seizures and tongue biting. Table 7: Treatment-Emergent Adverse Events Leading to Treatment Discontinuation, Dose Reduction, and Dose Discontinuation Apalutamide (n=524) Placebo (n=527) All Grades Grade >3 All Grades Grade >3 Discontinuation Patients with treatment-emergent adverse events leading to discontinuation - no. (%) 42 (8.0) 26 (5.0) 28 (5.3) 22 (4.2) Rash* 12 (2.3) 7(1.3) 1 (0.2) 1 (0.2) New cancer neoplasm + 7(1.3) 5(1.0) 5 (0.9) 3 (0.6) Infections* 1 (0.2) 1 (0.2) 3 (0.6) 0 Fatigue 4 (0.8) 1 (0.2) 0 0 Ischemic Cardiac Episodes§ 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) Seizures 2 (0.4) 1 (0.2) 1 (0.2) 0 Pulmonary embolism 1 (0.2) 1 (0.2) 2 (0.4) 1 (0.2) Sudden death 0 0 2 (0.4) 2 (0.4) Cerebrovascular disorder 1 (0.2) 1 (0.2) 0 0 Parkinson's disease 1 (0.2) 1 (0.2) 0 0 Radiculopathy 1 (0.2) 1 (0.2) 0 0 Cognitive disorder 0 0 1 (0.2) 0 Intracranial hemorrhage 0 0 1 (0.2 ) 1 (0.2) Loss of consciousness 0 0 1 (0.2) 1 (0.2) Atrial fibrillation 1 (0.2) 1 (0.2) 0 0 Cardiopulmonary arrest 1 (0.2) 1 (0.2) 0 0 Cardiogenic shock 1 (0.2) 1 ( 0.2) 0 0 Heart failure 0 0 1 (0.2) 1 (0.2) Sudden cardiac death 1 (0.2) 1 (0.2) 0 0 Hypothermia 0 0 1 (0.2) 1 (0.2) Anxiety 1 (0.2) 0 0 0 Euphoric mood 1 (0.2) 0 0 0 Suicide 0 0 1 (0.2) 1 (0.2) Perforation of large intestinal ulcer 1 (0.2) 1 (0.2) 0 0 Swelling of the lip 1 (0.2) 0 0 0 Dyspnea 0 0 1 (0.2) 0 Pleural effusion 0 0 1 (0.2) 1 (0.2) Pulmonary edema 0 0 1 (0.2) 1 (0.2) Respiratory failure 0 0 1 (0.2) 1 (0.2) Dehydration 1 (0.2) 0 0 0 Hot flashes 1 (0.2) 0 0 0 Subdural hemorrhage 0 0 1 (0.2) 1 (0.2) Alanine aminotransferase increased 0 0 1 (0.2) 1 (0.2) Dose reduction Patients with treatment-emergent adverse events leading to dose reduction the dose - no. (%) 37 (7.1) 19 (3.6) 11 (2.1) 1 (0.2) Rash* 28 (5.3) 11(2.1) 4 (0.8) 1 (0.2) Increased aspartate aminotransferase or alanine aminotransferase 0 0 4 (0.8) 0 Fatigue 2 (0.4) 2 (0.4) 0 0 Headache 1 (0.2) 0 1 (0.2) 0 Hypertension 1 (0.2) 1 (0.2) 1 (0.2) 0 Neutropenia 2 (0.4) 2 (0.4) 0 0 Cognitive disorder 1 (0.2) 1 (0.2) 0 0 General deterioration of physical health 1 (0.2) 1 (0.2) 0 0 Hot flashes 1 (0.2) 0 0 0 Asthenia 0 0 1 (0.2) 0 Dehydration 1 (0.2) 0 0 0 Lethargy 0 0 1 (0.2) 0 Pain** 1 (0.2) 0 0 0 Decreased performance status 0 0 1 (0.2) 0 Vertigo 1 (0.2) 1 (0.2) 0 0 Weight decreased 1 (0.2) 1 (0.2) 0 0 Dose Interruption Patients with treatment-emergent events leading to dose discontinuation - no. (%) 104 (19.8) 68(13.0) 63 (12.0) 43 (8.2) Rash* 44 (8.4) 20 (3.8) 5 (0.9) 2 (0.4) Increased aspartate aminotransferase or alanine aminotransferase 7(1.3) 4 ( 0.8) 12 (2.3) 7(1.3) Pain** 9(1.7) 4 (0.8) 7(1.3) 3 (0.6) Infections* 6(1-1) 4 (0.8) 9(1.7) 3 (0.6) Hypertension 6(1.1) 6(1.1) 6(1.1) 6(1.1) Fatigue 6(1.1) 1 (0.2) 2 (0.4) 1 (0.2) Vomiting 3 (0.6) 0 4 (0.8) 0 Anemia 2 (0.4) 0 3 (0.6) 2 (0.4) Asthenia 3 (0.6) 3 (0.6) 2 (0.4) 1 (0.2) Decreased appetite 2 (0.4) 1 (0.2) 3 (0.6) 1 (0.2) New cancer neoplasm + 3 (0.6) 1 (0.2) 1 (0.2) 1 (0.2) Diarrhea 1 (0.2) 0 3 (0.6) 0 Chronic obstructive pulmonary disease 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) Pyrexia 3 (0.6 ) 0 1 (0.2) 0 Urinary retention 2 (0.4) 2 (0.4) 2 (0.4) 2 (0.4) Arthralgia 2 (0.4) 0 1 (0.2) 0 Insomnia 3 (0.6) 0 0 0 Acute kidney injury 1 (0.2 ) 1 (0.2) 1 (0.2) 1 (0.2) Anxiety 2 (0.4) 0 0 0 Stroke 1 (0.2) 1 (0.2) 1 (0.2) 0 Dizziness 1 (0.2) 0 1 (0.2) 0 Dyspnea 1 ( 0.2) 0 1 (0.2) 1 (0.2) Fall 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Headache 1 (0.2) 0 1 (0.2) 1 (0.2) Hematuria 2 (0.4) 2 (0.4) 0 0 Hot flashes 1 (0.2) 0 1 (0.2) 0 Hypersensitivity 1 (0.2) 0 1 (0.2) 0 Hypertriglyceridemia 2 (0.4) 2 (0.4) 0 0 Hyponatremia 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Muscular weakness 1 (0.2) 0 1 (0.2) 1 (0.2) Nausea 1 (0.2) 0 1 (0.2) 0 Neutropenia 2 (0.4) 2 (0.4) 0 0 Compression of spinal cord 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Acute respiratory failure 1 (0.2) 1 (0.2) 0 0 Allergy to chemicals 1 (0.2) 1 (0.2) 0 0 Unstable angina 0 0 1 (0.2) 1 (0.2) Atrial fibrillation 1 (0.2) 1 (0.2) 0 0 Bile duct obstruction 0 0 1 (0.2) 1 (0.2) Blood alkaline phosphatase increased 1 (0.2) 1 (0.2) 0 0 Cardiac amyloidosis 0 0 1 (0.2) 1 (0.2) Cardiac disorder 0 0 1 (0.2) 1 (0.2) Heart failure 0 0 1 (0.2) 0 Congestive heart failure 1 (0.2) 1 (0.2) 0 0 Cheilitis 1 ( 0.2) 0 0 0 Chronic hepatitis 1 (0.2) 0 0 0 Cognitive disorder 1 (0.2) 1 (0.2) 0 0 Confusional state 1 (0.2) 1 (0.2) 0 0 Constipation 1 (0.2) 0 0 0 Dehydration 0 0 1 (0.2) 0 Depression 1 (0.2) 0 0 0 Diabetes mellitus 1 (0.2) 1 (0.2) 0 0 Diplegia 0 0 1 (0.2) 1 (0.2) Dysuria 1 (0.2) 1 (0.2) 0 0 Edema 1 (0.2) 0 0 0 Eyelid edema 1 (0.2) 0 0 0 Facial edema 1 (0.2) 0 0 0 Febrile neutropenia 1 (0.2) 1 (0.2) 0 0 Increased gamma-glutamyltransferase 1 (0.2) 1 ( 0.2) 0 0 Gastric ulcer perforation 1 (0.2) 1 (0.2) 0 0 Gastritis 0 0 1 (0.2) 1 (0.2) General deterioration of physical health 1 (0.2) 1 (0.2) 0 0 Hallucination 1 (0.2) 0 0 0 Hematoma 1 (0.2) 1 (0.2) 0 0 Erosive hemorrhagic gastritis 1 (0.2) 1 (0.2) 0 0 Intracranial hemorrhage 1 (0.2) 1 (0.2) 0 0 Liver cirrhosis 1 (0.2) 0 0 0 Liver failure 0 0 1 (0.2) 1 (0.2) Hip fracture 1 (0.2) 1 (0.2) 0 0 Hypokalemia 1 (0.2) 1 (0.2) 0 0 Hydronephrosis 0 0 1 (0.2) 1 (0.2) Hyperbilirubinemia 1 (0.2) 1 (0.2) 0 0 Influenza-Like Illness 1 (0.2) 0 0 0 Large Intestinal Ulcer Perforation 1 (0.2) 1 (0.2) 0 0 Mental Status Changes 1 (0.2) 0 0 0 Musculoskeletal Stiffness 0 0 1 (0.2) 0 Ischemic Cardiac Episodes§ 1 (0.2) 1 (0.2) 0 0 Osteoarthritis 0 0 1 (0.2) 1 (0.2) Osteoporosis 1 (0.2) 0 0 0 Pathologic Fracture 0 0 1 (0.2) 1 (0.2) Edema peripheral 1 (0.2) 0 0 0 Peripheral swelling 0 0 1 (0.2) 1 (0.2) Proctalgia 1 (0.2) 0 0 0 Kidney Injury 0 0 1 (0.2) 0 Rheumatoid Arthritis 1 (0.2) 1 (0.2) 0 0 Seizures 1 (0.2) 0 0 0 Stomatitis 1 (0.2) 0 0 0 Subarachnoid Hematoma 1 (0.2) 1 (0.2) 0 0 Hemorrhage subarachnoid 1 (0.2) 0 0 0 Subdural hemorrhage 0 0 1 (0.2) 1 (0.2) Syncope 1 (0.2) 1 (0.2) 0 0 Thrombocytopenia 1 (0.2) 0 0 0 Ulceration of tongue 1 (0.2) 0 0 0 Urinary incontinence 1 (0.2) 0 0 0 Urinary tract obstruction 1 (0.2) 1 (0.2) 0 0 Urethral stricture 0 0 1 (0.2) 0 Vertigo 1 (0.2) 1 (0.2) 0 0 Weight gain 0 0 1 (0.2) 0 * Rash was a pooled term including eczema, nummular eczema, exfoliating rash, generalized rash, rash, dermatitis, exfoliating dermatitis, psoriasis, hyperhidrosis, maculopapular rash, macular rash, drug eruption, erythema multiforme, lichenoid keratosis, pruritus, itchy rash, skin exfoliation, skin lesion, skin reaction and toxic skin rash. + New cancer neoplasms (benign, malignant, and unspecified [including cysts and polyps]) was a pooled term including malignant lung neoplasms, colon adenoma, colon neoplasms, leiomyosarcoma, oropharyngeal cancer, papilloma, rectal adenocarcinoma, carcinoma small cell, gastric adenocarcinoma, colon adenocarcinoma, bladder cancer, and non-small cell lung cancer. * Infections was a pooled term that included urinary tract infection, Klebsiella infection, sepsis, urosepsis, fungal infection, localized infection, pulmonary infection, pneumonia, respiratory tract fungal infection, acarodermatitis, cellulitis, bacterial bronchitis, influenza, necrotizing fasciitis, and viral infection of the upper respiratory tract. § Ischemic cardiac events was a cluster term that included myocardial infarction, acute myocardial infarction, acute coronary syndrome. * * Pain was a pooled term including pain in extremity, back pain, bone pain, upper abdominal pain, lower abdominal pain, musculoskeletal pain, neck pain, and non-cardiac chest pain. Table 8: Investigator reported cause of death in study in safety population zq LRnn / ίζηζ / Ε / γίΛΐ Apalutamide (n=524) Placebo (n=527) All deaths within 30 days of last dose no. (%) 18(3.4) 23 (4.4) Death due to prostate cancer 8(1.5) 7(1.3) Death due to adverse event 10(1.9) 16 (3.0) Adverse event leading to death - no. (%) Respiratory failure 1 (0.2) 2 (0.4) Acute kidney injury 2 (0.4) 0 Acute myocardial infarction 1 (0.2) 1 (0.2) Sudden death 0 2 (0.4) Acute coronary syndrome 0 1 (0.2) Heart failure 0 1 (0.2) Cardiopulmonary arrest 1 (0.2) 0 Cardiogenic shock 1 (0.2) 0 Cerebrovascular accident 1 (0.2) 0 Death 0 1 (0.2) Hypothermia 0 1 (0.2) Intracranial hemorrhage 0 1 (0.2) Perforation of large intestinal ulcer 1 (0.2) 0 Myocardial infarction 1 (0.2) 0 Pulmonary embolism 0 1 (0.2) Sepsis 0 1 (0.2) Subdural hemorrhage 0 1 (0.2) Sudden cardiac death 1 (0.2) 0 Suicide 0 1 (0.2) Urosepsis 0 1 (0.2) Vascular rupture 0 1 (0.2) A post-hoc analysis representing the competing risk of death based on the Fine-Gray model was performed (Table 9). Fine JP, Gray RJ. J Am Stat Assoc 1999;94:496-509. Estimates of a subdistribution hazard ratio for the apalutamide group relative to the placebo group are presented, along with the respective 95% confidence limits and Wald Chi-Square test P values. The results of this post-hoc analysis supported and confirmed the results of the previously planned analysis. Table 9: Subdistribution Hazard Ratio Calculations for the Apalutamide Group Relative to the Placebo Group zq LRnn / ίζηζ / Ε / γίΛΐ P value Hazard ratio 95% confidence limits of hazard ratio Time to cytotoxic chemotherapy <0.0001 0.408 0.286 0.581 Time to pain progression 0.1540 0.843 0.667 1.066 Time to chronic opioid use 0.2004 0.789 0.549 1.13 4 Time to the related event 0.2759 0.818 0.570 1.174 with the skeleton Management of the rash Rash associated with apalutamide was most often described as generalized or maculopapular. 27.1% of patients in the apalutamide group vs. 8.5% in the placebo group reported treatment-emergent rash. Grade 3 rashes were reported with apalutamide (6.3%) and placebo (0.6%) treatment. Stevens-Johnson syndrome and toxic epidermal necrolysis were not reported. Rash led to treatment discontinuation, dose reduction, and dose discontinuation in 12 (2.3%), 28 (5.3%), and 44 (8.4%) patients respectively in the apalutamide group, and 1 (0.2%), 4 (0.8%) and 5 (0.9%) patients, respectively, in the placebo group. Grade >3 rash led to discontinuation in 7 (1.3%) and 1 (0.2%) patients in the apalutamide and placebo groups, respectively (Table 7). For patients who developed a rash, treatment included topical corticosteroids, oral antihistamines, systemic corticosteroids, drug discontinuation, and dose reduction. The median time to rash onset was 81 days in the apalutamide group and 141 days in the placebo group. Analysis In this phase 3 study in men with metastatic castration-sensitive prostate cancer (mCSPC), apalutamide plus ADT significantly improved overall survival and radiographic progression-free survival compared with placebo plus ADT. The reduced risk of death did not differ based on volume of disease, and benefits in radiographic progression-free survival were consistently observed in all subgroups analyzed, including patients with prior docetaxel exposure. Longer survival was observed with apalutamide even though a higher proportion of patients in the placebo group who discontinued treatment received subsequent life-prolonging prostate cancer therapy (64 of 170 patients [38%] and 165 of 271 patients [61%] in the apalutamide and placebo groups respectively; Table 5). Based on the results of this first planned interim analysis, the independent data monitoring committee recommended unblinding to allow crossover of patients receiving placebo to receive apalutamide. Secondary and exploratory endpoints further favored apalutamide treatment, including time to cytotoxic chemotherapy and time to second progression-free survival. Apalutamide plus ADT also resulted in a higher proportion of patients achieving undetectable PSA levels and a delay in time to PSA progression compared with placebo plus ADT. In this illustrated study, initial therapy with apalutamide in patients with metastatic castration-sensitive prostate cancer led to better clinical outcomes. The intent of the trial was to enroll a large group of patients with metastatic castration-sensitive prostate cancer, resulting in the limitation that certain subgroups of patients were relatively small. For example, although all patients recognized the survival benefit of docetaxel during informed consent, only 11% received prior docetaxel prior to study enrollment. This probably reflects the perceived suitability of the patient for docetaxel and differences in patient choice or methods of care. However, the consistency of the clinical benefit of apalutamide across all subgroups is reasonable. The rates of high-grade and serious adverse events were not different in the apalutamide and placebo groups; discontinuation rates due to adverse events were low in both groups. Adverse events were generally consistent with the known safety profile of apalutamide. Apalutamide treatment-related rash was common and typically managed with topical antihistamines and glucocorticoids, dose discontinuation, and dose reduction. Hypothyroidism was mild to moderate, monitored by thyroid-stimulating hormone, and managed with levothyroxine. Health-related quality of life was also preserved, with no difference between groups, supporting the tolerability of apalutamide plus ADT. zq LRnn / ίζηζ / Ε / γίΛΐ In conclusion, in the exemplified study in patients with metastatic castration-sensitive prostate cancer, including those with high-volume and low-volume disease, prior docetaxel use, prior treatment for localized disease, and patients with de novo or prior disease. diagnosed, the addition of apalutamide to ADT significantly improved overall survival and delayed disease progression, with a safety profile not markedly different from placebo plus ADT, and health-related quality of life preserved. Apalutamide formulation The apalutamide tablet supplied for this study contains 60 mg of apalutamide. It was manufactured and supplied under the responsibility of the sponsor. The placebo was provided as a tablet formulation and will be matched in size, color and shape to keep the study blinded. Packing Apalutamide 60 mg tablets were packaged in 120 count, 160 cc high density polyethylene (HDPE) bottles with child resistant closures. Example 2: Final FDA-approved drug product label The FDA approved the following drug product labeling on September 17, 2019 for ERLEADA™ (apalutamide), which is the reference listed drug and reference standard for apalutamide. ZQ LRnn / LZnZ / Ε / ΥΙΛΙ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ERLEADA safely and effectively. Please see full prescribing information for ERLEADA. ERLEADA® (apalutamide) tablets for oral use Initial US Approval-2018 ......RECENT IMPORTANT CHANGES..... Indications and use (1) 09 / 2019 Warnings and precautions (5) 09 / 2019 --------------INDICATIONS and usage-------------ERLEADA is an androgen receptor inhibitor indicated for the treatment of patients with • prostate cancer sensitive to metastatic castration (1) Fractures occurred in patients who received ERLEADA. Assess patients at risk for fracture and fall, and treat patients with bone-targeted agents according to established guidelines. (5.2) Falls occurred in patients receiving ERLEADA with a higher incidence in the elderly. Assess patients at risk of falling. (5.3) Seizures occurred in 0.4% of patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop seizures during treatment. (5.4) Embryo-Fetal Toxicity ERLEADA may cause fetal harm. Advise men with female partners of reproductive potential to use effective contraception. (5.5, 8.1, 8.3). -......ADVERSE REACTIONS............. • metastatic castration resistant prostate cancer: (1) ......DOSAGE AND ADMINISTRATION..... ERLEADA 240 mg (four 60-mg tablets) taken orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food (2.1) Patients must also receive a gonadotropin-releasing hormone (GnRH) analog simultaneously or they should have had bilateral orchiectomy. (2.1) DOSAGE FORMS AND STRENGTHS Tablets: 60mg (3) ..........—CONTRAINDICATIONS............ None .......WARNINGS AND CAUTIONS....... • Ischemic cardiovascular events occurred in patients receiving ERLEADA. Manage the signs and symptoms of ischemic heart disease. Optimize the management of cardiovascular risk factors. (5.1). The most common adverse reactions (>10%) are fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, shortness of breath, diarrhea, and fracture. (6.1) To report a SUSPECTED ADVERSE REACTION, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800JANSSEN) or FDA at 1-800-FDA-.1088 or www.fda.gov / medwatch. ------DRUG INTERACTIONS...... • Concomitant use with drugs sensitive to CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 substrates could result in loss of activity of these drugs. (7.2) See PATIENT COUNSELING INFORMATION in Section 17 and FDA-approved patient labeling. Revised: 09 / 2019 zQLRnn / Lznz / E / Yi FULL PRESCRIBING INFORMATION: INDEX* INDICATIONS AND USE DOSAGE AND ADMINISTRATION 2.1 Recommended dosage 2.2 Dose modification DOSAGE FORMS AND CONCENTRATIONS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Ischemic cardiovascular events 5.2 Fractures 5.3 Falls 5.4 Seizures 5.5 Embryo-Fetal Toxicity ADVERSE REACTIONS 6.1 Experience in clinical trials DRUG INTERACTIONS 7.1 Effect of Other Drugs on ERLEADA 7.2 Effect of ERLEADA on other drugs USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Women and men with reproductive potential 8.4 Pediatric use 8.5 Geriatric use OVERDOSE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of action 12.2 Pharmacodynamics 12.3 Pharmacokinetics NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES HOW SUPPLIED / STORAGE AND HANDLING PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not noted. Full Prescribing Information 1 INDICATIONS AND USE ERLEADA is indicated for the treatment of patients with • metastatic castration-sensitive prostate cancer (mCSPC) • non-metastatic castration-resistant prostate cancer (nmCRPC) DOSAGE AND ADMINISTRATION 2.1 Recommended dosage The recommended dose 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. Patients must also receive a gonadotropin-releasing hormone (GnRH) analog simultaneously or they should have had a bilateral orchiectomy. 2.2 Dose modification If a patient experiences toxicity greater than or equal to Grade 3 toxicity or an intolerable side effect, stop dosing until symptoms improve to less than or equal to Grade 1 or original grade, then resume at the same dose or at a reduced dose (180 mg or 120 mg), if warranted. DOSAGE FORMS AND STRENGTHS Tablets (60 mg): slightly yellowish to greyish-green, oval, film-coated tablets, debossed with AR 60 on one side. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS 5.1 Ischemic cardiovascular events Ischemic cardiovascular events, including events leading to death, have occurred in patients receiving ERLEADA. Manage the signs and symptoms of ischemic heart disease. Optimize the management of cardiovascular risk factors, such as hypertension, diabetes or dyslipidemia. Consider discontinuation of ERLEADA for grade 3 and 4 events. 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) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of ERLEADA-treated patients and 2% of placebo-treated patients. Between the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died of an ischemic cardiovascular event. Patients with zq LRnn / ίζηζ / Ε / γίΛΐ current evidence of unstable angina, myocardial infarction, or congestive heart failure within six months of randomization were excluded from the SPARTAN and TITAN studies. 5.2 Fractures Fractures occurred in patients who received ERLEADA. Assess patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider the use of bone-directed agents. In a randomized study (SPARTAN) of patients with non-metastatic castration-resistant prostate cancer, fractures occurred in 12% of ERLEADA-treated patients and 7% of placebo-treated patients. Grade 3-4 fractures were observed in 3% of ERLEADA-treated patients and 1% of placebo-treated patients. The median time to fracture onset was 314 days (range: 20 to 953 days) for patients treated with ERLEADA. Routine assessments of bone density and treatment of osteoporosis with bone-targeted agents were not performed in the SPARTAN study. In a randomized study (TITAN) of patients with metastatic castration-sensitive prostate cancer, fractures occurred in 9% of ERLEADA-treated patients and 6% of placebo-treated patients. Grade 3-4 fractures were similar in both arms by 2%. The median time to fracture onset was 56 days (range: 20 to 111 days) for patients treated with ERLEADA. Routine assessments of bone density and treatment of osteoporosis with bone-targeted agents were not performed in the TITAN study. 5.3 Falls Falls occurred in patients receiving ERLEADA, more frequently in the elderly [see Use in Specific Populations (8.5J\. Assessing Patients at Risk for Falls. In a randomized study (SPARTAN), falls occurred in 16% of ERLEADA-treated patients compared to 9% of placebo-treated patients. Falls were not associated with loss of consciousness or seizures. 5.4 Seizures Seizures occurred in patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop seizures during treatment. It is not known if antiepileptic drugs will prevent seizures with ERLEADA. Inform patients of the risk of developing a seizure when receiving ERLEADA and of participating in any activity in which a sudden loss of consciousness could cause harm to themselves or others. In two randomized studies (SPARTAN and TITAN), five ERLEADA-treated patients (0.4%) and one placebo-treated patient (0.1%) experienced a seizure. The 7Q LRnn / ίΖΠΖ / Ε / ΥΙΛΙ seizures occurred 159 to 650 days after ERLEADA initiation. Patients with a history of seizures, predisposing factors for seizures, or receiving medications known to lower the seizure threshold or induce seizure were excluded. There is no clinical experience with re-administration of ERLEADA to patients who experienced seizures. 5.5 Embryo-Fetal Toxicity The safety and efficacy of ERLEADA in women have not been established. Based on its mechanism of action, ERLEADA may cause fetal harm and miscarriage when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)]. ADVERSE REACTIONS The following are discussed in greater detail in other sections of the labeling: • Ischemic cardiovascular events [see Warnings and Precautions (5.1)]. • Fractures [see Warnings and Precautions (5.2)]. • Falls [see Warnings and Precautions (5.3)]. • Convulsions [see Warnings and Precautions (5.4)]. 6.1 Experience in clinical trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials for one drug cannot be directly compared with rates in clinical trials for another drug and may not reflect rates observed in practice. The most common adverse reactions (>10%) that occurred more frequently in ERLEADA-treated patients (>2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash , decreased appetite, fall, weight loss, hypertension, hot flashes, diarrhea and fracture. Metastatic Castration Sensitive Prostate Cancer (mCSPC) TITAN, a randomized (1:1), double-blind, placebo-controlled, multicenter clinical trial, enrolled patients who had mCSPC. In this study, patients received ERLEADA at a dose of 240 mg daily or placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had an orchiectomy ZQ LRnn / Lznz / Ε / ΥΙΛΙ bilateral. The median duration of exposure was 20 months (range: 0 to 34 months) in patients receiving ERLEADA and 18 months (range: 0.1 to 34 months) in patients receiving placebo. Ten patients (2%) who were treated with ERLEADA died from adverse reactions. Reasons for death were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardiorespiratory arrest (n=l), sudden cardiac death (n=l), respiratory failure (n=l), cerebrovascular accident (n=l) and large intestinal ulcer perforation (n=l). ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly rash (2%). Adverse reactions leading to dose discontinuation or reduction of ERLEADA occurred in 23% of patients: the most common (>1%) were rash, fatigue, and hypertension. Serious adverse reactions occurred in 20% of ERLEADA-treated patients and 20% of placebo-treated patients. Table 1 shows adverse reactions occurring in >10% in the ERLEADA arm in TITAN and occurring at an absolute increase in frequency of >2% compared to placebo. Table 2 shows laboratory abnormalities that occurred in >15% of patients and more frequently (>5%) in the ERLEADA amm group compared to placebos. Table 1: Adverse reactions in TITAN fmCSPO ZQ LRnn / Lznz / Ε / ΥΙΛΙ Systemic Group Adverse Reaction ERLEADA N=524 All Grade 3- Placebo N=527 All Grade 3- Grades % 4% Grades % 4% General Disorders and Administration Site Conditions Fatigue1 3 26 3 25 2 Musculoskeletal Tissue Disorders and connective tissue Arthralgia3 Arthralgia3 17 0.4 15 0.9 Skin and subcutaneous tissue disorders Rash2 28 6 9 0.6 Pruritus 11 <1 5 <1 Vascular disorders Hot flashes 23 0 16 0 Hypertension 18 8 16 9 Includes fatigue and asthenia2Includes rash, rash maculopapular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, exfoliation, rash genital, rash erythematous, stomatitis, drug eruption, mouth ulceration, pustular rash , bullae, papule, pemphigoid, skin erosion and vesicular rash According to the Common Terminology Criteria for Adverse Events (CTCAE), the highest severity for these events is Grade 3. Additional adverse reactions of interest that occurred in 2% but less than 10% of ERLEADA-treated patients included diarrhea (9% vs. 6% placebo), muscle spasm (3% vs. 2% placebo) , dysgeusia (3% vs. 1% placebo) and hypothyroidism (4% vs. 1% placebo). Table 2: Laboratory abnormalities occurring in >15% of patients treated with ERLEADA and at a higher incidence than placebo (between arm difference > 5% of all grades) in TITAN (mCSPC) Laboratory abnormality ERLEADA N=524 Placebo N=527 All grades % Grade 34% All G grades % rado 34% Hematology Leukocyte count decreased 27 0.4 19 0.6 Chemistry Hypertriglyceridaemia117 3 12 21Does not reflect fasting values Non-metastatic castration resistant prostate cancer (nmCRPC); SPARTAN, a multicenter, randomized (2:1), double-blind, placebo-controlled clinical study, enrolled patients with amCRPC. In this study, patients received ERLEADA at a dose of 240 mg daily or placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analogue or had bilateral orchiectomy. The median duration of exposure was 16.9 months (range: 0.1 to 42 months) in patients receiving ERLEADA and 11.2 months (range: 0.1 to 37 months) in patients receiving placebo. Eight patients (1%) who were treated with ERLEADA died from adverse reactions. Reasons for death were infection (n=4), myocardial infarction (n=3), and cerebral hemorrhage (n=1). One patient (0.3%) treated with placebo died from an adverse reaction of cardiopulmonary arrest (n=1). ERLEADA was discontinued due to adverse reactions in 11% of patients, most commonly rash (3%). Adverse reactions leading to dose discontinuation or reduction of ERLEADA occurred in 33% of patients: the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of ERLEADA-treated patients and 23% of placebo-treated patients. The most frequent serious adverse reactions 5 (>2%) were fractures (3%) in the ERLEADA arm and urinary retention (4%) in the placebo arm. Table 3 shows the adverse reactions that occurred in >10% in the treatment arm. ERLEADA in SPARTAN and which occurred at an absolute increase in frequency of >2% compared to placebo. Table 4 shows laboratory abnormalities that occurred in >15% of patients and more frequently (>5%) in the ERLEADA arm compared to placebos. Table 3: Adverse reactions in SPARTAN (nmCRPO zq LRnn / ίζηζ / Ε / γίΛΐ System / Organ Class Adverse Reaction ERLEADA N=803 All Grade 3- Placebo N=398 All Grade 3- Grades % 4% Grades % 4% General Disorders and Administration Site Conditions Fatigue1'4 39 1 28 0.3 Disorders Musculoskeletal and connective tissue arthralgia4 16 0 8 0 Skin and subcutaneous tissue disorders Rash2 25 5 6 0.3 Metabolism and nutrition disorders Decreased appetite5 12 0.1 9 0 Peripheral edema6 11 0 9 0 Injuries, poisoning and procedural complications Fall4 16 2 9 0.8 Fracture3 12 3 7 0.8 Investigations Weight decreased4 16 1 6 0.3 Vascular disorders Hypertension 25 14 20 12 Hot flashes 14 0 9 0 Gastrointestinal disorders Diarrhea 20 1 15 0.5 Nausea 18 0 16 0 1Includes fatigue and asthenia Includes rash, rash maculopapular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, exfoliation, rash genital, rash erythematous, stomatitis, drug eruption, mouth ulceration, pustular rash, blistering, papule, pemphigoid, skin erosion, dermatitis and vesicular rash Includes rib fracture, lumbar vertebra fracture, spinal compression fracture, spine fracture, foot fracture, hip fracture, humerus fracture, thoracic vertebra fracture, upper limb fracture, fractured sacrum, hand fracture, hip fracture pubis, acetabulum fracture, knee fracture, compression fracture, rib cartilage fracture, facial bone fracture, lower limb fracture, osteoporotic fracture, wrist fracture, avulsive fracture, fibula fracture, coccyx fracture, pelvic fracture, radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebra fracture, femoral neck fracture, and tibial fracture4Based on Common Terminology Criteria for Adverse Events (CTCAE), the highest severity for these events is grade 35Includes appetite disorder, decreased appetite, early satiety, and hypophagia θ Includes peripheral edema, generalized edema, edema, genital edema, peripheral edema, peripheral swelling, scrotal edema, lymphedema, swelling, and localized edema Other clinically significant adverse reactions that occurred in 2% or more of ERLEADA-treated patients were hypothyroidism (8.1% vs. 2% placebo), pruritus (6.2% vs. 2% placebo), and heart failure (2.2 % vs. 1% on placebo). Table 4: Laboratory Abnormalities Occurring in > 15% of Patients Treated With ERLEADA and at a higher incidence than placebo (between arm difference > 5% of all grades) in SPARTAN (nmCRPC) ERLEADA Placebo No.=803 No.=398 Laboratory Abnormality All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hematology Anemia 70 0.4 64 0.5 Leukopenia 47 0.3 29 0 Lymphopenia 41 2 21 2 Chemical Hypercholesterolemia1 76 0.1 46 0 Hyperglycemia1 70 2 59 1 Hypertriglyceridemia 1 67 2 49 0.8 Hyperkalemia 32 2 22 0.5 Does not reflect fasting values Rash In pooled data from two randomized placebo-controlled trials, ERLEADA-associated rash was most commonly described as macular or maculopapular. Rash adverse reactions were reported for 26% of patients treated with ERLEADA vs. 8% of patients treated with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA treatment (6%) versus placebo (0.5%). Rash onset occurred at a median of 83 days of ERLEADA treatment. The rash cleared in 78% of patients with a median of 78 days from rash onset. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose discontinuation occurred in 14% and 28% of patients, respectively. Of the patients whose dose was discontinued, 59% experienced a recurrence of the rash after reintroduction of ERLEADA. hypothyroidism In pooled data from two randomized placebo-controlled clinical studies, hypothyroidism was reported in 8% of ERLEADA-treated patients and 2% of placebo-treated patients, as assessed by thyroid-stimulating hormone ( TSH) every 4 months. Elevated TSH was observed in 25% of ERLEADA-treated patients and 7% of placebo-treated patients. The median onset was at the first scheduled evaluation. There were no grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 5% of ERLEADA-treated patients. Thyroid replacement therapy, when clinically indicated, should be initiated or dose titrated [see Drug Interactions (7.2)]. DRUG INTERACTIONS 7.1 Effect of Other Drugs on ERLEADA Strong inhibitors of CYP2C8 or CYP3A4 Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is anticipated to increase the steady-state exposure of active entities (sum of unbound apalutamide plus unbound N-desmethyl apalutamide adjusted for power). However, no initial dose adjustment is necessary, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)]. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect apalutamide exposure. ZQ LRnn / Lznz / Ε / ΥΙΛΙ 7.2 Effect of ERLEADA on other drugs CYP3A4, CYP2C9, CYP2C19 v UGT substrates ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with drugs that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 may result in lower exposure to these drugs. Substitution of these drugs is recommended when possible or assess for loss of activity if medication is continued. Co-administration of ERLEADA with medicinal products that are substrates of UDP-glucuronosyl transferase (UGT) may result in decreased exposure. Use caution if TIG substrates must be administered in combination with ERLEADA and assess for loss of activity [see Clinical Pharmacology (12.3)]. Substrates of P-qp, BCRP or QATP1B1 Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and organic anion transporting polypeptide 1B1 (OATPIB1) clinically. At steady state, apalutamide reduced plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP / OATPIB1 substrate). Concomitant use of ERLEADA with drugs that are substrates of P-gp, BCRP, or OATP1B1 may result in decreased exposure of these drugs. Use caution if P-gp substrates, BCRP, or OATPIB1 should be given in combination with ERLEADA, and assess for loss of activity if medication is continued [see Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The safety and efficacy of ERLEADA in women have not been established. Based on its mechanism of action. ERLEADA may cause fetal harm and pregnancy loss [see Clinical Pharmacology (12.1)]. There are no human data from the use of ERLEADA in pregnant women. ERLEADA is not indicated for use in women, therefore embryonic-fetal developmental toxicology studies in animals have not been conducted with apalutamide. 8.2 Lactation Risk Summary The safety and efficacy of ERLEADA in women have not been established. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. ZQ LRnn / Lznz / Ε / ΥΙΛΙ 8.3 Women v men with reproductive potential Contraception males Based on the mechanism of action and findings in an animal reproduction study, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. [see Use in Specific Populations (8.1)]. infertility males Based on animal studies. ERLEADA may affect fertility in human males of reproductive potential [see Nonclinical Toxology (13.1)]. 8.4 Pediatric use The safety and efficacy of ERLEADA in pediatric patients have not been established. 8.5 Keriatric use Of the 1327 patients who received ERLEADA in clinical studies. 19% of patients were under 65 years of age, 41% of patients were 65 to 74 years of age, and 40% were 75 years of age or older. No overall differences in efficacy were observed between older patients and younger patients. Of ERLEADA-treated patients (n=1073). Grade 3-4 adverse reactions occurred in 39% of patients less than 65 years of age. 41% of patients aged 65-74 and 49% of patients aged 75 and over. Falls in patients receiving ERLEADA with androgen deprivation therapy were elevated in the elderly, occurring in 8% of patients younger than 65 years. 10% of patients aged 65-74 and 19% of patients aged 75 and over. OVERDOSE There is no known specific antidote for apalutamide overdose. In case of overdose, discontinue ERLEADA, take general supportive measures until clinical toxicity has been reduced or resolved. DESCRIPTION Apalutamide, the active ingredient in ERLEADA, is an androgen receptor inhibitor. The chemical name is 4-[7-(6-cyano-5-tr¡fluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6-thioxo-5,7diazaspiro[3,4] oct-5-¡l]-2-fluoro-N-methylbenzamida). Apalutamide is a white to slightly yellowish powder. Apalutamide is practically insoluble in aqueous media over a wide range of pH values. The molecular weight is 477.44 and the molecular formula is C21H15F4N5O2S. The structural formula is: ZQ LRnn / Lznz / Ε / ΥΙΛΙ ERLEADA (apalutamide) is supplied as film-coated tablets for oral administration containing 60 mg of apalutamide. The inactive ingredients of the core tablet are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. The tablets are finished with a commercially available film coating comprising the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. CLINICAL PHARMACOLOGY 12.1 Mechanism of action Apalutamide is an androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and prevents AR-mediated transcription. A major metabolite. Ndesmethylapalutamide is a less potent AR inhibitor and exhibited one-third the activity of apalutamide in in vitro transcriptional delivery. Analutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer. 12.2 Pharmacodynamics cardiac electrophysiology The effect of apalutamide 240 mg once daily on the QTc interval was evaluated in a single-arm, multicentre, open-label, uncontrolled QT study in 45 patients with CRPC. The mean maximum change in QTcF from baseline was 12.4 ms (bilateral upper 90% CI: 16.0 ms). A QT challenge analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. 12.3 Pharmacokinetics Apalutamide pharmacokinetic parameters are presented as mean [standard deviation (SD)] unless otherwise specified. Cmax and area under the concentration curve (AUC) of apalutamide increased proportionally after repeated once daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage): After administration of the recommended dose, the apalutamide steady state after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide Cmax was 6.0 mcg / ml (1.7) and AUC was 100 mcg'h / ml (32) at steady state. Daily fluctuations in apalutamide plasma concentrations were low, with a peak-to-trough ratio of 1.63. An increase in apparent tolerance (CL / F) was observed with repeated dosing, probably due to the induction of apalutamide's own metabolism. The autoinduction effect probably peaked at the recommended dose because apalutamide exposure over the dose range 30 to 480 mg is dose proportional. The Cmax of the major active metabolite N-desmethylapalutamide was 5.9 mcg / mL (1.0) and the AUC was 124 mcg-h / mL (23) at steady state after recommended dosing. Ndesmethyl apalutamide was characterized by a flat steady-state time concentration profile with a mean peak-to-trough ratio of 1.27. The mean metabolite / parent drug AUC ratio for N-desmethyl apalutamide after repeat dosing was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethylapalutamide probably contributed to the clinical activity of apalutamide. Absorption The mean absolute oral bioavailability is approximately 100%. The median time to achieve maximum plasma concentration (Tmax) was 2 hours (range: 1 to 5 hours). food effect Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 calories from fat, 250 calories from carbohydrate, and 150 calories from protein) produced no clinically relevant changes in Cmax and AUC. The median time to reach tmax was delayed by approximately 2 hours with food. ZQ LRnn / Lznz / Ε / ΥΙΛΙ Distribution The mean apparent volume of distribution at steady state of apalutamide was approximately 276 I. Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins without concentration dependence. Elimination The CL / F of apalutamide was 1.3 L / h after a single dosing and increased to 2.0 L / h at steady state after once-daily dosing, possibly due to CYP3A4 autoinduction. The median effective half-life for apalutamide in patients was approximately 3 days at steady state. Metabolism Metabolism is the major route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2CS and CYP3A4 to form the active metabolite, N-desmethylapalutamide. The contribution of CYP2CS and CYP3A4 to apalutamide metabolism is estimated to be 58% and 13% after a single dose, but changes to 40% and 37%, respectively, at steady state. Apalutamide accounted for 45% and N-desmethyl apalutamide accounted for 44% of the total AUC following a single oral administration of radiolabeled apalutamide 240 mg. Excretion Up to 70 days after single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethylapalutamide) and 24% was recovered in feces (1.5 % dose as unchanged apalutamide and 2% as N-desmethylapalutamide). Specific populations No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethylapalutamide were observed based on age (18-94 years); race (black, non-Japanese Asian, Japanese), mild to moderate renal insufficiency (eGFR 30-89 mL / min 1.73 m. calculated by dietary modification in the venous disease [MDRD] equation) or mild hepatic insufficiency ( Child-Pugh A) to moderate (Child-Pugh B) The effect of severe renal impairment or end-stage renal disease (eGFR <29 mL / min / 1.73m2. MDRD) or severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of apalutamide. ZQ LRnn / Lznz / Ε / ΥΙΛΙ drug interactions Effect of other drugs on ERLEADA Strong CYP2C8 inhibitors Apalutamide Cmax decreased by 21% while AUC increased by 68% after co-administration of ERLEADA as a single 240 mg dose with gemfibrozil (a strong CYP2C8 inhibitor). Gemfibrozil is expected to increase apalutamide steady-state Cmax by 32% and AUC by 44%. For active entities (sum of unbound apalutamide plus power adjusted unbound N-desmethyl apalutamide) predicted steady-state Cmax was increased by 19% and AUC by 23%. Strong CYP3A4 inhibitors Apalutamide Cmax was decreased by 22% while AUC was similar after co-administration of ERLEADA as a single 240 mg dose with itraconazole (a strong CYP3A4 inhibitor). Ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase single-dose apalutamide AUC by 24% but has no impact on Cmax- Ketoconazole is predicted to increase apalutamide steady-state Cmax by 38% and AUC by 51%. For active entities, predicted steady-state Cmax was increased by 23% and AUC by 28%. CYP3A4 / CYP2C8 inducers Rifamin (a strong CYP3A4 and moderate CYP2C8 inducer) is predicted to decrease steady-state apalutamide Cmax by 25% and AUC by 34%. For active entities, the predicted steady-state Cmax was decreased by 15% and the AUC by 19%. Acid reducing agents Apalutamide is not ionizable under relevant physiological pH conditions; therefore, acid-reducing agents (eg, proton pump inhibitors, H2-receptor antagonists, antacids) are not expected to affect the solubility and bioavailability of apalutamide. Transporters that affect drugs In vitro, apalutamide and N-desmethyl apalutamide are substrates for P-gp but not BCRP, OATPIB1, and OATP1B3. Because apalutamide is completely absorbed after oral administration. P-gp does not limit the absorption of apalutamide and therefore inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide. ZQ LRnn / Lznz / Ε / ΥΙΛΙ Effect of ERLEADA on other drugs CYP substrate In vitro studies have shown that apalutamide and N-desmethylapalutamide are moderate to strong inducers of CYP3A4 and CYP2B6, moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Analutamide and N-desmethylapalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations. Co-administration of ERLEADA with single oral doses 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 Swarfarin (a CYP2C9 substrate). ERLEADA did not produce clinically meaningful changes in exposure to a CYP2CS substrate. P-gp, BCRP v OATP1B1 substrates Co-administration of ERLEADA with single oral doses of transporter substrates resulted in a 30% reduction in the AUC of fexofenadine (a P-gp substrate) and a 41% reduction in the AUC of rosuvastatin (a BCRP / OATPIB1 substrate) but had no impact on Cmax. UGT substrates Apalutamide can induce UGT. Co-administration of ERLEADA with drugs that are UGT substrates may result in lower exposure to these drugs. OCT2, OAT1, OAT3 v MATES substrates In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusions (MATE) and do not inhibit organic anion transporter 1. predicts that apalutamide produces clinically significant changes in exposure to an OAT3 substrate. GnRH analog In subjects with mCSPC receiving leuprolide acetate (a GnRH analogue) co-administered with apalutamide. The PK data indicated that apalutamide had no apparent effect on the steady-state exposure of leuprolide. ZQ LRnn / Lznz / Ε / ΥΙΛΙ NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutaaenesis, impaired fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of apalutamide. Apalutamide does not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in the in vitro chromosome aberration test or in vivo rat bone marrow micronucleus test or in vivo rat Comet test. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia / hypospermia, tubular degeneration, and / or hyperplasia or hypertrophy of prostatic cells were observed. interstitial tissues in the reproductive system at > 25 mg / kg / day in rats (1.4 times the human exposure based on AUC) and > 2.5 mg / kg / day in dogs (0.9 times the human exposure based on AUC). In a fertility study in male rats, decreased sperm concentration and motility, increased abnormal sperm morphology, decreased fertility copulation rates (after mating with untreated females) along with reduced weights of the secondary sex glands were observed. and epididymis after 4 weeks of dosing at > 25 mg / kg / day (0.8 times the human exposure based on AUC). Reduced numbers of live fetuses were observed due to increased pre- and / or post-implantation loss after 4 weeks of 150 mg / kg / day of administration (5.7 times the human exposure based on AUC). The effects on male rats were reversible after 8 weeks from the last administration of apalutamide. CLINICAL STUDIES The efficacy and safety of ERLEADA was established in two international randomized placebo-controlled clinical trials. TITAN (NCT02489318): Metastatic Castration Sensitive Prostate Cancer (mCSPC) TITAN was a multinational, randomized, double-blind, placebo-controlled clinical trial in which 1052 patients with mCSPC were randomized (1:1) to receive oral ERLEADA at a dose of 240 mg once daily (N=525 ) or placebo once daily (N=527). All patients in the TITAN trial received a GnRH analogue or had a prior bilateral orchiectomy. Patients were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. Patients with high and low volume mCSPC were eligible for the study. A high volume of disease was defined as metastasis involving the viscera with bone lesion I or the presence of 4 or more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral column and pelvic bones. zq LRnn / ίζηζ / Ε / γίΛΐ 100 The following baseline patient demographic and disease characteristics were balanced between treatment groups. The median age was 68 years (range 4394) and 23% of patients were 75 years of age or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three percent (63%) of patients had high volume disease and 37% had low volume disease. Sixteen percent (16%) of patients had prior surgery, radiation therapy to the prostate, or both. Most of the patients had a Gleason score of 8 or higher (67%). Sixty-eight percent (68%) of patients received prior treatment with an antiandrogen (bicalutamide, flutamide, or nilutamide). All but one patient in the placebo group had an Eastern Cooperative Oncology Group (ECOG PS) performance status of 0 or 1 at study entry. The main 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 the identification of 2 or more new bone lesions on a confirmed bone scan (Prostate Cancer Workgroup 2 criteria) and / or progression into soft tissue disease. A statistically significant improvement in OS and rPFS was demonstrated in patients randomized to receive ERLEADA compared with patients randomized to placebo. Results for OS are based on a prespecified interim efficacy analysis. The TITAN efficacy results are summarized in Table 5 and Figures 1 and 2. Table 5: Summary of efficacy results - mCSPC intended-to-treat population (TITAN) zq LRnn / ίζηζ / Ε / γίΛΐ Endpoint ERLEADA N=525 Placebo N=527 Overall Survival3 Deaths (%) 83 (16%) 117 (22%) Median, months (95% CI)d NE (NE, NE) NE(NE, NE) Ratio risk (95% CI)b 0.67 (0.51, 0.89) pc value 0.0053 Radiographic progression-free survival Disease progression or death (%) 134 (26%) 231 (44%) Median, months (95% CI) d NE (NE, NE) 22.1 (18, 33) Hazard ratio (95% CI)b 0.48 (0.39, 0.60) pc value <0.0001 101aInterim analysis is based on 50% of the number of events planned for the final analysis assigned to alpha-0.01. 13The hazard ratio is from a stratified proportional hazards model. Hazard ratio <1 favors ERLEADA. cP-value is from Mantel-Cox test stratified by Gleason score at diagnosis (<7 vs. >7), region (NA / EU vs. other countries), and prior docetaxel use (Yes vs. No) d NE=Not estimable 4 A consistent improvement in rPFS was observed among the following patient subgroups: disease volume (high vs. low), prior docetaxel use (yes or no), and Gleason score at diagnosis (<7 vs. >7). A consistent improvement in OS was observed among the following patient subgroups: disease volume (high vs. low) and Gleason score at diagnosis (<7 vs. >7). Treatment with ERLEADA statistically significantly delayed the initiation of cytotoxic chemotherapy (HR=0.39, 95% CI 0.27, 0.56: p<0.0001). zq LRnn / ίζηζ / Ε / γίΛΐ Figure 1: Kaplan-Meier plot of overall survival (OS); Population with mCSPC that is Subjects at risk Placebo 527 524 509 502 743 456 387 263 142 59 16 3 0 ERLEADA 525 519 513 500 490 467 410 289 165 60 14 3 0 102 Figure 2: Kaplan-Meier plot of radiographic progression-free survival (rPFS); Intended-to-treat population with mCSPC (TITAN) ZQ LRnn / Lznz / Ε / ΥΙΛΙ Subjects at risk Placebo 527 488 437 381 325 240 229 140 57 14 3 1 ERLEADA 525 498 469 434 389 326 315 194 89 21 2 1 SPARTAN (NCT01946204): Non-metastatic castration resistant prostate cancer (nmCRPC); SPARTAN was a multicenter, randomized (2:1), double-blind, placebo-controlled clinical trial in which 1,207 patients with nmCRPC were randomized (2:1) to receive oral ERLEADA at a dose of 240 mg once daily. (N=806) or placebo once daily (N=401). All patients in the SPARTAN trial received a concomitant GnRH analogue or had bilateral orchiectomy. Patients were stratified by prostate-specific antigen (PSA) doubling time (PSADT), use of bone-protective agents, and locoregional disease. Patients were required to have a PSADT < 10 months and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were assessed blindly and were not used to discontinue treatment. Patients randomized to either arm discontinued treatment for BICR-confirmed radiographic disease progression, locoregional progression only, initiation of new treatments, unacceptable toxicity, or withdrawal. The following baseline patient demographic and disease characteristics were balanced between treatment groups. Median age was 74 years (range 48-97) 103 and 26% of patients were 80 years of age or older. The racial distribution was 66% Caucasian, 12% Asian, and 6% Other. Seventy-seven percent (77%) of patients in both treatment arms had prior surgery or radiation therapy to the prostate. Most patients had a Gleason score of 7 or greater (78%), percentage (15%) of patients had pelvic lymph nodes 2 cm at study entry. Seventy-three percent (73%) of patients received prior treatment with an antiandrogen; 69% of patients received bicalutamide and 10% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group (ECOG PS) performance status of 0 or 1 at study entry. Among patients who discontinued study treatment (N=279 for placebo and N=314 for ERLEADA), a higher proportion (80%) of placebo-treated patients received further treatment compared with ERLEADA-treated patients (56 %). Locoregional progression only occurred in 2% of patients overall. The primary efficacy outcome measure of the study was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of BICR-confirmed distant metastasis, defined as new lesions or in soft tissue or nodes. enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first. Additional efficacy endpoints were time to metastasis (TMT), progression-free survival (PFS), which also includes locoregional progression, time to symptomatic progression, and overall survival (OS). A statistically significant improvement in MFS was demonstrated in patients randomized to receive ERLEADA compared to patients randomized to placebo. Consistent results were observed in subgroups of patients including PSADT (<6 months or >6 months), use of an anterior bone-protective agent (yes or no), and locoregional disease (NO or NI). The primary efficacy outcome was supported by statistically significant improvements in TTM, PFS, and time to symptomatic progression. Overall survival (OS) data were immature at the time of the final MFS analysis (24% of the required number of events). The efficacy results of SPARTAN MFS, TTM, and PFS are summarized in Figure 3 and Table 6. 7Q LRnn / ίΖΠΖ / Β / ΥΙΛΙ 104 Figure 3: Kaplan-Meier metastasis-free survival (MFS) curve in SPARTAN (nmCRPC) Subjects at risk Placebo 401 291 220 153 91 58 34 13 5 1 0 0 ERLEADA 806 713 652 514 398 282 180 96 36 1 3 0 Table 6: Efficacy results evaluated BICR (SPARTAN) Endpoint Number of events (%) Median [months (95% CI)] HR (95% CI) p-value (Mantel-Cox test) ERLEADA (n=806) Placebo (N=401) ERLEADA Placebo Survival without metastasis 184 (23%) 194 (48%) 40.5 (NE, NE) 16.2 (15, 18) 0.28 (0.23, 0.35) 0.0001 Time to metastasis 175(22%) 191 (48%) 40.5 (NE, NE) 16.6 (15, 18) 0.27 (0.22, 0.34) <0.0001 Progression-free survival 200(25%) 204 (51%) 40.5 (NE, NE) 14.7 (14, 18) 0.29 (0.24, 0.36) 0.0001 1All analyzes stratified by PSA doubling time, use of bone protective agents, and locoregional disease status. NE=Not estimable HOW SUPPLIED / STORAGE AND HANDLING ERLEADA (apalutamide) 60 mg film-coated tablets are slightly yellow to gray-green, oval, debossed with AR 60 on one side. ERLEADA 60 mg tablets are available in bottles of 120 tablets. Each bottle contains silica gel desiccant. NDC number 59676-600-12 105 storage and handling Stores at 68°F to 77°F (20°C to 25°C): Excursions allowed at 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature]. Store in the original package. Do not discard the desiccant. Protect from light and moisture. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (patient information). Ischemic cardiovascular events • Inform patients that ERLEADA has been associated with ischemic cardiovascular events. Advise patients to seek immediate medical attention if symptoms suggestive of a cardiovascular event occur [see Warnings and Precautions (5.1)]. Falls and Fractures • Inform patients that ERLEADA is associated with an increased incidence of falls and fractures [see Warnings and Precautions (5.2, 5.3]]. Seizures • Inform patients that ERLEADA has been associated with an increased risk of seizures. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients about the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider if they experience a seizure [see Warnings and Precautions (5.4)]. Rash • Inform patients that ERLEADA is associated with rash and notify their healthcare provider if they develop a rash [see Adverse Reactions (6.1]]. Dosage and Administration: • Inform patients concomitantly receiving gonadotropin-releasing hormone (GnRH) analog therapy that they should maintain this therapy during the course of treatment with ERLEADA. • Instruct patients to take their dose at the same time each day (once daily). ERLEADA can be taken with or without food. Each tablet must be swallowed whole. ZQ LRnn / Lznz / Ε / ΥΙΛΙ 106 • 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 return to the normal schedule the following day. The patient should not take additional tablets to make up for a missed dose \ see Dosage and Administration (2.1)]. Embryo-Fetal Toxicity • Inform patients that ERLEADA may be harmful to a developing fetus. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. Advise male patients to use a condom if having sexual intercourse with a pregnant woman \see Warnings and Precautions (5.5)]. Infertility • Advise male patients that ERLEADA may impair fertility and not to donate sperm during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.3)]. Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 Manufactured for: Janssen Products, L.P. Horsham, PA 19044 ©2019 Janssen Pharmaceutical Companies ZQ LRnn / Lznz / Ε / ΥΙΛΙ Information for the patient ERLEADA® (er lee'dah) (apalutamide) Tablets What is ERLEADA? ERLEADA is a prescription medicine used for the treatment of prostate cancer: • that has spread to other parts of the body and is still responding to testosterone-lowering medical or surgical treatment, OR • that has not spread to other parts of the body and is no longer responding to medical or surgical testosterone. It is not known if ERLEADA is safe and effective in women. It is not known if ERLEADA is safe or effective in children. 107 Before taking ERLEADA, tell your healthcare provider about all of your medical conditions, including if: • have a history of heart disease • have high blood pressure • have diabetes • have abnormal amounts of fat or cholesterol in your blood (dyslipidemia) • have a history of seizures, brain injury, stroke, or brain tumors, if you are pregnant or plan to become pregnant, ERLEADA can harm your unborn baby and cause miscarriage • (miscarriage) • have a partner who is pregnant or may become pregnant. o Men who have female partners who are capable of becoming pregnant should use effective birth control (contraception) during treatment and for 3 months after the last dose of ERLEADA. o Men must use a condom during sex with a pregnant woman. Talk to your health care provider if you have questions about birth control. • are breastfeeding or plan to breastfeed. It is not known if ERLEADA passes into breast milk. Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ERLEADA can interact with many other medicines. You should not start or stop taking any medication before talking to the health care provider who prescribed ERLEADA. Know the medicines you take. Bring a list of these to show your health care provider and pharmacist when you get a new medicine. How can I take ERLEADA? • Take ERLEADA exactly as your healthcare provider tells you. • Your health care provider may change your dose if necessary. • Do not stop taking the prescribed dose of ERLEADA without talking to your health care provider. • Take the prescribed dose of ERLEADA 1 time a day, at the same time every day. • Take ERLEADA with or without food. • Swallow ERLEADA tablets whole. • If you miss a dose of ERLEADA, take your normal dose as soon as possible on the same day. Return to your normal schedule the next day. You should not take extra tablets to make up for a forgotten dose. • You should start or continue gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with ERLEADA unless you have had surgery to reduce the amount of testosterone in your body (surgical castration). • If you take too much ERLEADA, call your health care provider or go to the nearest hospital emergency room. What are the possible side effects of ERLEADA? ERLEADA can cause serious side effects including: • Heart disease. Blockage of the arteries in the heart that can lead to death has occurred in some people during treatment with ERLEADA. Your healthcare provider will monitor your signs and symptoms of heart problems during your treatment with ERLEADA. Call your health care provider or go to the nearest emergency room if you experience pain or discomfort at rest or with activity, or shortness of breath during your treatment with ERLEADA. • Fractures and falls. Treatment with ERLEADA can weaken your bones and muscles and increase your risk of falls and fractures. Falls and fractures have occurred in people during the ZQ LRnn / Lznz / Ε / ΥΙΛΙ 108 treatment with ERLEADA. Your health care provider will monitor your risks for falls and fractures during treatment with ERLEADA. • Seizures. Treatment with ERLEADA may increase your risk of seizures. You should avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others. Tell your healthcare provider if you experience loss of consciousness or seizures. Your healthcare provider will stop ERLEADA if you have a seizure during treatment. The most common side effects of ERLEADA include: • feeling very tired • joint pain • rash Tell your healthcare provider if you develop a rash. • decreased appetite. • fall • weight loss • high blood pressure • hot flashes • diarrhea • fracture ERLEADA can cause fertility problems in males, which may affect the ability to have children. Talk to your health care provider if you have fertility concerns. Do not donate sperm during treatment with ERLEADA and for 3 months after the last dose of ERLEADA. Tell your health care provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ERLEADA. Call your doctor for medical advice about side effects. You can report side effects to the FDA at 1-800-FDA-1088. How can I store ERLEADA? • Store ERLEADA at room temperature between 68°F to 77°F (20°C to 25°C). • Store ERLEADA in the original container. • The ERLEADA bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not throw away (dispose of) the desiccant. • Protect ERLEADA from light and moisture. Keep ERLEADA and all medicines out of the reach of children. General information on the safe and effective use of ERLEADA. Sometimes drugs are prescribed for purposes other than those indicated in a patient information leaflet. Do not use ERLEADA for a condition for which it was not prescribed. Do not share ERLEADA with other people, even if they have the same symptoms as you, it may harm them. For more information, talk to your health care provider. You can ask your health care provider or pharmacist for information about ERLEADA that is written for health professionals. What are the ingredients of ERLEADA? Active ingredient: apalutamide Inactive Ingredient: Colloidal Anhydrous Silica, Croscarmellose Sodium, Hydroxypropyl Methylcellulose Acetate Succinate, Magnesium Stearate, Microcrystalline Cellulose, and Silicified Microcrystalline Cellulose. Film coating contains iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Manufactured by: Janssen Ortho LLC, Gurabo, PR 00778 Manufactured for: Janssen Products, LP, Horsham, PA 19044 zq LRnn / ίζηζ / Ε / γίΛΐ 109 ©2019 Janssen Pharmaceutical Companies For more information, contact Janssen Products, LP at 1-800-526-7736 (1-800JANSSEN) or go to www.erleada.com. This patient information has been approved by the US Food and Drug Administration. Revised: 09 / 2019 The examples and embodiments described in the present description are for illustrative purposes only and various modifications or changes suggested to those skilled in the art are to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. The use of an antiandrogen in the preparation of a medicine to treat metastatic prostate cancer susceptible to castration in a male human, where the antiandrogen is: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5¡l]-2-fluoro-N-methylbenzamida, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxo¡m¡dazolid¡nl-¡l)-2-fluoro-N-met¡lbenzamida, 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6thioxo-5,7-diazasp¡ro[3.4]oct-5-yl]-2-fluoro-N-met¡lbenzamida, or N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)lH-pyrazol-l-yl]propan-2-¡l}-5-(l-hidroxyethyl)-lH-p¡razol-3-carboxamida.

2. The use as claimed in claim 1, wherein administration of the antiandrogen provides an increase in the overall survival of the human male relative to the overall survival rate of a population of human males with metastatic castration-sensitive prostate cancer, the population being administered a placebo combined with androgen deprivation therapy.

3. The use as claimed in claim 1 or 2, wherein administration of the antiandrogen provides an increase in progression-free survival of the human male relative to the progression-free survival rate of a population of human males with metastatic castration-sensitive prostate cancer, the population being administered a placebo combined with androgen deprivation therapy.

4. Use as claimed in any of the preceding claims, wherein the human male received at least one prior cancer treatment therapy, wherein the prior cancer treatment therapy is radiation, surgical intervention, or docetaxel therapy.

5. The use as claimed in any of claims 1 to 3, wherein the subject is a previously untreated patient.

6. The use as claimed in any of the preceding claims, wherein the antiandrogen is 4-[7-(6-cyano-5-trifluoromethylpridin-3-1)-8-oxo-6-thioxo-5,7diazaspiro[3,4]oct-5-1]-2-fluoro-N-methylbenzamide.

7. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-1)-8-oxo-6-tioxo-5,7-diazaspiro[3.4]oct-5-1]-2-fluoro-N-methylbenzamide is administered daily to a human male. ZQ LAnn / Lznz / E / YILI 111 8. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male.

9. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male on a continuous daily dosing plan.

10. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-yl)-8-oxo-6-tioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male at a dose of approximately 30 mg per day to approximately 480 mg per day.

11. The use as claimed in claim 6, 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 administered orally to a human male at a dose of approximately 180 mg per day to approximately 480 mg per day.

12. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male at a dose of: (a) approximately 30 mg per day; (b) approximately 60 mg per day; (c) approximately 90 mg per day; (d) approximately 120 mg per day; or (e) approximately 240 mg per day.

13. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridin-3-1)-8-oxo-6-tioxo-5,7-diazaspiro[3.4]oct-5-1]-2-fluoro-N-methylbenzamide is administered orally to a human male at a dose of approximately 240 mg per day.

14. The use as claimed in claim 13, wherein the dose of 4[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is reduced to 180 mg per day or 120 mg per day if the male human experiences toxicity greater than or equal to grade 3 toxicity.

15. The use as claimed in claim 6, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-1)-8-oxo-6-tioxo-5,7-diazaspiro[3.4]oct-5-1]-2-fluoro-N-methylbenzamide is administered in combination with androgen deprivation therapy.

16. The use as claimed in claim 15, wherein 4[7-(6-cyano-5-trifluoromethylpridine-3-yl)-8-oxo-6-tioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered in combination with at least one gonadotropin-releasing hormone (GnRH) agonist or antagonist. ZQ LRnn / Lznz / E / YILI 112 17. The use as claimed in claim 16, wherein the at least one GnRH agonist or antagonist is or comprises leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109 or triptorelin.

18. The use as claimed in claim 15, wherein 4-[7-(6cyano-5-trifluoromethylpyridine-3-1)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-1]-2-fluoro-N-methylbenzamide is used in combination with bilateral orchiectomy.

19. The use as claimed in claim 6, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridine-3-1)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-1]-2-fluoro-N-methylbenzamide is not co-administered with (a) a drug that is a strong inhibitor of CYP2C8 or CYP3A4; (b) a drug that is primarily metabolized by CYP3A4, CYP2C19 or CYP2C9; (c) a drug that is a substrate of UDP-glucuronosyltransferase; or (d) a drug that is a substrate of P-glycoprotein, breast cancer resistance protein or organic anion transporting polypeptide 1B1.

20. The use as claimed in claim 1, wherein the antiandrogen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidinyl)-2-fluoro-N-methylbenzamide.

21. The use as claimed in claim 20, wherein 4-(3-(4-cyano-3-(n-fluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidinyl)-2-fluoro-N-methylbenzamide is administered orally to a human male at a dose of approximately 160 mg per day.

22. The use as claimed in claim 1, wherein the antiandrogen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3,4]oct-5-1]-2-fluoro-N-methylbenzamide.

23. The use as claimed in claim 1, wherein the antiandrogen is N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-l]propan-2-l}-5-(lhydroxyethyl)-lH-pyrazol-3-carboxamide.

24. The use of an antiandrogen in the preparation of a medicine to treat metastatic prostate cancer susceptible to castration in a male human, where the antiandrogen is one or more of: 4-[7-(6-c¡ano-5-tr¡fluoromet¡lp¡r¡d¡n-3-¡l)-8-oxo-6-t¡oxo-5,7diazasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-met¡lbenzamida, 4-(3-(4-c¡ano-3-(trifluoromet¡l)fen¡l)-5,5-d¡met¡l4-oxo-2-t¡oxo¡midazol¡d¡nl-¡l)-2-fluoro-N-met¡lbenzam¡da, 4-[7-[4-cyano-3-(tr¡fluoromet¡l)fen¡l]-8oxo-6-thioxo-5,7-d¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N-met¡lbenzam¡da, or N-{(2S)-l-[3-(3-chloro-4c¡anofen¡l)-lH-p¡razol-l-¡l]propan-2-yl}-5-(lh¡drox¡et¡l)-lH-p¡razol-3-carboxam¡da. zq LRnn / ίζηζ / Ε / γίΛΐ 113 25. The use as claimed in the claim 23, where the antiandrogen is 4-[7-(6-c¡ano-5-tr¡fluoromethylp¡r¡d¡n-3-¡l)-8-oxo-6-t¡oxo-5,7-d¡azasp¡ro[3.4]oct-5-¡l]-2-fluoro-N- methylbenzamida.

26. The use as claimed in claim 25, wherein 5 4-[7-(6-cyano-5-1nfluoromethylpyridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to a human male at a dose of: (a) approximately 30 mg per day; (b) approximately 60 mg per day; (c) approximately 90 mg per day; (d) approximately 120 mg per day; or (e) approximately 240 mg per day.

27. The use of an approved drug product comprising apalutamide in the manufacture of a castration-sensitive metastatic prostate cancer drug in an amount described in a drug product label for the drug product.

28. The use as claimed in claim 27, wherein the approved drug product comprising apalutamide is an ANDA drug product, a Supplemental New Drug Application drug product, or a 15 505(b)(2) drug product.

29. Use as claimed in any of claims 27 to 28, wherein the method is clinically proven to be safe and / or effective.