Androgen receptor inhibitors for the treatment of non-metastatic castration-resistant prostate cancer in subjects with severe hepatic impairment

Abstract

Methods of treating non-metastatic castration-resistant prostate cancer in a subject having severe liver damage are provided.SOLUTION: Provided are methods of treating non-metastatic castration-resistant prostate cancer in a subject with severe hepatic impairment with an androgen receptor inhibitor comprising 4 - [7 - (6-cyano-5-trifluoromethylpyridin-3-yl) - 8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl] - 2-fluoro-N-methylbenzamide (apalutamide).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Technical Field As used herein, the term "cyano-5-trifluoromethylpyridinyl" includes, but is not limited to, 4-[7-(6-cyano-5-trifluoromethylpyridinyl] ... Lysin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octyl Androgen receptor inhibitors containing [tert-5-yl]-2-fluoro-N-methylbenzamide US20130122666A1 - Method for treating non-metastatic castration-resistant prostate cancer in subjects with severe liver damage with an agent - Google Patents It will be disclosed.

[0002] background Prostate cancer is the second most commonly diagnosed cancer and the sixth leading cause of cancer death in men. 14% (903,500) of all new cancer cases and 6% of all cancer deaths in men worldwide The progression from diagnosis to death of prostate cancer depends on the severity of the disease, hormone levels, and Mon status and presence or absence of detectable metastases: localized disease, detectable after radiation therapy or surgery Elevated prostate-specific antigen (PSA) levels without metastasis and non-castration stage or is best classified as a series of clinical stages based on clinical progression in the castration stage. Surgery, radiation, or a combination of these can be curative for patients with localized disease. However, a significant proportion of these patients will undergo relapse as evidenced by rising PSA levels. This can also lead to the formation of metastases, especially in high-risk groups, and progression to terminal disease. This may result in:

[0003] Androgen ablation is the standard of care and generally results in good outcomes, i.e., PSA decline, tumor size, and A plateau in which no tumor growth occurs, followed by a rise in PSA and recurrence of castration-resistant disease, is predictable. For many years, ADT was the standard of care for patients with metastatic prostate cancer.

[0004] A subgroup of prostate cancer patients also has severe liver damage.

[0005] Overcome potential therapeutic deficiencies of existing therapies, especially for patients with severe liver impairment There is a need for androgen receptor inhibitors. The disclosed methods are useful in treating these and other important conditions. Regarding the necessity.

[0006] overview Herein, we describe the treatment of non-metastatic castration-resistant prostate cancer in human males. A method for treating cancer-resistant prostate cancer (nmCRPC), comprising: A human male in need of such treatment with severe liver damage was administered approximately 30 mg / day to approximately 100 mg / day of or comprising or consisting of administering apalutamide at a dose of about 480 mg per In some embodiments, the human male is a normal In certain embodiments, normal cardiac condition and function includes sinus tone. rhythm, heart rate of about 50 to about 100 beats per minute, and a QTc interval of about 480 ms or less In a further embodiment, a male human has a blood flow rate of about 45 mL / min / 17.3 m 2 Creatinine below In yet a further embodiment, the male human has stable liver damage. In some embodiments, the human male has a systolic blood pressure of about 90 to about 170 mmHg. In certain embodiments, the male human has a diastolic blood pressure of less than about 100 mmHg. .

[0007] In some embodiments, the male human is receiving combination therapy for severe liver damage. In embodiments, the combination therapy includes an antihypertensive agent, a calcium channel blocker, an angiotensin inhibitor, Angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, diuretic, cholesterol lowering agent In further embodiments, the therapeutic agent comprises one or more of a cholesterol-lowering agent, an oral antidiabetic agent, and electrolyte replacement. In humans, males were not administered potent inhibitors or inducers of CYP2C8 or CYP3A4. stomach.

[0008] In a further embodiment, administration of palliative care to a male human with nmCRPC who has severe liver damage. Administration of apalutamide is recommended for patients with nmCRPC with severe liver damage who are not receiving treatment with apalutamide. In a further embodiment, the method is without increased risk of adverse events compared to a male human having Administration of apalutamide to human males with nmCRPC and severe liver damage was Comparison with men with nmCRPC and severe liver damage who were not treated with thiamin. and is associated with an increased risk of adverse events.

[0009] In certain embodiments, the nmCRPC is high-risk nmCRPC. In this form, apalutamide administration is effective in patients with nmCRPC who are not previously treated with apalutamide. The present invention provides an increase in metastasis-free survival in human males compared to the metastasis-free survival rate of a population of human males receiving the treatment. In certain embodiments, the male human has a prostate specific antigen doubling time (pros) that is 10 months or less. PSADT (Protein-specific antigen doubling time).

[0010] In some embodiments, the human male has received at least one prior therapy for the treatment of cancer. In a further embodiment, the prior therapy for the treatment of cancer includes bicalutamide, flutamide, In yet a further embodiment, the male human is treatment-naive.

[0011] In some embodiments, apalutamide is administered daily to a male human. In a further embodiment, apalutamide is administered orally to a male human. The drug is administered orally to male humans on a continuous daily dosing schedule.

[0012] In still further embodiments, apalutamide is administered at a dose of from about 180 mg per day to about 4 mg per day. In a specific embodiment, apalutamide is administered orally to a male human at a dose of 1 mg. It is administered orally to a male human at a dose of about 240 mg per day. Palutamide is administered orally to male humans at a dose of approximately 60 mg four times daily. In some embodiments, apalutamide is administered at a dose of about 120 mg per day. do.

[0013] In some embodiments, apalutamide is formulated as a solid dosage form. In its formulation, apalutamide is formulated as a tablet.

[0014] In certain embodiments, apalutamide is administered in combination with androgen deprivation therapy (ADT). In some embodiments, apalutamide is administered in combination with antidepressant therapy (ADT). is administered in combination with a gonadotropin-releasing hormone agonist or antagonist. In certain embodiments, apalutamide is used concomitantly with bilateral orchiectomy.

[0015] Also described herein are methods for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in human males. 1. A method for treating a male human having severe liver damage, comprising determining whether the male human has severe liver damage. In humans with severe liver damage, the daily dose ranges from about 30 mg to about 480 mg. and administering apalutamide at a dose of 1 mg to male humans to treat nmCRPC. In some embodiments, a method is provided in which a male human is examined for normal cardiac condition and function. In certain embodiments, normal cardiac condition and function is defined as sinus rhythm, approximately 1 / 2 beat per minute. A heart rate of 50 to about 100 beats per minute and a QTc interval of about 480 ms or less. In the case of a human male, the rate is approximately 45 mL / min / 17.3 m 2 Have the following creatinine clearance: In yet a further embodiment, the male human has stable liver damage. In one embodiment, a human male has a systolic blood pressure of about 90 to about 170 mmHg. In general, a human male has a diastolic blood pressure of less than about 100 mmHg.

[0016] In some embodiments, the male human is receiving combination therapy for severe liver damage. In embodiments, the combination therapy includes an antihypertensive agent, a calcium channel blocker, an angiotensin inhibitor, Angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, diuretic, cholesterol lowering agent In further embodiments, the therapeutic agent comprises one or more of a cholesterol-lowering agent, an oral antidiabetic agent, and electrolyte replacement. In humans, males were not administered potent inhibitors or inducers of CYP2C8 or CYP3A4. stomach.

[0017] In certain embodiments, the therapeutic efficacy of apalutamide in male humans with severe liver impairment is The amount is adjusted. [Brief explanation of the drawings]

[0018] The Summary of the Invention, as well as the Detailed Description below, should be read in conjunction with the accompanying drawings. For the purpose of illustrating the disclosed method, the drawings include exemplary embodiments of the method. However, the method is not limited to the specific embodiments disclosed herein. Drawings: [Figure 1A-1] 1A and 1B show a schematic diagram of the time and event schedule of the clinical trial study described in Example 1, for the screening and open-label phases, days -1 to 8 (FIG. 1A) and the open-label phase, days 10 to 57 (FIG. 1B). [Figure 1A-2] 1A and 1B show a schematic diagram of the time and event schedule of the clinical trial study described in Example 1, for the screening and open-label phases, days -1 to 8 (FIG. 1A) and the open-label phase, days 10 to 57 (FIG. 1B). [Figure 1B-1] 1A and 1B show a schematic diagram of the time and event schedule of the clinical trial study described in Example 1, for the screening and open-label phases, days -1 to 8 (FIG. 1A) and the open-label phase, days 10 to 57 (FIG. 1B). [Figure 1B-2] 1A and 1B show a schematic diagram of the time and event schedule of the clinical trial study described in Example 1, for the screening and open-label phases, days -1 to 8 (FIG. 1A) and the open-label phase, days 10 to 57 (FIG. 1B).

[0019] Detailed Description of the Embodiments Certain aspects of the invention are described herein for clarity in the context of separate embodiments. It will be appreciated that certain features may also be provided in combination in a single embodiment. That is, each individual embodiment is included unless expressly incompatible or specifically excluded. are considered combinable with any other embodiment, and such combinations are not considered to be part of another embodiment. Conversely, for ease of explanation, the embodiments may be considered in the context of a single embodiment. The different features of the invention described may be provided separately or in any subcombination. Finally, the embodiments may be implemented as part of a series of steps or as part of a larger structure. Although each step may be considered an independent embodiment in itself, , and can be combined with others.

[0020] The transitional phrases "comprising" and "consisting essentially of" "ly of" and "consisting of" are generally accepted terms in patent language. The meaning of "comprising" is intended to imply that ) is synonymous with "comprises," "contains," or "features" and is inclusive or open-ended. and does not exclude other, unrecited elements or method steps. (ii) "consisting of" is not specified in the claims , excludes any element, step, or ingredient; and (iii) "consisting essentially of" means The material or process identified and the basic and novel feature(s) of the claimed patent Limit the scope of the claims to those that do not materially affect the invention. More specifically, limit the scope of the claims to those that are fundamental and novel. The new characteristics are those in which the method compares survival to that of a human male comparison population, as described elsewhere herein. The present invention provides a method for improving the survival of the human male population compared to conventional methods, including, but not limited to, improving the survival of the human male population compared to conventional methods. The invention relates to the ability to provide at least one of the benefits described in the document.

[0021] Embodiments described with the term "comprising" (or its equivalents) may also In embodiments, the terms "consisting of" and "consisting essentially of" are independently described. Provide what is needed.

[0022] When values ​​are expressed as approximations, by use of the descriptor "about," the particular value shall remain the same. It is understood that the use of the term "about" generally refers to the extent to which the disclosed subject matter forms an embodiment of the present invention. It indicates approximations that may vary depending on the desired properties sought to be obtained by the problem, and The term "common sense" should be interpreted in the context of the specific context in which it is used. can be interpreted as a matter of routine. The number of significant figures used may be one non-limiting way of determining the extent of the term "about." The incremental changes used in the series of values ​​are used to refer to each value in the series. If present, all ranges are inclusive. and combinable, i.e., references to values ​​stated in ranges include all values ​​within that range. Includes all values.

[0023] Unless otherwise specified, the term "about" means a ±10% variation of the associated value, but In some embodiments, the variation is ±5%, ±15%, ±20%, ±25%, or ±50%. This also includes cases where:

[0024] Where a list is presented, unless otherwise specified, each individual element of the list and its sublists It should be understood that all combinations of the above are separate embodiments. A list of embodiments presented as "A," "B," "C," or "D" is not intended to be limiting. shall be construed to include "A or B," "A or C," "B or C," or "A, B, or C." It is.

[0025] The present invention should be read in conjunction with the accompanying figures and examples, all of which form a part of this disclosure. The present invention can be more readily understood by reference to the following description. It is not intended to be limited to the specific products, methods, conditions or parameters described or shown in the specification. The terminology used herein is for the purpose of describing specific embodiments by way of example only. are for illustrative purposes only and are not intended to limit any claimed invention. Likewise, unless otherwise specified, possible mechanisms or modes of action or modifications Any statements regarding the reasons are intended to be merely exemplary and the invention herein is not intended to be limiting. the accuracy or inaccuracy of any such proposed mechanism or mode of action or reason for improvement; Throughout this document, these statements are used in various It is recognized that the present invention refers to compounds, compositions, and methods of using those compounds and compositions. That is, in this disclosure, features or embodiments relating to the composition or methods of using the composition are When describing or claiming embodiments, such description or claim shall be construed as including those features or implementations. It is intended that the embodiments be shown in each of these contexts (i.e., compositions and methods of use). It is understood that.

[0026] In this disclosure, when methods of treatment are described, these methods include, for example, antiandrogen or androgen receptor inhibitors, or compounds used in such methods of treatment. The method may also be defined in terms of the composition in question, e.g., an antiandrogen or anti-androgen. Use of compounds such as androgen receptor inhibitors or for treatment with such methods It can also be defined in terms of the composition of matter from which the drug is made.

[0027] The androgen receptor (AR) is a steroid and nuclear receptor Within this large family of proteins, the vertebrate spindle There are only five known steroid receptors: androgen receptors, estrogen receptors, and These include the progesterone receptor, the glucocorticoid receptor, and the mineralocorticoid receptor. AR is a soluble protein that acts as an intracellular transcription factor. It is regulated by androgen binding, which leads to receptor-protein interaction. Sequential conformational changes in the receptor occur that affect its function and receptor-DNA interaction. Cut.

[0028] The AR is involved in androgen target tissues such as the prostate, skeletal muscle, liver, and central nervous system (CNS). NS), with the highest expression levels in the prostate, adrenal gland, and epididymis. endogenous androgen, such as testosterone and 5-dihydrotestosterone (5a-DHT) It can be activated by binding of an agonist.

[0029] The androgen receptor (AR) is a 110 kD nuclear receptor located in Xql 1-12. When activated by androgens, it mediates the transcription of target genes and stimulates the prostate epithelium. Regulates cell growth and differentiation. Like other steroid receptors, the unbound form of the AR is primarily It is located in the cytoplasm and binds to heat shock proteins through interaction with the ligand-binding domain. Upon agonist binding, the AR undergoes a series of conformations. This causes the heat shock proteins to dissociate from the AR, and the transformed AR dimerizes and It undergoes phosphorylation and nuclear localization mediated by a nuclear localization signal. The receptors used consisted of a six-nucleotide half-site complex with three random nucleotides between them. androgen response element (ARE) characterized by the census sequence 5'-TGTTCT-3' It binds to and is located in the promoter or enhancer region of the target of the AR gene. By recruiting transcriptional coregulators (including coactivators and corepressors) and the transcription machinery These processes further ensure the transactivation of AR-regulated gene expression. All of these processes are initiated by ligand-induced conformational changes in the ligand-binding domain. It will begin.

[0030] In genetic males with loss-of-function AR mutations and in mice genetically engineered to lack AR, AR signaling is essential for the prostate gland to function properly, as evidenced by the lack of glandular development or prostate cancer progression. This is important for the development and maintenance of male reproductive organs, such as the prostate gland. Dependence continues during neoplastic transformation. Androgen deprivation (e.g., GnRH antagonist) androgens) remain the mainstay of prostate cancer treatment. Removal of the hormone is usually effective for a limited period of time, and prostate cancer develops and develops into circulating androgen. Even low levels of rhodamine restore growth potential.

[0031] Castration-resistant prostate cancer (CRPC) is a terminal condition CRPC is a rare phenotype, and almost all patients die from prostate cancer. While a small proportion of these patients bypass the need for AR signaling, most of the patients with CRPC Most cases are classified as "androgen-independent prostate cancer" or "hormone-refractory prostate cancer." Although termed AR-associated phenotypes, they retain their lineage dependence on AR signaling.

[0032] Prostate cancer is the second most common cause of cancer death in men in the United States, killing 6 in 10 men in the United States. Approximately 1 in 10 people will be diagnosed with the disease during their lifetime. Targeted treatment fails in 30% of men, who develop recurrent disease. The disease usually first manifests as elevated plasma prostate-specific antigen (PSA), followed by distant metastases. Prostate cancer cells have the ability to bind androgen receptors (ARs) for growth and survival. ), these men are more likely to take drugs that block testosterone production. (e.g., GnRH agonists) alone or in combination with any residual testosterone AR Treatment is usually with antiandrogens (e.g., bicalutamide) to antagonize the effects of androgen depletion. This approach has resulted in a decline in PSA and visible tumor regression (if present) in some patients. However, after this, castration-resistant prostate cancer (CRP) C) and most patients ultimately die. Study shows CRPS continues to depend on AR signaling, key to acquired resistance The mechanism has been demonstrated to be increased levels of AR protein (Nat.Med, 2004,10,33-39). Activity in castration-sensitive and castration-resistant prostate cancer AR-targeting agents with potent anti-cancer drugs hold promise for the treatment of this terminal disease.

[0033] The progression from diagnosis to death in prostate cancer varies depending on the extent of disease, hormonal status, and detectable metastases. Presence or absence of metastasis, localized disease, no detectable metastasis after radiation therapy or surgery, prostate-specific antigen Based on elevated PSA levels and clinical metastasis in the non-castrated or castrated stage. It is best classified as a series of clinical stages. Surgery, radiation, or a combination of these may be used to treat localized It can be curative for patients with sexual disorders, but a significant proportion of these patients have recurrent disease as evidenced by rising PSA levels, which is also particularly This may result in the formation of metastases in the tumor group and progression to the terminal stage of the disease.

[0034] Androgen ablation is the standard of care and generally results in good outcomes, i.e., PSA decline, tumor size, and A plateau in which no tumor growth occurs, followed by a rise in PSA and recurrence of castration-resistant disease, is predictable. Molecular profiling studies of castration-resistant prostate cancer generally focus on androgen receptors. Increased expression of the steroid receptor (AR) has been shown to occur, which may be due to amplification of the AR gene or other mechanisms. do.

[0035] Antiandrogens are useful in treating early-stage prostate cancer. In many cases, the disease progresses in the presence of continued androgen deprivation or antiandrogen therapy. Cases of antiandrogen withdrawal syndrome also progress to a "hormone refractory" stage. Antiandrogen withdrawal syndrome has been reported after long-term treatment with antiandrogens. Clinically observed tumor regression or symptomatic relief observed upon cessation of antiandrogen therapy These anti-AR mutants are defined from the perspective of the receptor binding specificity. The agonistic ability of androgens may at least partially account for this phenomenon. For example, hydroxyflutamide and bicalutamide are T877A and W7 It acts as an AR agonist in the 41L / W741C AR mutant.

[0036] Bicalutamide inhibits the growth of prostate cancer cells in conditions where AR overexpression has led to castration resistance. Certain antiandrogen compounds, such as benzodiazepines, have mixed antagonist / agonist properties. It has been demonstrated that (Science, 2009 May 8;324(5928):7 87-90) This agonistic activity may result in a clinical finding known as antiandrogen withdrawal syndrome. This antiandrogen withdrawal syndrome is useful for explaining the effects of AR antagonists. Approximately 30% of men receiving rituximab experienced a decline in serum PSA when treatment was discontinued. (J Clin. Oncol, 1993.11(8):p.1566-72).

[0037] Prostate Cancer Stages In the early stages of prostate cancer, the cancer is confined to the prostate gland. In these early stages, treatment Typically involves either surgical removal of the prostate or radiation therapy to the prostate. In some patients, prostate cancer is localized and no active treatment is performed. In the early stages where intervention is required, surgery or radiation therapy can destroy cancer cells. In approximately 30% of cases, these procedures fail and the prostate Adenocarcinoma typically continues to progress as evidenced by rising PSA levels. Men whose prostate cancer progresses after these early treatment regimens have progressive or recurrent prostate cancer. It is said that...

[0038] Prostate cancer cells depend on the androgen receptor (AR) for growth and survival. Men with advanced prostate cancer are taking drugs that block testosterone production (e.g., GnR H agonist) alone or in combination with any residual testosterone to determine the effect of AR These are treated with antiandrogens (e.g., bicalutamide) that antagonize the effects of androgens. Treatment of steroids reduces serum testosterone to castrate levels, which generally lasts for some time. This approach has been shown to result in PSA decline and delayed disease progression in some patients. However, ultimately, This is followed by a recurrence called castration-resistant prostate cancer (CRPC), and most patients eventually Castration-resistant prostate cancer (CRPC) occurs when prostate cancer spreads to other parts of the body. Cancer is classified as non-metastatic or metastatic depending on whether it has progressed beyond the initial stage.

[0039] In some embodiments, a man with non-metastatic CRPC prior to treatment with apalutamide Gender is characterized as having: 1. Histologically or cytologically confirmed prostate cancer without neuroendocrine differentiation or small cell features Adenocarcinoma, with a high risk of metastasis formation. 2. Pre-castration resistance demonstrated during continuous androgen deprivation therapy (ADP) / after orchiectomy Prostate cancer. For example, identified as three consecutive increases in PSA within a one-week interval, two increases by 50% from the nadir, ultimately resulting in a PSA > 2ng / mL. 3. Castrate-level testosterone levels within 4 weeks of randomization and throughout the study Maintain a blood glucose level of <50 ng / dL (1.72 nmol / L). 4. No distant metastasis as determined by bone scan, CT, or MRI scan.

[0040] antiandrogens As used herein, the term "antiandrogen" has its generally accepted meaning. and interfere with the biological effects of androgens on normally responsive tissues in the body. The term may refer to a group of hormone receptor antagonist compounds that can effectively inhibit the action of hormone receptors. In some embodiments, the antiandrogen is a small molecule. In some embodiments, the antiandrogen is an AR inhibitor. The antiandrogen is a complete AR inhibitor. Any antiandrogen may be used in the embodiments described herein. It may also be used in certain conditions, for example, in relation to certain antiandrogens such as apalutamide. It is contemplated that other anti-androgens may also be useful in related embodiments.

[0041] As used herein, the terms "AR antagonist" or "AR inhibitor" refer to and inhibit, i.e., decrease, at least one activity of an AR polypeptide. Exemplary AR activities include coactivator binding, DNA binding, These include, but are not limited to, ligand binding or nuclear translocation.

[0042] As used herein, a "full antagonist" or "full inhibitor" is a compound that, at effective concentrations, In this context, the term "antagonist" refers to an antagonist that essentially completely inhibits the activity of an AR polypeptide. As used herein, a "partial antagonist" refers to an agent that partially inhibits the activity of an AR polypeptide. Antagonists that are capable of damaging a drug but are not full antagonists even at the highest concentrations "Essentially completely" means that the AR polypeptide retains at least about 80% of its activity, at least About 90%, at least about 95%, at least about 96%, at least about 97%, at least By about 98%, at least about 99%, or greater inhibition is meant.

[0043] In certain embodiments, the androgen receptor inhibitor is a wild-type androgen receptor polypeptide. These androgen receptor inhibitors exhibit full antagonist activity against the peptides. For example, in castration-resistant prostate cancer (CRPC), cells expressing elevated levels of AR It acts as a complete antagonist in the cells.

[0044] Exemplary androgen receptor full inhibitors include 4-[7-(6-cyano-5-trimethylsilyl)-2-(4-methyl-2-oxo-2-oxo-1,4-dioxo-2,4-di ... Fluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspirillum Bis[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (also known as Apar Tamithamide, ARN-509, or JNJ-56021927, CAS number 956104-4 0-8), 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- Dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N- Methylbenzamide (also known as MDV3100 or enzalutamide, CAS number 915087) -33-1), 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-ox So-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro -N-methylbenzamide (RD162, CAS number 915087-27-3), and N -{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1 -yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3 These androgen receptor agonists include α-carboxamide (also known as darolutamide). Any of the above inhibitors may be useful in the embodiments described herein.

[0045] In some embodiments, the androgen receptor inhibitor is a ligand of an AR polypeptide. It binds to the AR polypeptide at or near the binding site.

[0046] [ka]

[0047] [ka]

[0048] In some embodiments, the androgens contemplated in the methods described herein Receptor inhibitors, such as darolutamide, bind to androgen response elements and promote activation of the DNA. In some embodiments, the method described herein inhibits the nuclear translocation of AR, such as by mobilizing a factor. The androgen receptor inhibitor contemplated in the method is an androgen receptor inhibitor that inhibits AR-overexpressing prostate cancer cells. It does not exhibit agonist activity.

[0049] Apalutamide is an androgen receptor inhibitor that directly binds to the ligand-binding domain of the AR. It is an agent that impairs nuclear translocation, AR binding to DNA, and AR target gene regulation, Apalutamide inhibits tumor growth and promotes apoptosis by inhibiting the growth of tumors. It binds to the AR with higher affinity than α-glucan, and inhibits the growth of non-castrated hormone-sensitive and bicalutamide-resistant human prostates. Induces partial or complete tumor regression in adenocarcinoma xenograft models (Clegg et al. al.Cancer Res.March 15,2012 72;1494). Lutamide exhibits partial agonist activity similar to that seen with bicalutamide in the setting of AR overexpression. It lacks.

[0050] Darolutamide, BAY1841788, or ODM-201, exists as two diastereomers. androgen receptor inhibitors, including ORM-16497 and ORM-16555 This is in response to known AR mutations that are resistant to other second-generation antiandrogens. Darolutamide binds to AR with high affinity and then acts as an antagonist of AR. Impairs steroidogen-induced nuclear translocation and transcription of AR gene targets. Matsubara, N. ,Mukai,H.,Hosono,A.et al.Cancer Chemothe r.Pharmacol.(2017)80:1063.

[0051] Specific Terms For the avoidance of doubt, terms used herein have their generally accepted meanings. To aid in understanding, some definitions are provided here.

[0052] As used herein, the term "cancer" refers to a cancer that tends to grow uncontrolled and in some cases It refers to an abnormal proliferation of cells that tends to infiltrate (spread) in some cases.

[0053] As used herein, the term "prostate cancer" refers to histologically or cytologically confirmed prostate cancer. This refers to adenocarcinoma.

[0054] The term "androgen deprivation therapy (ADT)" refers to the treatment of androgen levels in patients with prostate cancer. This refers to the reduction of testosterone levels to castrate levels (<50 ng / dL). Treatment includes orchiectomy or administration of gonadotropin-releasing hormone agonists or antagonists. ADT includes surgical castration (removal of the testicles) and / or the use of steroids. or luteinizing hormone-releasing hormone (L Gonadotropin-releasing hormone (HRH) / GnRH agonists or antagonists Examples of GnRH agonists or antagonists include Leuconostoc and leuconostoc. Prolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degas Relics, Ozarelix, ABT-620 (elagolix), TAK-385 (relagolix) EP-100, KLH-2109, or triptorelin, or In certain embodiments, examples of GnRH agonists include goserelin acetate, hydroxybenzoates, and hydroxybenzoates. These include strelin acetate, leuprolide acetate, and triptorelin palmate.

[0055] The term "localized advanced prostate cancer" refers to a condition in which all active cancer cells are present in the prostate and related or adjacent organs. It refers to prostate cancer that appears exclusively in the gallbladder (e.g., seminal vesicles, bladder neck, and rectal wall).

[0056] The term "high-risk localized prostate cancer" refers to patients with metastatic or recurrent disease after primary therapy with curative intent. In some embodiments, metastatic forms of prostate cancer are considered to be metastatic. High risk of maturation was <20 months, <19 months, <18 months, <17 months, and <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 is defined as a prostate-specific antigen doubling time (PSADT) of <1 month. Morphologically, a high risk for metastasis formation is indicated by a prostate-specific antigen doubling time (PSA) of <10 months. In some embodiments, a high risk for metastasis formation is defined as a high Defined as having a Gleason score or bulky tumor.

[0057] For the avoidance of doubt, the terms "castration-sensitive prostate cancer" and "hormone-sensitive prostate cancer" are used interchangeably. They have the same meaning and are used interchangeably.

[0058] The terms "castration-sensitive prostate cancer" and "hormone-sensitive prostate cancer" refer to localized disease, biochemical androgen deprivation therapy (ADT) either as a primary relapse or in the metastatic setting. This refers to cancer that responds to

[0059] The terms "metastatic castration-sensitive prostate cancer" and "metastatic hormone-sensitive prostate cancer" refer to the Invasion (metastasis) of the cancer to other areas, such as the bones, lymph nodes, or other parts of the body Refers to cancer that responds to androgen deprivation therapy (ADT).

[0060] The term "non-metastatic castration-sensitive prostate cancer" refers to the treatment of men with non-invasive (metastatic) castration-sensitive prostate cancer. In some embodiments, non-metastatic cancers are those that respond to antidepressant therapy (ADT). Sensitive prostate cancer can be diagnosed by bone scan and computed tomography (CT) or magnetic resonance imaging (MRI). As used herein, the term "C" refers to a skeletal muscle (CSM) or a muscular muscular (M) muscle (M) muscle (M). RPC stands for castration-resistant prostate cancer. CRPC is a condition in which a male hormone called steroid hormone stimulates the growth of prostate cancer cells. This is prostate cancer that continues to grow despite the suppression of sex hormones.

[0061] The term "metastatic castration-resistant prostate cancer" refers to castration-resistant prostate cancer that has spread to other parts of the body. Refers to...

[0062] Metastatic castration-sensitive prostate cancer (CSPC) remains responsive to testosterone suppression therapy This refers to prostate cancer.

[0063] As used herein, the term "nmCRPC" refers to non-metastatic castration-resistant prostate cancer. In some embodiments, nmCRPC is diagnosed by bone scan and computed tomography (CT). It is assessed by CT or magnetic resonance imaging (MRI) scan.

[0064] The term "chemotherapy-naive metastatic castration-resistant prostate cancer" refers to cancer that has not previously been treated with chemotherapy. This refers to metastatic castration-resistant prostate cancer that has not been treated with chemotherapy.

[0065] The term "non-metastatic castration-resistant prostate cancer after abiraterone acetate-prednisone treatment" refers to Refers to non-metastatic castration-resistant prostate cancer that has been previously treated with abiraterone.

[0066] The term "high-risk nmCRPC" refers to the probability that men with nmCRPC will develop metastases. In some embodiments, a high risk for metastasis formation refers to a risk of <20 months , <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 <12 months, <11 months, <10 months, <9 months, <8 months, <7 months, <6 months When prostate-specific antigen doubling occurs in ≥ 5 months, < 5 months, < 4 months, < 3 months, < 2 months, or < 1 month In some embodiments, a high risk of metastasis formation is defined as Prostate cancer is defined as a prostate-specific antigen doubling time (PSADT) of <10 months. In embodiments, the high risk of metastasis formation is determined by the risk of locoregional recurrence (e.g., primary tumor bed, bladder cervical, anastomotic, and pelvic lymph nodes).

[0067] As used herein, the term "co-administration" or the like refers to the administration of selected therapeutic agents to a single patient. administration of the drugs by the same or different routes of administration or at the same or different times. It is intended to include therapeutic regimens administered between doses.

[0068] As used herein, the term "pharmaceutical combination" refers to a mixture of two or more active ingredients. or products resulting from combinations, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" includes both combinations of the active ingredients, e.g. Both palutamide and the co-agent may be administered to the patient simultaneously in a single unit or dosage form. The term "non-fixed combination" means a combination of active ingredients, e.g., apalutamide and The co-medications may be administered either simultaneously, concurrently, or sequentially, without any specific interruption time limit. and administered to a patient as separate units or separate dosage forms, such administration resulting in the production of This means providing safe and effective levels of the two active ingredients in It also applies to cocktail therapy, eg the administration of three or more active ingredients.

[0069] The term "FDHT-PET" refers to 18F-16P-fluoro-5a-dihydrotestosterone. This refers to positron emission tomography (PET), which uses a tracer based on dihydrotestosterone. This technology allows for visual assessment of ligands binding to the androgen receptor in patients. This can be used to evaluate the pharmacokinetics of androgen receptor-directed therapy. .

[0070] The term "continuous daily dosing schedule" does not include drug holidays for a particular therapeutic agent. In some embodiments, continuous daily administration of a particular therapeutic agent. A dosing schedule involves administering a particular therapeutic agent at approximately the same time each day.

[0071] The terms "treat" and "treatment" refer to the treatment of a patient affected by a condition, including killing cancer cells. It not only alleviates the pathological condition by increasing the level of the hormone, but also inhibits the progression of the disease. and includes slowing the rate of progression, stopping the rate of progression, ameliorating the condition, and curing the condition. Unless otherwise specified, the term "treat" also includes treatment as a therapeutic measure (i.e., prophylaxis). " and "treatment" refer to the totality of the effects described, however, in other embodiments, these terms may also refer to any one of the effects described, or at least one of It can also refer to something that excludes effects.

[0072] The term "metastasis-free survival" or "MFS" refers to the time it takes for cancer to spread over a defined period or to death. MFS refers to the proportion of subjects in a clinical trial who survive without any adverse events. MFS is reported as the time from enrollment, randomization, or start of treatment in an individual. or study population. In this situation, the increase in metastasis-free survival compared with treatment with placebo will occur first. This results in an extension of the time observed without cancer or death, regardless of the presence of invasive disease. The increase in metastasis-free survival is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months. 7 months, 8 months, 10 months, 11 months, 12 months, 13 months, 14 months 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, or In some embodiments, the administration of an androgen receptor inhibitor is for more than 20 months. and optionally, the increased metastasis-free survival is associated with non-metastatic castration-resistant Relative to the mean survival rate of a population of placebo-treated human men with prostate cancer In some embodiments, metastasis-free survival is determined by BICR, whichever occurs first. First report of distant metastases of bone or soft tissue or death from any cause confirmed by This refers to the period from randomization to time of evidence.

[0073] The term "time to metastasis" refers to the BICR of radiographically detectable bone or soft tissue distant metastases. The time from randomization to the time of the first scan showing evidence confirmed by MRI. In some embodiments, administration of the androgen receptor inhibitor is continued for a period of time to metastasis (time to The present invention provides improved anti-tumor activity as measured by tumor metastasis (TTM).

[0074] The term "radiographic progression-free survival" refers to the time to progressive disease, whichever occurs first. Time from randomization to first imaging documentation of disease or death. worsening of soft tissue lesions as measured by computed tomography or magnetic resonance imaging, or If a subject has either a new lesion on bone scan or a new lesion on radiological imaging, the subject will be are considered to have progressive disease.

[0075] The term "progression-free survival" is based on RECIST v1.1 and is defined as follows: Defined as: For subjects with at least one measurable lesion, progressive disease is considered curable. Defined as an increase of at least 20% in the sum of target lesion diameters, based on the smallest sum in the study (This includes the baseline total, if smallest in the trial). 20% relative increase In addition to the increase, the sum must also show an absolute increase of at least 5 mm. The appearance of new lesions on CT or MRI scans is also considered progression. For subjects with only nonmeasurable disease, overt progression (change in overall disease status) Progression was considered to occur when there was a significant decrease in the disease (representing a progressive disease) or the appearance of one or more new lesions. For new bone lesions detected, a second imaging modality (e.g., CT or In some embodiments, administration of an androgen receptor inhibitor , providing improved anti-tumor activity as measured by progression-free survival.

[0076] The term "prostate cancer-specific survival" refers to the time from randomization to the date of death due to prostate cancer. is defined as:

[0077] The term "PFS2" refers to the time from randomization in the first trial to the occurrence of a second disease progression or progression of any cause. This refers to the time to death from a cause.

[0078] The term "time to disease progression" refers to either of the following (whichever occurs first): ), defined as the time from randomization to CRF documentation: (1) skeletal-related events Development of spinal recurrence syndrome (SRE): pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy (2) Progression or worsening of disease-related symptomatic pain requiring the initiation of new systemic anticancer therapy or (3) due to locoregional tumor progression requiring surgical intervention or radiation therapy. In some embodiments, the development of clinically significant symptoms associated with the administration of an androgen receptor inhibitor. Administration provides improved anti-tumor activity as measured by time to disease progression.

[0079] The term "time to pain progression" refers to the time to pain progression (two consecutive assessments separated by at least 3 weeks). Brief Pain Inventory-Short Form (BPI-SF) mean increase of 2 points from baseline in worst pain intensity, whichever comes first Whatever may occur, a patient receiving non-tapered opioids or initiation of long-term opioids will have a risk of >4. Pain progression is defined as the time from randomization to the worst pain score (with a mean worst pain score of 100 or more). For the endpoint of time to treatment, the BPI-SF worst pain score (item 3) will be used. The score ranges from 0 to 10, with lower scores representing lower levels of pain intensity. The change in was the least important difference.

[0080] The term "time to skeletal-related event (SRE)" refers to the time to an SRE (symptomatic pathological fracture, spinal cord compression, etc.). Date of randomization to the date of first observed event (anxiety, radiation to bone, or surgery to bone) It is defined as the period from

[0081] The term "time to chronic opioid use" refers to the time from the date of randomization to the date of confirmed chronic opioid use. Defined as the time to first day of opioid use. Chronic opioid use is defined as the time to first day of oral opioid use. It is defined as administration of opioid analgesics for 3 weeks or more for oral formulations and 7 days or more for parenteral formulations. Patients already receiving opioids at study entry were not included in the long-term Use of opioids for oral preparations lasts for 3 weeks or more, and for parenteral preparations lasts for 7 days or more. was defined as a ≥ 30% increase in the total daily dose of opioid analgesics taken. As-needed administration of opioid analgesics for treatments other than prostate cancer (e.g., non-fixed or unscheduled administration) or chronic opioid use, discontinuation of study treatment is not permitted. It wasn't necessary.

[0082] The term "time to symptomatic local progression" refers to the time to symptomatic local progression, whichever occurs first. Symptomatic local progression is defined as the time from the date of randomization to progression. Examples of symptomatic local progression include: These include, but are not limited to, urethral obstruction or bladder outlet obstruction.

[0083] The term "time to worsening of ECOG PS grade" refers to the time to worsening of ECOG PS grade. defined as the time from the date of randomization to the first date of a worsening of (defined as a worsening of the patient's ECOG PS grade at baseline).

[0084] The term "overall survival" is defined as the time from randomization to the date of death from any cause. Survival data for subjects alive at the time of analysis are based on the most recent data for which survival is known. In addition, subjects who were not alive after the baseline information were excluded from the study. Data was censored on the date of randomization, and if the whereabouts of the subjects were unknown and they were lost to follow-up, For subjects who withdraw consent or withdraw consent, data will be retained until the subject's survival is known. In some embodiments, androgen receptor receptor agonists were censored at the most recent date of the study. Administration of a receptor inhibitor provides improved anti-tumor activity as measured by overall survival.

[0085] The term "time to cytotoxic chemotherapy" refers to the time until the documentation of a new cytotoxic chemotherapy. Defined as the period from randomization.

[0086] The term "progression-free survival with first subsequent therapy (PFS2)" refers to the progression-free survival (PFS) of Investigator-assessed disease progression (PSA, X-ray, or other biomarkers) during the first subsequent anticancer therapy radiographic, symptomatic, or any combination) or the initiation of a second subsequent anticancer therapy The time to death (any cause) before the start of treatment is defined as the time from randomization to death.

[0087] The term "time to PSA progression" is based on the Prostate Cancer Working Group 2 criteria. Defined as the time from randomization to the date of SA exacerbation. Scher HI, et al. J Clin Oncol 2008;26:1148-1159.

[0088] The term "time to second progression-free survival" refers to the time until a patient reaches prostate cancer, whichever occurs first. Investigator-assessed disease progression (PSA progression) while receiving first-line subsequent cancer therapy Time to first occurrence of refractory disease (e.g., radiographic progression, or clinical progression) or death from any cause , defined as the time from randomization. Subjects without documented progression after subsequent therapy For , progression data were censored at the most recent known progression-free date or date of death. In some embodiments, administration of the androgen receptor inhibitor is administered as a first subsequent therapy. The present invention provides improved anti-tumor activity as measured by progression-free survival.

[0089] According to the Prostate Cancer Working Group (PCWG2) criteria Therefore, prostate-specific antigen response and time to PSA progression were assessed at the time of the primary analysis of MFS. Time to PSA progression is assessed by the time the PCWG2 criteria for PSA progression are met. The time to treatment is calculated as the time from randomization to the time at which the patient is admitted.

[0090] As used herein, the term "placebo" does not include androgen receptor inhibitors. In the context of the treatment of non-metastatic castration-resistant prostate cancer, Men receiving a GnRH receptor inhibitor or placebo were Castrate levels of testosterone were maintained either by co-administration of steroids or by orchiectomy. It is necessary to maintain it.

[0091] As used herein, the term "survival effect" refers to the effect of a randomized controlled trial of an administered drug on a patient's survival. In some embodiments, survival refers to an increase in a patient from the time of induction to death. Profits are calculated as follows: about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 15 months, about 20 months, about 25 months, about 30 months, about 35 months, approximately 40 months, approximately 45 months, approximately 50 months, approximately 55 months, approximately 60 months, approximately 80 months , about 100 months, or more than 100 months.

[0092] The term "randomization," when referring to a clinical trial, refers to the time at which patients are identified as eligible for the clinical trial. This refers to when a patient is assigned to a treatment group.

[0093] As used herein, the term "delay in symptoms associated with disease progression" refers to the delay in symptoms associated with the administration of a drug. Increased time from randomization to the onset of symptoms such as pain or urinary obstruction in clinical trials of the drug and increased time for quality of life considerations.

[0094] The terms "kit" and "article of manufacture" are used synonymously.

[0095] The terms "subject" and "patient" and "human" are used interchangeably.

[0096] The term "severe liver impairment" refers to the severity of liver disease according to the modified Child-Pugh classification ( Classification C according to the Modified Child-Pugh Classification of Severity of Liver Disease This refers to those who achieve a score of 10 to 15.

[0097] Treatment regimen In one aspect, methods are described herein for treating non-metastatic castration-resistant prostate cancer in human males. The method comprises administering a therapeutically effective amount of an androgen receptor inhibitor to a patient with severe liver damage. or (c) administering to a human male in need of such treatment or a method consisting essentially of administering to a subject in need thereof, wherein the androgen receptor inhibitor is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo- 6-Thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N -methylbenzamide (apalutamide), 4-(3-(4-cyano-3-(trifluoromethyl)benzamide) Methyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1 -yl)-2-fluoro-N-methylbenzamide (enzalutamide), 4-[7-[4 -cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7 -diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (RD162), or N-{(2S)-1-[3-(3-chloro-4-cyanophenyl )-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl) -1H-pyrazole-3-carboxamide (darolutamide).

[0098] In one aspect, provided herein are methods for treating non-metastatic castration-resistant prostate cancer in human males. 4-[7-(6-cyano-5-trifluoromethyl (pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4] Oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide) administering to a human male in need of such treatment, the human male having a liver disorder of A method is described that consists of, or consists essentially of:

[0099] In one aspect, provided herein are methods for treating non-metastatic castration-resistant prostate cancer in human males. 4-(3-(4-cyano-3-(trifluoromethyl)methyl)-2-(2-methyl- ... (phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1- (enzalutamide) in patients with severe liver damage. or comprising or consisting of administering to a human male in need of such treatment, A method is described that comprises, or consists essentially of,

[0100] In one aspect, provided herein are methods for treating non-metastatic castration-resistant prostate cancer in human males. 20. A method for treating a cancer, comprising administering to a patient a therapeutically effective amount of 4-[7-[4-cyano-3-(trifluoromethyl)methyl]phenyl]propanol. (ethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octa -5-yl]-2-fluoro-N-methylbenzamide (RD162) in patients with severe liver damage to a male human in need of such treatment, Methods are described that comprise or consist essentially of:

[0101] In one aspect, provided herein are methods for treating non-metastatic castration-resistant prostate cancer in human males. 20. A method for treating a cancer comprising administering to a patient a therapeutically effective amount of N-{(2S)-1-[3-(3-chloro-4- cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyphenyl)- (Darolutamide) is used in severe cases of administering to a human male having liver damage and in need of such treatment. Methods are described that consist of, or consist essentially of,

[0102] In the disclosure below, the "method of treating non-metastatic castration-resistant prostate cancer" may alternatively include: It may be described as a method of treating a human male with non-metastatic castration-resistant prostate cancer. To be clear, each possible alternative is not analyzed, but each is fully described. are considered separately as follows.

[0103] In certain embodiments, the male human has normal cardiac condition and function. In an embodiment, normal cardiac condition and function is defined as sinus rhythm, a heart rate of about 50 to about 100 beats per minute. heart rate, QT corrected (QTc) interval of approximately 480 ms or less, and QT of 120 mg or more RS interval, PR interval of 220 ms or greater, or any other pattern consistent with healthy cardiac condition and function In certain embodiments, the present invention includes a normal heart condition and Functions include sinus rhythm, heart rate of approximately 50 to 100 beats per minute, and QT correction of approximately 480 ms or less. Includes the QTc interval.

[0104] In some embodiments, a human male has an average blood flow of about 45 mL / min / 17.3 m 2 The following Creati Creatinine clearance (CrCL) The study is part of the Chronic Kidney Disease Epidemiology Collaboration. n: CKD-EPI) creatinine formula.

[0105] In yet a further embodiment, the male human has stable liver damage. If present, "stable liver damage" is defined as a screening test documented by the participant's recent medical history. This refers to the absence of a clinically significant change in disease status within the last 90 days prior to the screening visit. Examples of no clinically significant change in status include, but are not limited to, clinical signs of liver damage. No worsening of bed signs and / or >50% reduction in total bilirubin or prothrombin and there is no deterioration in prothrombin time (PT).

[0106] In certain embodiments, the male human has controlled hypertension. The human male has a medical problem directly related to the primary diagnosis of liver damage.

[0107] In some embodiments, the human male has a systolic blood pressure of about 90 to about 170 mmHg. In certain embodiments, the male human has a diastolic blood pressure of less than about 100 mmHg. In a further embodiment, the male human has a systolic blood pressure of about 90 to about 170 mmHg and a blood pressure of about 100 mmHg. As used herein, "blood pressure" refers to a blood pressure in a human male. Refers to blood pressure measurements taken after the patient has been in a supine position for 5 minutes. If the blood pressure is out of range, Two replicate evaluations are permitted.

[0108] In some embodiments, the male human is receiving combination therapy for severe liver damage. In embodiments, the combination therapy includes an antihypertensive agent, a calcium channel blocker, an angiotensin inhibitor, Angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, diuretic, cholesterol lowering agent Examples of antihypertensive agents include one or more of the following: blood sugar lowering agents, oral antidiabetic agents, and electrolyte replacement. include alpha-1 and beta-blockers.

[0109] The doses of all permitted concomitant medications for subjects with severe hepatic impairment are limited to androgen. The patient should be stabilized for a minimum of 2 weeks before and during administration of an agonist receptor inhibitor. Minor dose adjustments of the drug are permitted within 2 weeks prior to administration of an androgen receptor inhibitor. It is possible.

[0110] In some embodiments, the human male is receiving a combination therapy for another medical condition. Examples of acceptable combination therapies for certain medical conditions include, but are not limited to, vitamins, progesterone, and niacin. Protein supplements, lactulose, rifaximin, neomycin, vancomycin , metronidazole, and oral L-ornithine-L-aspartate.

[0111] In a further embodiment, the male human is a potent inhibitor of CYP2C8 or CYP3A4 or No inducers are administered. Examples of strong CYP3A4 inhibitors include, but are not limited to, cytochrome P454, cytochrome P455, cytochrome P456, cytochrome P457, cytochrome P458, cytochrome P459 ... Laconazole, clarithromycin, delavirdine, atazanavir, indinavir, Nef Azodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voricona Examples of strong CYP3A4 inducers include, but are not limited to, phenylalanine, phenytoin ... Toxicant, carbamazepine, phenobarbital, and St. John's wort (St. Examples of CYP2C8 inhibitors include, but are not limited to, gemcitabine, cefotaxime ... CYP2C8 inducers include fibrozil, felodipine, and zafirlukast. Examples include, but are not limited to, rifampin.

[0112] In a further embodiment, administration of palliative care to a male human with nmCRPC who has severe liver damage. Administration of apalutamide is recommended for patients with nmCRPC with severe liver damage who are not receiving treatment with apalutamide. In some embodiments, the method is not associated with an increased risk of adverse events compared to a male human having The study found that administration of apalutamide to male humans with nmCRPC and severe liver damage was associated with significant patients with severe liver damage who are treated with apalutamide but not with apalutamide There is no increased risk of adverse events compared with men with nmCRPC. In some embodiments, administration of palliative care to male humans with nmCRPC who have severe liver damage. Administration of tamide was compared with placebo in patients with nmCRPC who had severe liver damage. In some embodiments, the risk of severe adverse events is not increased compared to males. Administration of apalutamide to male humans with nmCRPC and liver damage was The risk of adverse events was significantly reduced in men with nmCRPC who had severe liver damage compared with men with nmCRPC who had severe liver damage. No increase.

[0113] In certain embodiments, administration of palliative care to a human male with nmCRPC with severe liver damage. Administration of apalutamide is recommended in patients with nmCRP who have severe liver dysfunction and are not receiving treatment with apalutamide. In some embodiments, the risk of adverse events is increased compared to male humans with C. Administration of apalutamide to male humans with nmCRPC and severe liver damage patients with severe liver damage who are treated for liver damage but not treated with apalutamide Compared with men with nmCRPC, men with nmCRPC are at increased risk of adverse events. In one embodiment, apalutamide is administered to a male human with nmCRPC who has severe liver damage. The study will involve male humans with nmCRPC and severe liver damage receiving placebo. In some embodiments, the risk of adverse events is increased compared to patients with severe liver damage. Administration of apalutamide to human men with nmCRPC is associated with untreated, severe Increased risk of adverse events compared with men with nmCRPC and liver damage .

[0114] As used herein, the term "adverse event" refers to a condition that occurs after administration of an androgen receptor inhibitor. Adverse events refer to any unintended medical occurrence in a human male. A secondary event (AE) does not necessarily have a causal relationship with treatment. E is a temporary androgen-related condition, whether or not it is related to an androgen receptor inhibitor. Any unfavourable and unintended symptoms (abnormal findings) associated with the use of genotoxic receptor inhibitors This may be a condition or disease, including new onset or a change from baseline. Any episode that is a worsening in severity or frequency, or diagnostic findings, including laboratory test abnormalities This includes abnormal results of the diagnostic procedure.

[0115] In a further embodiment, the adverse event may occur following administration of an androgen receptor inhibitor. Examples of adverse events that occur after administration of androgen receptor inhibitors include treatment-emergent adverse events. Treatment-emergent adverse events (TEAEs) and worsening from baseline In certain embodiments, adverse events are reported. If so, a "reported adverse event" is a predefined event about which the subject is specifically asked. Local and systemic events. In certain embodiments, no adverse events are reported. When used in this context, an "unreported adverse event" refers to an adverse event that is not specifically questioned about by the subject. It is not something that can be done.

[0116] In certain embodiments, the adverse event is a serious adverse event (SAE). As used herein, the term "serious adverse event" or "SAE" refers to any Any medical occurrence other than the intended purpose at this dose, i.e., resulting in death, life-threatening threatening the patient's condition, requiring hospitalization or prolongation of an existing hospitalization, or causing permanent or or significant organ-wide instability / disability, congenital anomalies / birth defects, the supply of some infectious agent via the medicine is suspected, or the medicine is of medical importance and / or any combination thereof.

[0117] As used herein, "life-threatening" means that the subject is at risk of death at the time of the event. "Life-threatening" means that there was a risk of death if the condition was more severe. In determining whether an SAE is medically significant, Emergency reporting may be necessary to prevent a subject from being endangered, even if not immediately life-threatening or resulting in death or hospitalization. or to prevent one of the other consequences listed in the definition above. It may also be appropriate in other situations, such as serious medical events, where intervention to prevent Medical and scientific judgment must be exercised in determining whether to administer the drug.

[0118] In certain embodiments, the adverse event is an unlisted or unexpected adverse event. If the quality or severity is inconsistent with the applicable product reference safety information, the adverse event will be In some embodiments, the adverse event is considered to be due to androgen receptor inhibition. Related to the use of drugs.

[0119] If there is a plausible causal relationship between the administration of an androgen receptor inhibitor and the adverse event, The event is said to be "related." If the adverse event is not related to the use of an androgen receptor inhibitor, If so, the adverse event is "not related."

[0120] Also described herein are methods for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in human males. 1. A method for treating a male human having severe liver damage, comprising determining whether the male human has severe liver damage. In humans with severe liver damage, the daily dose ranges from about 30 mg to about 480 mg. and administering apalutamide at a dose of 1 mg to male humans to treat nmCRPC. In some embodiments, a method is provided in which a male human is examined for normal cardiac condition and function. In certain embodiments, normal cardiac condition and function is defined as sinus rhythm, approximately 1 / 2 beat per minute. A heart rate of 50 to about 100 beats per minute and a QTc interval of about 480 ms or less. In the case of a human male, the rate is approximately 45 mL / min / 17.3 m 2Have the following creatinine clearance: In yet a further embodiment, the male human has stable liver damage. In one embodiment, a human male has a systolic blood pressure of about 90 to about 170 mmHg. In general, a human male has a diastolic blood pressure of less than about 100 mmHg.

[0121] In certain embodiments, the nmCRPC is high-risk nmCRPC. In this form, apalutamide administration is effective in patients with nmCRPC who are not previously treated with apalutamide. The present invention provides an increase in metastasis-free survival in human males compared to the metastasis-free survival rate of a population of human males receiving the treatment. In certain embodiments, the male human has a prostate-specific antigen doubling time (PS) that is 10 months or less. ADT).

[0122] In some embodiments, the human male has received at least one prior therapy for the treatment of cancer. In a further embodiment, the prior therapy for the treatment of cancer includes one or more of acetaminophen, ... Biraterone plus prednisone, bicalutamide, flutamide, nilutamide, chemotherapy , docetaxel, cabazitaxel, radium-223, or sipuleucel-T. In a further embodiment, the prior therapy for the treatment of cancer is bicalutamide, flutamide, or nivolumab. In a further embodiment, the male human is treatment-naive.

[0123] In some embodiments, androgen receptor inhibitors are used broadly, specifically apalutamine. androgen deprivation therapy (ADT) In a further embodiment, the androgen receptor inhibitor is administered in combination with at least At least one gonadotropin-releasing hormone (GnRH) agonist or antagonist In yet a further embodiment, at least one GnRH agonist is administered in combination. The inhibitor or antagonist is leuprolide, buserelin, nafererin, histrelin, Serelin, deslorelin, degarelix, ozalelix, ABT-620 (elagolix) ), TAK-385 (relugolix), EP-100, KLH-2109, or tri It is or comprises putrelin.

[0124] A physician may prescribe a GnRH agonist according to instructions, recommendations, and practice. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is In some embodiments, leuprolide is administered at a dose of about 7.5 mg every 4 weeks. mg, or 22.5 mg every 3 months, or about 30 mg every 4 months, or every 6 months It is administered as a depot injection at a dose of approximately 45 mg. It is administered over a period of approximately 3 days to approximately 12 months. 0.01 mg to about 200 mg of leuprolide, preferably for a period of about 3 days to about 12 months In some embodiments, the leuprolide is administered at a dose of about 3.6 mg of leuprolide. The gonadotropin-releasing hormone agonist or antagonist is buserelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is In some embodiments, gonadotropin-releasing hormone agonists are In some embodiments, the gonadotropin or antagonist is histrelin. A typical example of a prohormone-releasing hormone agonist or antagonist is histrelin acetate. In this embodiment, the histrelin acetate is administered at a dose of about 50 mg of histrelin over a 12 month period. It is administered as a phosphate acetate or approximately 50 μg of histrelin acetate per day. In some embodiments, the GnRH agonist or antagonist is goserelin. In embodiments, goserelin is administered at a dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 weeks. g. In some embodiments, goserelin is administered as a subcutaneous implant at a dose of about about 0.01 mg to about 20 mg of goserelin, preferably about 0.01 mg to about 20 mg of goserelin, for a period of 28 days to about 3 months The dose is approximately 3.6 mg to 10.8 mg of goserelin administered over a period of approximately 28 days to approximately 3 months. In some embodiments, the GnRH agonist or antagonist is administered In some embodiments, the agonist is a gonadotropin-releasing hormone agonist or agonist. In some embodiments, the antagonist is degarelix. It is administered as a subcutaneous injection at a dose of 40 mg, followed by approximately 80 mg every four 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-6 20 (elagolix). In some embodiments, a GnRH agonist or antagonist In some embodiments, the GnR agonist is TAK-385 (relugolix). The H agonist or antagonist is EP-100. The nRH agonist or antagonist is KLH-2109. So, the gonadotropin-releasing hormone agonist or antagonist is triptorelin. In some embodiments, triptorelin is administered at a dose of about 0.0 mg / kg for a period of about 1 month. 1 mg to about 20 mg of triptorelin, preferably about 3.75 mg over a period of about one month Triptorelin is administered at 1 mg.

[0125] In certain embodiments, androgen receptor inhibitors broadly, specifically apalutamide, Enzalutamide, RD162, or darolutamide is used in combination with bilateral orchiectomy. In embodiments, androgen receptor inhibitors in broad terms, specifically apalutamide, enzalutamide, Tamide, RD162, or darolutamide is administered after bilateral orchiectomy.

[0126] Administration method In one aspect, provided herein are methods for treating non-metastatic castration-resistant prostate cancer in human males. 1. A method for administering to a male human in need of such treatment, the method comprising administering to said male human a compound having severe liver damage: comprising or consisting of administering a therapeutically effective amount of an androgen receptor inhibitor; A method is described, consisting essentially of: The medicament is one or more of enzalutamide, RD162, or darolutamide. In the present specification, a method for treating non-metastatic castration-resistant prostate cancer in human males is described. 1. A method comprising administering to a male human in need of such treatment, having severe liver damage, Administer androgen receptor inhibitors at doses of approximately 10 mg to approximately 1,200 mg per day. A method is described, comprising, consisting of, or consisting essentially of: Genitor receptor inhibitors include apalutamide, enzalutamide, RD162, or darolutamide. One or more of the following:

[0127] Broadly, androgens used to treat the diseases or conditions described herein in humans. Doses for steroid receptor inhibitors typically range from 10 mg to 1200 mg per day. In some embodiments, the androgen receptor inhibitor is administered in a dose of about 30 mg per day to about 100 mg per day. In some embodiments, androgens are administered to humans at a dose of about 1200 mg per day. The steroid receptor inhibitors are administered to humans at doses ranging from approximately 30 mg per day to approximately 600 mg per day. In some embodiments, the androgen receptor inhibitor is administered at a dose of about 30 mg per day. , about 60 mg per day, about 90 mg per day, about 120 mg per day, Approximately 160 mg per day, approximately 180 mg per day, approximately 240 mg per day, approximately 300 mg per day mg, approximately 390 mg per day, approximately 480 mg per day, approximately 600 mg per day, 1 Doses of about 780 mg per day, about 960 mg per day, or about 1200 mg per day It is administered to humans at

[0128] In certain embodiments, the compounds are used to treat a disease or condition in a human described herein. , androgen receptor inhibitors in a broad sense, specifically apalutamide, enzalutamide, RD 162, or the dose of darolutamide is 30-40 mg / day, 40-50 mg / day, 50- 60mg / day, 60~70mg / day, 70~80mg / day, 80~90mg / day, 90~ 100mg / day, 100~120mg / day, 120~140mg / day, 140~160m g / day, 160~180mg / day, 180~200mg / day, 200~220mg / day, 220~240mg / day, 240~260mg / day, 260~280mg / day, 280~ 300mg / day, 300~320mg / day, 320~340mg / day, 340~360m g / day, 360~380mg / day, 380~400mg / day, 400~420mg / day, 420-440mg / day, 440-460mg / day, 460-480mg / day, 480- 500mg / day, 500~520mg / day, 520~540mg / day, 540~560m g / day, 560-580 mg / day, 580-600 mg / day, 600-620 mg / day, 620-640mg / day, 640-660mg / day, 660-680mg / day, 680- 700mg / day, 700~720mg / day, 720~740mg / day, 740~760m g / day, 760~780mg / day, 780~800mg / day, 800~820mg / day, 820-840mg / day, 840-860mg / day, 860-880mg / day, 880- 900mg / day, 900-920mg / day, 920-940mg / day, 940-960mg g / day, 960~980mg / day, 980~1000mg / day, 1000~1020mg / day, 1020~1040mg / day, 1040~1060mg / day, 1060~1080 mg / day, 1080~1100mg / day, 1100~1120mg / day, 1120~11 40mg / day, 1140~1160mg / day, 1160~1180mg / day, 1180~ 1200 mg / day, or any range defined by two or more of these The range may be any range, or any single value recited therein.

[0129] In some embodiments, the compounds are used to treat a disease or condition in a human described herein. In a broad sense, androgen receptor inhibitors, specifically apalutamide, enzalutamide, The dose of RD162 or darolutamide is 0.3 to 0.4 mg / kg / day, 0.4 to 0. 5mg / kg / day, 0.5-0.6mg / kg / day, 0.6-0.7mg / kg / day, 0 .7~0.8mg / kg / day, 0.8~0.9mg / kg / day, 0.9~1mg / kg / day, 1-1.2 mg / kg / day, 1.2-1.4 mg / kg / day, 1.4-1.6 mg / kg / day, 1.6-1.8 mg / kg / day, 1.8-2 mg / kg / day, 2-2.2 mg / kg / day, 2.2-2.4mg / kg / day, 2.4-2.6mg / kg / day, 2.6- 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, 3.8-4.0mg / kg / day, 4.0-4.2mg / kg / day, 4.2- 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 It can be any single value quoted in these.

[0130] In a further embodiment, apalutamide is administered at a dose of from about 30 mg per day to about 480 mg per day. In a further embodiment, apalutamide is administered to a male human at a dose of about 100 mg / day. In a further embodiment, the dosage is between 30 mg and about 300 mg per day administered to a male human. Apalutamide is administered to male humans at doses ranging from approximately 30 mg per day to approximately 240 mg per day. In a further embodiment, apalutamide is administered at a dose of about 30 mg per day to about 100 mg per day. In a further embodiment, apalutamide is administered to a male human at a dose of about 120 mg. It is administered to human males at a dose of about 30 mg per day to about 60 mg per day. In its active form, apalutamide is administered to humans at doses of approximately 60 mg per day to approximately 300 mg per day. In a further embodiment, apalutamide is administered at a dose of about 60 mg to 100 mg per day. In a further embodiment, apalutamivir is administered to a male human at a dose of about 240 mg per day. It is administered to human males at a dose of about 60 mg per day to about 120 mg per day. In a further embodiment, apalutamide is administered at a dose of from about 120 mg per day to about 300 mg per day. In a further embodiment, apalutamide is administered to a male human at a dose of about 100 mg / day. It is administered to a human male at a dose of 120 mg to about 240 mg per day. In this condition, apalutamide is administered at doses of approximately 180 mg per day to approximately 480 mg per day. In some embodiments, apalutamide is administered to a male subject at a dose of (a) about 3 times per day. 0 mg, (b) approximately 60 mg per day, (c) approximately 90 mg per day, (d) approximately 100 mg per day or (d) administered orally to a human male at a dose of about 120 mg per day, or (e) about 240 mg per day. In some embodiments, apalutamide is administered to a human male at a dose of about 240 mg per day. In a particular embodiment, apalutamide is administered at a dose of about 60 mg and In a further embodiment, apalutamide is administered to a male human at a frequency of 4 doses per day. In a further embodiment, apalutamide is administered to a male human at a dose of about 120 mg. It is administered to human males at a dose of approximately 60 mg per day.

[0131] In some embodiments, enzalutamide is administered at a dose of about 160 mg per day. In some embodiments, greater than 160 mg of enzalutamide is administered per day. can be.

[0132] In some embodiments, RD162 is administered in a dose ranging from about 30 mg per day to about 480 mg per day. In yet a further embodiment, RD162 is administered orally to a male human at a dose of 100 mg daily. It is administered orally to human males at a dose of approximately 180 mg per day to approximately 480 mg per day. In some embodiments, RD162 is administered at a dose of (a) about 30 mg per day, (b) about 10 mg per day, 60 mg, (c) about 90 mg per day, (d) about 120 mg per day, or (d) 1 A dosage of about 240 mg per day is administered orally to a male human. RD162 is administered orally to male humans at a dose of approximately 240 mg per day.

[0133] In some embodiments, darolutamide is administered orally at a dose of about 1200 mg per day. In some embodiments, more than 1200 mg of darolutamide is administered per day. In some embodiments, darolutamide is administered at a dose of 600 mg twice daily. It is administered in doses.

[0134] In certain embodiments, where no improvement in the disease state or condition is observed in humans, broadly speaking, androgen receptor inhibitors, specifically apalutamide, enzalutamide, RD162, or In some embodiments, a once-daily dosing schedule is used. In some embodiments, the dose is changed to a twice-daily dosing schedule. A three-times-daily dosing schedule is recommended to increase the amount of androgen receptor inhibitor administered. It is used.

[0135] In some embodiments, an androgen receptor inhibitor, broadly defined, administered to a human, Generally, the amount of apalutamide, enzalutamide, RD162, or darolutamide is limited. The nature and severity of the disease or condition, as well as human characteristics (e.g., body weight), and It will vary depending on factors such as the particular additional therapeutic agent being administered (if applicable).

[0136] In one aspect, provided herein are methods for treating non-metastatic castration-resistant prostate cancer in human males. The method comprises administering a therapeutically effective amount of an androgen receptor inhibitor to a patient with severe liver damage. or A method is described consisting essentially of, wherein the androgen receptor inhibitor is administered orally. In some embodiments, the androgen receptor inhibitor is administered daily. In some embodiments, the androgen receptor inhibitor is administered twice daily. In some embodiments, the androgen receptor inhibitor is administered three times daily. In some embodiments, the androgen receptor inhibitor is administered four times daily. In some embodiments, the androgen receptor inhibitor is administered every other day. In some embodiments, the androgen receptor inhibitor is administered once a week. In some embodiments, the androgen receptor inhibitor is administered once a week. In some embodiments, the androgen receptor inhibitor is administered daily. It is administered orally on a dosing schedule.

[0137] In one embodiment, the desired dose of androgen receptor inhibitor is administered in a single dose or in the same dose. In divided doses administered occasionally (or over a short period of time) or at appropriate intervals, e.g. Conveniently, the dose may be given in two, three, four or more subdoses. In some embodiments, the androgen receptor inhibitors are administered once daily simultaneously (or shortly thereafter). In some embodiments, the androgen receptor inhibitors are administered in divided doses. The inhibitor is conveniently administered in divided doses administered twice daily in equal portions. In this condition, androgen receptor inhibitors are conveniently administered in divided doses three times daily. In some embodiments, the androgen receptor inhibitor is administered four equally divided doses daily. It is conveniently administered in divided doses administered sequentially.

[0138] In certain embodiments, the desired dose of androgen receptor inhibitor is administered in portions throughout the day. The total amount of androgen receptor inhibitor delivered by a unit dose is the total daily dose. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 subunit doses throughout the day The amount can be delivered.

[0139] In a further embodiment, apalutamide is administered daily to a male human. In some embodiments, apalutamide is administered orally to a male human. Tamide is administered orally to male humans on a continuous daily dosing schedule.

[0140] In a further embodiment, enzalutamide is administered daily to a male human. In some embodiments, enzalutamide is administered orally to a male human. Izalutamide is administered orally to male humans on a continuous daily dosing schedule.

[0141] In a further embodiment, RD162 is administered daily to a male human. In some embodiments, RD162 is orally administered to a male human. is administered orally to human males on a continuous daily dosing schedule.

[0142] In a further embodiment, darolutamide is administered daily to a male human. In some embodiments, darolutamide is administered orally to a male human. Rolutamide is administered orally to male humans on a continuous daily dosing schedule.

[0143] Routes of Administration and Pharmaceutical Compositions The therapeutic agents described herein may be administered in any suitable manner or in any suitable formulation. Suitable routes of administration of the drug include oral and parenteral (e.g., intravenous, subcutaneous, intramuscular). All formulations are in dosages suitable for administration to humans. The Summary of Pharmaceutical Compositions is incorporated herein by reference for such disclosure, e.g. Remington: The Science and Practice of Pharmacy,Nineteenth Ed(Easton,Pa.:Mack P publishing Company,1995);Hoover, John E.,R emington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmac. eutical Dosage Forms,Marcel Decker,New Y ork, NY, 1980; and Pharmaceutical Dosage Fo rms and Drug Delivery Systems,Seventh Ed (Lippincott Williams & Wilkins 1999) It has been done.

[0144] Safety studies also identify any potential adverse effects that exposure to a drug may have. Effectiveness is often determined by appropriate circumstances, e.g., tightly controlled Active pharmaceutical ingredients have been shown to have greater health benefits than placebo or other interventions when tested in controlled clinical trials The variance is measured by determining whether the variance exhibits

[0145] Unless otherwise indicated, as used herein, the terms "effective amount" or "therapeutically effective amount" mean and treating an underlying disease or condition, including halting or slowing the progression of the disease or condition. The dose of an androgen receptor inhibitor is

[0146] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means , the harmful effects of the formulation, composition or ingredients thereof on the general health of the human male under treatment. This means that the beneficial effects substantially outweigh the adverse effects.

[0147] In some embodiments, the androgen receptor inhibitor is formulated as a solid dosage form. In some embodiments, the androgen receptor inhibitor is administered in an oral dosage form, a unit oral dose or solid dosage forms (e.g., capsules, tablets, or pills). In some embodiments, for example, the androgen receptor inhibitor is formulated as a tablet. In some embodiments, the androgen receptor inhibitor is apalutamide. In some embodiments, the androgen receptor inhibitor is enzalutamide. In some embodiments, the androgen receptor inhibitor is RD162. The androgen receptor inhibitor is darolutamide.

[0148] The formulation may also contain a combination of two or more of these ingredients. Solid oral dosage forms containing steroid receptor inhibitors are also disclosed, each of which is incorporated herein by reference. The present invention is disclosed in International Publication No. 2014113260 and Chinese Patent Application Publication No. 104857157. It may be provided as a softgel capsule as shown, or as a medicament for use in a pharmaceutical composition, each of which is incorporated herein by reference. International Publication Nos. 2016090098, 2016090101, and 2016090102 are incorporated herein by reference. 2016090105 and 2014043208, which are presented as tablets. Suitable techniques for preparing the solid oral dosage forms of the present invention are described in Remington's P pharmaceutical sciences,18th edition,edit ed by AR. Gennaro, 1990, Chapter 89 and Reming ton-The Science,and Practice of Pharmacy ,21st edition,2005,Chapter 45.

[0149] In certain embodiments, the androgen receptor inhibitor is in a solid unit dosage form and is suitable for oral administration. The unit dosage form is formulated in a suitable solid unit dosage form. The unit dosage form may be about 10, 20, 30, or 40 mg of the active ingredient per unit dosage form. , 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 1 50, 160, 170, 180, 190, 200, 210, 220 or 240 mg, Alternatively, the amount of the androgen receptor inhibitor may be in a range defined by two of these values.

[0150] To prepare the pharmaceutical compositions of the present invention, the active pharmaceutical ingredient is mixed with the pharmaceutical composition by conventional pharmaceutical compounding techniques. The pharmaceutical composition is thoroughly mixed with a pharmaceutical carrier, which carrier is then mixed in the desired preparation for administration (e.g., oral or parenteral). Depending on the form of the formulation, it can take a wide variety of forms. Suitable pharmaceutically acceptable carriers include: A description of some of these pharmaceutically acceptable carriers is well known in the art. , published by the American Pharmaceutical Association and the British Pharmaceutical Association. Pharmaceutical Excipients.

[0151] For example, dry powders for reconstitution or inhalation, granules, capsules, caplets, gelcaps, Solid oral dosage forms such as pills and tablets (each including immediate-release, sustained-release, and extended-release formulations) In the formulation, suitable carriers and additives include diluents, granulating agents, lubricants, binders, glidants, Disintegrants and the like are included, but are not limited to these. Capsules are the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated with sugar, gelatin, or other suitable coatings by standard techniques. The formulation may be coated, film coated, or enteric coated.

[0152] Preferably, these compositions are administered orally, intranasally, sublingually, intraocularly, transdermally, parenterally, intravaginally, Tablets, pills, capsules, etc. for administration by dry powder inhalation or other inhalation or delivery means. capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered dose It is a unit dosage form such as an aerosol or liquid spray, drops, or suppository.

[0153] These formulations are manufactured by conventional formulation techniques. To prepare the formulation, the main active ingredient is mixed with a pharmaceutical carrier, such as a diluent, binder, adhesive, disintegrant, The tablet is mixed with conventional tablet-forming ingredients such as lubricants, anti-adherents, and glidants. Starches (i.e., those that can be hydrolyzed, such as corn starch, wheat starch, etc.) starch, or potato starch), lactose (granulated, spray-dried, or anhydrous), sucrose sucrose, sucrose-based diluents (confectionery manufacturer's sugar; sucrose + about 7-10% by weight of invert sugar; Sucrose + about 3% by weight of modified dextrin; sucrose + about 4% by weight of invert sugar, about 0. 1-0.2% by weight of corn starch and magnesium stearate), dextromethorphan cellulose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e., FM AVICEL microcrystalline cellulose available from C Corp.), dicalcium phosphate, Examples include, but are not limited to, calcium sulfate dihydrate, and calcium lactate trihydrate. Suitable binders and adhesives include acacia gum, guar gum, and tragacanth gum. , sucrose, gelatin, glucose, starch, and cellulosic (i.e., Methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydro hydroxypropylmethylcellulose, and hydroxypropylcellulose), water-soluble or Dispersible binders (i.e., alginic acid and its salts, magnesium aluminum silicate, hydroxybenzoates, Hydroxyethylcellulose [i.e., available from Hoechst Celanesel] [Polyesteryl ester], polyethylene glycol, polysaccharide acid, bentonite, polyvinylpyrrolidone lolidone, polymethacrylate, and pregelatinized starch), but these Suitable disintegrants include, but are not limited to, starch (corn, potato, etc.), Sodium Starch Glycolate, Pregelatinized Starch, Clay (Magnesium Aluminum Silicate) Nesium), Cellulose (Cross-linked Sodium Carboxymethylcellulose and Microcrystalline cellulose), alginates, pregelatinized starches (i.e., corn starch, etc.), Gums (i.e., agar, guar, carob, karaya, pectin, and tragacanth gum) , as well as cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and anti-blocking agents include stearates (magnesium, calcium, and Sodium), stearic acid, talc wax, stearowet, boric acid Acid, Sodium Chloride, DL-Leucine, Carbowax 4000, Carbowax 600 0, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate Examples of suitable anti-inflammatory agents include, but are not limited to, magnesium sulfate, magnesium lauryl sulfate, and the like. Suitable lubricants include talc, corn starch, and silica (i.e., C available from Cabot). AB-O-SIL Silica, SYLO available from W.R. Grace / Davison ID silica, and AEROSIL silica available from Degussa). Sweeteners and flavoring agents may be used to improve the palatability of the oral dosage form, including, but not limited to: Additionally, colorants and coatings may be added to the drug solid dosage form. They may be added or applied to solid dosage forms for ease of identification or for aesthetic purposes. The carrier is formulated with the pharmaceutically active agent to provide a therapeutically effective dose of the pharmaceutically active agent. Provide a release profile.

[0154] One aspect of the present invention is a solid dispersion comprising an androgen receptor inhibitor. There are various techniques for preparation, including melt extrusion (e.g., hot melt extrusion), spray drying, and solution evaporation, especially hot melt extrusion and spray drying, One aspect of the present invention is a particle comprising a solid dispersion as described herein. In one aspect of the present invention, particles as described herein are available, in particular In a broad sense, androgen receptor inhibitors, more specifically apalutamide and HPMCAS, are preferred. In one embodiment, the particles can be obtained by spray drying a mixture of the particles in a suitable solvent. is available, particularly by melt extrusion.

[0155] HPMCAS, or Hydroxypropyl Methylcellulose Acetate Succinate Hypromellose acetate succinate (CAS number 71138-97-1) is a It is a mixture of acetate and monosuccinate esters of hydroxypropyl methylcellulose. (IUPAC name: Cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate). Degree of substitution / substitution rate (acetyl content, succinic acid content) and particle size (micronized Various grades are available, differentiated based on their size (wt. and granularity). The HPMCAS in the dispersion with apalutamide was HPMCAS LG (Granular Grade ) or HPMCAS LF (micronized grade) (Shin-Etsu Chemical Co., Ltd.), and in particular HPMCAS LG.

[0156] Suitable binders for use in the pharmaceutical compositions provided herein include starch, cellulose, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carbohydrates, Carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose cellulose, hydroxypropyl methylcellulose), polyvinyl 1-pyrrolidone, and Examples include, but are not limited to, mixtures of these.

[0157] Examples of suitable fillers for use in the pharmaceutical compositions provided herein include microcrystalline cellulose, cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch , pregelatinized starch, and mixtures thereof.

[0158] A binder or filler in pharmaceutical compositions typically accounts for about 50 to 100% of the total mass of the pharmaceutical composition or dosage form. It is present at about 99% by weight.

[0159] Disintegrants are used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage. On the other hand, tablets containing too little may disintegrate at a desired rate or under desired conditions. Therefore, it is important that the amount is not excessively large enough to adversely alter the release of the active ingredient. A sufficient amount of disintegrant, but not too little, must be used to form a solid oral dosage form. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions contain from about 0.5 to about 15% by weight of a disintegrant, particularly from about 1 to about Disintegrants that can be used in the pharmaceutical compositions provided herein include 5% by weight of a disintegrant. The drugs used include croscarmellose sodium, crospovidone, and sodium starch glycolate. Thorium, potato starch or tapioca starch, pregelatinized starch, other starches These include, but are not limited to, polyethylene, other celluloses, gums, and mixtures thereof. .

[0160] Lubricants that can be used in the pharmaceutical compositions provided herein include stearin Calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol , polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, Sodium stearyl fumarate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil) oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), stearate lead, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Lubricants are typically used in pharmaceutical compositions or formulations in which they are incorporated. It is used in an amount of less than about 1% by weight of the formulation.

[0161] The compressed tablet formulation may optionally be filled with a filler to provide color, light protection, and / or taste masking. Tablets may also be film-coated to minimize the patient's biological exposure to the API. The onset and / or rate of release in the gastrointestinal tract may be adjusted to optimize or maximize It may be coated.

[0162] Hard capsule formulations are made of, for example, gelatin or hypromellose shells with an aqueous soluble sorbent. Manufactured by filling a blend or granulation of lutamide or enzalutamide can be done.

[0163] A softgel capsule formulation can be prepared.

[0164] Pharmaceutical compositions intended for oral use include solid dispersion formulations and the like, which can be prepared by the methods described herein. The blended materials may be prepared by other methods known in the art for preparing pharmaceutical compositions. Such compositions may be sweetened to provide a pharmaceutically excellent and palatable preparation. The composition may further comprise one or more agents selected from the group consisting of taste agents, flavoring agents, coloring agents, and preservatives. It may have.

[0165] Tablets are prepared by mixing the active ingredient with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, granulating agents, and disintegrating agents. Disintegrants, binders, glidants, lubricants, and antioxidants, such as propyl gallate, butylated hydroxybenzoates, The tablets may be uncoated. It may be coated or film coated to modify the appearance. or to prolong the action by delaying disintegration and absorption in the gastrointestinal tract , may be coated with a functional coat.

[0166] Compositions for oral use also include those in which the active ingredient is not present in an inert solid diluent, such as calcium carbonate. capsules (e.g., hard gelatin capsules) mixed with starch, calcium phosphate, or starch or when the active ingredient is in a liquid or semi-liquid form, e.g., peanut oil, liquid paraffin soft gelatin capsules mixed with glycerides, surfactants, or olive oil Aqueous suspensions may be prepared by dissolving the active substances in excipients suitable for the manufacture of aqueous suspensions. It contains in a mixed state with a dispersible substance suitable for preparation of an aqueous suspension by adding water. Powders and granules are mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. In certain embodiments of the present invention, the pharmaceutical compositions of the present invention are obtained by dissolving the active ingredient in a diluent system. , disintegrant, salt, lubricant, glidant, and film coating, each in an amount of about 3% to about 5% by weight / weight. 8wt / wt%, about 4wt / wt% to about 20wt / wt%, about 4wt / wt% to about 20wt Amount / wt%, approx. 0.5 wt / wt% to approx. 4 wt / wt%, approx. 0 wt / wt% to approx. 2 wt / % wt., and about 1% wt. / wt. to about 5% wt. / wt., or about 18% wt. / wt., respectively. ~40 wt / wt%, approx. 7 wt / wt%~approx. 15 wt / wt%, approx. 7 wt / wt%~approx. 18 wt / wt%, approx. 1.0 wt / wt% ~ approx. 3.0 wt / wt%, approx. 0.1 wt / wt % to about 1.0 wt / wt%, and at concentrations of about 2.0 wt / wt% to about 4.0 wt / wt% In certain embodiments, the solid dispersion formulation comprises a diluent, one or more disintegrants, a lubricant, and An exemplary blended composition or oral dosage form is blended with mannitol, fine particles, and a lubricant. Microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silica, Contains sodium stearyl fumarate, and magnesium stearate.

[0167] The disintegrant is about 4% w / w to about 20% w / w, or about 7% w / w to about 15% w / w. A salt may also be present, such as sodium chloride. , potassium chloride, or a combination thereof. , present in a concentration of about 5% w / w to about 35% w / w of the final pharmaceutical composition.

[0168] In certain embodiments, the inactive ingredients of the core tablet include anhydrous colloidal silica, croscarmellose, Sodium cellulose, hydroxypropyl methylcellulose acetate succinate, Magnesium tearate, microcrystalline cellulose, and silicified microcrystalline cellulose. In embodiments, the tablets contain the following excipients: black iron oxide, yellow iron oxide, polyethylene A film coating consisting of polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. It is finished with coating.

[0169] In another embodiment, a single unit dose of the pharmaceutical composition contains about 60 mg of apalutamide. In some embodiments, the pharmaceutical composition comprises a single A single unit-administered multiple dose comprises, consists of, or consists of about 60 mg of apalutamide. It consists essentially of, for example, four or individual unit dosage forms, which are administered to a human. The total daily dose of apalutamide may be about 240 mg per day.

[0170] In some embodiments, a single unit dose of the pharmaceutical composition comprises about 40 mg of enzalutamide. In some embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of A single unit dose of the composition contains approximately 40 mg of enzalutamide, or consisting essentially of, for example, four or individual unit dosage forms The total daily dose of enzalutamide may be about 160 mg per day.

[0171] In still further embodiments, a single unit dose of the pharmaceutical composition contains about 300 mg of darolutamide. In some embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of A single unit dose of the composition contains approximately 300 mg of darolutamide, or consisting essentially of, for example, two or individual unit dosage forms The total daily dose of darolutamide may be approximately 600 mg twice daily. The total daily dose of darolutamide may be about 1200 mg per day.

[0172] All formulations for oral administration are in a form suitable for such administration. [Example]

[0173] These examples are not intended to limit the scope of the claims provided herein, but are illustrative. Provided for illustrative purposes only.

[0174] Example 1: In subjects with severe liver impairment compared to subjects with normal liver function A Single-Dose, Open-Label Study to Evaluate the Pharmacokinetics of Apalutamide in Patients with HIV / AIDS the purpose Main purpose Apalliative care in subjects with severe hepatic impairment compared with subjects with normal liver function To characterize the single-dose pharmacokinetics (PK) of tamoxifen.

[0175] Secondary Objectives To evaluate the safety profile of single-dose apalutamide in subjects with severe hepatic impairment To value.

[0176] Study design The test described in Example 1 will be carried out according to the criteria described herein. Subjects with impaired liver function (Child-Pugh class C) or healthy subjects with normal liver function An open-label, single-dose, multicenter, non-randomized, randomized, randomized, open-label, multicenter, randomized, randomized, randomized, open-label, single-dose, multicenter, randomized ... This is a Phase 1 PK study. Subjects with severe hepatic impairment (Class C, Child-Pugh syndrome) Cores 10-15) were characterized according to the modified Child-Pugh classification of liver disease severity. Determine.

[0177] Scoring using the Child-Pugh classification is as shown in Table 1 below.

[0178] ●Total score of 5 or 6: Mild liver damage Total score of 7-9: Moderate liver damage ●Total score of 10-15: Severe liver damage

[0179] [Table 1]

[0180] Apalutamide is expected to be used in patients with prostate cancer. The liver function is similar to that of normal healthy subjects. The healthy subjects are expected to represent the intended patient population with normal liver function. Therefore, healthy male subjects will be used as the control group in this study.

[0181] After providing written informed consent, subjects were enrolled within 21 days (days 21-22). During the screening phase, subjects will be screened based on the inclusion and exclusion criteria. During the open-label treatment phase, eligible subjects with severe hepatic impairment and those with normal liver function will be evaluated. Functional subjects will receive a single oral dose of 120 mg on Day 1 under fasting conditions. Restrict food for at least 10 hours before and 2 hours after dosing (with a light snack afterward) Lunch is provided 4 hours after dosing.

[0182] Subjects were randomly assigned to complete 168-hour pharmacokinetic (PK) blood sampling from Day -1 to Day 8. Subjects will be admitted to the study facility until completion of the study. Patients returned to the study facility on days 10, 12, and 15 for measurements of plasma concentrations of 57 Return to the study site weekly for PK evaluation until day 1. Plasma protein binding binding (PPB) and time to Cmax of apalutamide and N-desmethylapalutamide Pre-dose and post-dose plasma samples were used in the same time period to test the unbound fraction. Subject safety and tolerability will be monitored throughout the study. The study will be conducted on Day 57, when 1,344 hours of PK sampling is completed. For subjects who withdrew from the study, the trials performed before withdrawal from the clinical site were considered to be study completion. The duration of participation in the study for each subject will be approximately 78 days (screening time). (including g).

[0183] A total of 16 subjects are expected to be enrolled in this study. Subjects with liver disease were classified according to the modified Child-Pugh classification of severity of liver disease. Subjects with liver impairment are classified as having normal liver function after all tests are completed. The healthy subjects in the control group will be compared to the subjects with severe liver impairment. (average ±10 years) and body mass index (BMI, average ±20%) I will.

[0184] Subjects who withdrew from the study before completing 1,008 hours of PK blood sampling were randomly assigned to the same liver. A replacement subject with normal liver function can also be used to identify subjects belonging to the matching group. standards must be met.

[0185] Survey period The duration of study participation for each subject is approximately 78 days (including screening). do.

[0186] Subject selection General Considerations Approximately 16 subjects (severely affected according to the modified Child-Pugh classification at baseline) Eight subjects with severe liver damage [Class C] and eight subjects with normal liver function in the control group 8 healthy subjects with severe liver impairment will be enrolled. or at least 1,008-hour PK timepoint completed), mean age (±10 years) and mean A control group of subjects matched for mean BMI (±20%) will be enrolled (signing the ICF). must be present).

[0187] Men aged 18 to 80 years were randomly assigned to the study according to their liver function (normal liver function or severe liver damage). The degree of liver damage will be assessed using a modified Chiropractic Scale for Severity of Liver Disease. Based on the d-Pugh classification. Using this classification, two clinical features (hepatic encephalopathy and ascites) and three laboratory-based parameters (albumin, bilirubin, and INR / prothrombin). Based on the binge time and taking into account the use of medications for hepatic encephalopathy and ascites, At least 16 subjects (8 per liver function) will be assigned to each group. The intention is to complete the treatment provided.

[0188] Subjects who withdraw from the study before completing all required testing will be excluded from the study. Exchange subjects with normal liver function must also meet matching criteria.

[0189] Inclusion criteria All subjects must meet the following criteria to be enrolled in this study: ●Be a man between 18 and 80 years old. The subject understands the purpose of the study and the procedures required, and is willing to participate in the study. Subjects must sign an Informed Consent Form (ICF) stating that they agree to participate in the study. be deemed by the investigator to lack the capacity to provide informed consent Patients must not have hepatic encephalopathy ≥ grade 3. Mild or moderate hepatic encephalopathy that is deemed not to interfere with informed consent is permitted. ● Comply with the prohibitions and restrictions. Agree to use an appropriate method of contraception as deemed appropriate by the investigator Kito. ●Body mass index (BMI: weight [kg] / height 2 [m] 2 ) is 18.0 to 40.0 kg / m 2 and body weight >50 kg. After a subject has undergone a puncture, the subject's BMI must be recalculated. The eligibility of subjects will be determined based on the calculated BMI. Non-smokers, or those who smoke 10 or fewer cigarettes per day, or 2 or fewer cigars, or He was a light pipe smoker, smoking less than 100 cigarettes, and had been smoking 4 cigarettes per day during his hospital stay. or agree to a smoking limit of one cigar.

[0190] Subjects with normal liver function must meet the following additional inclusion criteria to be enrolled in the study: must be met. Unless deemed clinically significant by the investigator, Italic signs and laboratory evaluations showed no clinically significant findings and the patient was in good health. It is necessary. A 12-lead ECG is consistent with normal cardiac conduction and function, including: Sinus rhythm Heart rate of 50 to 100 beats per minute Corrected QT interval (QTc) ≤ 450 ms (Fridericia correction; QTcF) ○ QRS interval ≤ 120 ms ○PR interval≦220ms Morphology consistent with healthy cardiac conduction and function Subjects were required to have serum bilirubin, blood glucose, or serum creatinine levels ≤ upper limit of normal (ULN). Serum albumin, INR, alanine aminotransferase e, ALT), and aspartate aminotransferase ase, AST) levels. Subjects were within normal limits and were participants in the Chronic Kidney Disease Epidemiology Collaborative Study. When calculated according to the creatinine formula of the CKD-EPI (Chemology Collaboration) >60mL / min / 1.73m 2 Creatinine clearance (CrCL) of serum creatinine It is necessary to have thymine. Liver damage was observed in the experimental group with respect to age (±10 years) and BMI (±20% of the mean). be equivalent to. At screening (after the subject has been lying supine for 5 minutes), blood pressure should be 95-100 systolic. 50mmHg in the diastolic direction and 90mmHg in the diastolic direction. If the blood pressure is out of range, Repeated evaluations are allowed.

[0191] Subjects with severe hepatic impairment must meet the following additional inclusion criteria to be enrolled in the study: must be met: ● 12-lead ECG consistent with normal cardiac conduction and function as follows: ○ Sinus rhythm, Heart rate of 50 to 100 beats per minute ○QTc interval ≦480 ms (Fridericia correction; QTcF), Subjects will be required to: Must have a total Child-Pugh score of 10-15 on Day 1. Diagnosis (e.g., ultrasound, liver biopsy, liver / spleen scan, laboratory results, or clinical findings) Source documentation substantiating this, and medical history will be reviewed and signed by the investigator. The subjects were from the Chronic Kidney Disease Epidemiology Collaborative Study (CKDEC). Creatinine level calculated according to the CKD-EPI formula is ≥ 45 mL / min / 1.73m 2 The patient must have a creatinine clearance (CrCL) of ≥ 100 mg / kg. ● Patient's recent medical history (no worsening of clinical signs of liver damage, total bilirubin or prothrombin The immediate period before the screening visit was documented by a PT (no worsening of >50% of the time). Stable liver disease, defined as no clinically significant change in disease status within the last 90 days. Subjects with controlled hypertension and problems directly related to the primary diagnosis of liver damage Subjects may be included if the investigator and sponsor determine that the condition poses additional risk factors. Subjects should be simultaneously placed in a stable position, taking into consideration that this does not interfere with the purpose and procedures of the study. Patients may have medical conditions and be included in the study (i.e., mild degenerative joint disease, controlled diabetes, Subjects with urinary disease, controlled thyroid conditions, and other conditions treated case by case). If the chemical or hematological test results are not within the laboratory reference ranges, the investigator will Subjects may be enrolled only if the effects of the study are deemed not to be clinically significant. Laboratory results related to underlying liver conditions may be outside the normal range. ● (After the subject has been in a supine position for 5 minutes) Blood pressure is 90-170 mmHg systolic and diastolic. BP should be ≤100 mmHg during the diastolic phase. If BP is out of range, up to two repeat assessments are required. Acceptable. Concomitant medications to treat medical conditions related to the stage of the underlying disease or liver damage are not permitted. Subjects will be on a consistent dose of drug and / or should be subjected to a treatment regimen.

[0192] The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine formula referenced in this example is , expressed as follows: Estimated glomerular filtration rate = 141 × min(SCr / κ, 1)α × m ax(SCr / κ, 1) - 1.209 x 0.993 age x 1.018 [for women] x 1 0.159 [for blacks]. eGFR is mL / min / 1.73m 2 It is expressed as: SCr (standardized serum creatinine) = mg / dL. κ = 0.7 (women) or 0.9 (men) ). α = -0.329 (female) or -0.411 (male). Min = SCr / κ or 1 Indicates the minimum value. Max = indicates the maximum value of SCr / κ or 1. Age = years.

[0193] Exclusion criteria Potential subjects who meet any of the following criteria will be excluded from participating in the study:

[0194] All subjects: • Screening TSH level >ULN; - (including but not limited to) cardiac arrhythmias or other cardiac disorders, hematological disorders, coagulation disorders (any abnormal bleeding or blood disorders), bronchopathic respiratory disease, uncontrolled diabetes mellitus, or renal failure, neurological or psychiatric disease, significant infection, or Subjects should be excluded if they have any other illnesses that may interfere with the interpretation of the study results. Clinically significant medical conditions, including abnormal coagulation parameters and other conditions associated with underlying liver disease. Abnormalities of do not exclude subjects with severe liver impairment. ●It is not possible to fast for 12 hours. • Active gallbladder or biliary tract disease (e.g., cholecystitis or symptomatic cholelithiasis). • Previous cholecystectomy. • Pre-planned surgical operations or procedures that would interfere with the conduct of the study. - Have had a relationship with the father of a child while enrolled in this study or within 3 months of the most recent dose of study medication The man who is to become. - Diagnostic and Statistical Manual of Mental Disorders (DSM) within 6 months prior to screening Medication according to the Statistical Manual of Mental Disorders (DSM-V) (5th edition) criteria A history of substance abuse or use of drugs of abuse (barbiturates) at screening and on day -1 drugs, opiates, cocaine, cannabinoids, amphetamines, and benzodiazepines (In subjects with liver impairment, the use of approved therapeutic agents is prohibited.) (It was only permitted if its use resulted in a positive test.) History of seizures or symptoms that may be precursors to seizures (i.e., transient ischemic attack, stroke, cerebral arteriovenous malformations, neoplasms in the brain or meninges, etc. Any surgical or medical condition, except hepatic impairment, that may alter the absorption, metabolism, or excretion of the study drug and medical conditions (e.g., gastrectomy, Crohn's disease). • History of clinically significant allergies. • Known allergy, hypersensitivity, or intolerance to apalutamide or its excipients. Donation of blood or blood products or blood substance within 3 months prior to administration of the study drug loss (>500 mL) or intent to donate blood or blood products during the study. within 1 month or less than 5 half-lives of the drug before planned administration of the study drug; Have received an experimental drug or used an experimental medical device within the longer period of time Ta. Inability to swallow solid oral dosage forms with the aid of water (participant was unable to chew or disintegrate the study medication) , dissolve, or crush). Human immunodeficiency virus (HIV) at the screening visit IV) 1 and HIV2 antibody tests were positive. • Lack of adequate venous access.

[0195] Subjects with normal liver function: Performance dysfunction (abnormal sexual desire, erectile dysfunction, etc.) or any medical condition that affects sexual function The existence of. • Screening for serum testosterone levels less than 200ng / dL. - Take any of the following medications (including vitamins and Use of any prescription or non-prescription medications (including prescription and non-prescription herbal supplements) (if the investigator (clinically irrelevant in the context of the study unless specific use of the previous medication can be understood) Acetaminophen use is not permitted within 3 days prior to study drug administration. Hepatitis A immunoglobulin M positive, Hepatitis B surface antigen positive n, HBsAg) positive, serum positive for hepatitis B or hepatitis C antibodies. Hepatitis B surface antibody positive Being a hepatitis B vaccine recipient is not an exclusion if the subject can provide evidence of hepatitis B vaccination. Diagnostic and Statistical Manual of Mental Disorders (5th ed.) within 5 years prior to screening A history of alcoholism according to the MV criteria or alcoholism at screening and on day -1 The breathalyzer test was positive. At screening or Day -1, as deemed appropriate by the investigator, Clinically significant abnormal hematological or clinical chemistry values. Subjects with impaired hepatic function: Use of acetaminophen at a dose greater than 2 g / day within 2 weeks prior to study drug administration. Drugs known to induce or inhibit drug-metabolizing enzymes (CYP2C8 and / or C YP3A4), which must be discontinued at least 2 weeks before Day 1. Yes (preliminary studies and combination therapy). A history or current diagnosis of uncontrolled or significant heart disease, including any of the following: presents significant risks to safety for participation in the study, including: ○ Recent myocardial infarction (within 6 months of check-in) New York Heart Association Class III or IV congestive heart failure Unstable angina (within 6 months of check-in) Clinically significant (symptomatic) cardiac arrhythmias (e.g., persistent cardiac arrhythmias without a pacemaker) ventricular tachycardia, second- or third-degree atrioventricular block) Uncontrolled high blood pressure Gilbert syndrome, liver transplantation, Wilson's disease, autoimmune liver disease, successful banding bleeding esophageal varices within 3 months prior to screening if not treated with steroids, known gastrointestinal varices aneurysms, spontaneous bacterial peritonitis within 3 months prior to screening, cholestatic liver disease (e.g., For example, primary biliary cirrhosis or primary sclerosing cholangitis), biliary sepsis within the past 2 years History of a portosystemic shunt, performed at least 6 months prior to the screening period In this case, a transjugular intrahepatic portosystemic shunt (transjugular intrahepatic portosystemic shunt, Subjects with TIPS are allowed. ●Previous diagnosis of hepatocellular carcinoma. Acute or worsening hepatitis, either by the investigator or by the sponsor's medical monitor by widespread change or worsening of clinical and / or laboratory signs of liver damage, as determined by Fluctuations or rapid decline in liver function indicated. In the opinion of the investigator, evidence of current or recent alcohol abuse is Subject safety due to study procedures or positive alcohol breath test at screening or Day -1 impairs safety or compliance. - Having received any treatment known to worsen liver dysfunction within 2 weeks of administration of the study drug and. • Antiviral therapy for treatment of active hepatitis infection at the time of screening. The presence of clinically significant laboratory findings at screening is grounds for exclusion, particularly: These include: Hemoglobin < 8.5 g / dL ○Platelet count<25,000 / mm 3 ○ALT or AST>5×ULN.

[0196] Prohibitions and Restrictions Potential subjects must comply with the following prohibitions and restrictions to be eligible to participate during the study: are willing to comply with the At least 12 hours before administration of the study drug until 168 hours after administration of the study drug (Day 8) You will be required to stay at the testing facility for any subsequent testing until the end of the test. You need to agree to that. Always use condoms during sexual intercourse (and if you have had a vasectomy, or sexual intercourse with a pregnant woman), or during the study and for 3 months after receiving the study drug. In the case of sexual activity with a woman of childbearing potential, the patient must agree to refrain from engaging in sexual activity for the duration of the study and and use another effective form of birth control (hormonal contraception [pill, patch, injection]) for 3 months after receiving the study drug. , implant], intrauterine device [IUD], intrauterine hormone-releasing system [IUS] , tubular ligand / occlusion, or hysterectomy / bilateral oophorectomy or salpingectomy) and Both require condoms. Throughout the study, healthy subjects with normal liver function received no treatment other than the study drug. Prescription or nonprescription medicines (including vitamins and herbal supplements) contain acetaminophen. The primary investigator, in consultation with the sponsor, must notify the patient of the intake of any prohibited medications. If so, determine whether the subject should be excluded from the study. Foods containing alcohol, grapefruit juice, or Seville oranges Foods or beverages were consumed within 24 hours on the first day (grapefruit juice and Seville oranges). For the 72 hours before the trial, the last PK sample was collected at 1,344 hours on Day 57. Do not consume until - 48 hours before administration of the study drug and during hospitalization, , chocolate bars, or drinks (coffee, tea, or cola) should be avoided. and throughout the study, cuffs were worn at all outpatient visits (including the screening period). Avoid excessive intake of niacin (i.e., less than about 500 mg / day, tea or coffee) (Limit of 5 cups for beer and 8 cans for cola) False positive urine drug screening test 72 hours before screening or on day -1 To avoid testing positive, one should avoid consuming any foods containing mustard seeds. During your stay at the study facility, you will need to consume the facility's food. Excessive eating is not permitted. . Alcohol, barbiturates, and opioids during screening and on Day -1 Drugs such as acetaminophen, cocaine, cannabinoids, amphetamines, and benzodiazepines A blood, urine, or saliva sample must be negative for both the drug and the substance. The questionnaire was collected both before and during the study and included recent use of drugs of abuse, alcohol, and caffeine. Drugs that may interfere with drug screening (e.g., For example, for patients receiving prescriptions for opiates, cannabinoids, and benzodiazepines, A positive test for this condition is acceptable. If you have had a recent fever (over 38°C) within 3 days of the planned date of drug intake, you will be asked to refrain from taking the study drug. Initiation should be delayed until temperature has been normal for at least 72 hours. Subjects must be followed for at least 2 months after completing the study or at least 3 months after receiving the study drug. For months, people are advised not to donate blood to take part in investigational drug trials. Subjects were to donate sperm from the study drug for at least three months after receiving the drug. do not have. All types of jogging and strenuous exercise were prohibited upon admission to the study facility and 48 hours prior to admission. It is necessary to refrain from doing so. Strong inhibitors or inducers of CYP2C8 and / or CYP3A4 were tolerated during the study. and must be discontinued for at least 2 weeks before administering study drug.

[0197] Subject Completion If the subject completed evaluations up to and including Day 57 (end-of-study , EOS] visit), the subject is considered to have completed the study.

[0198] Study drug, formulation, dose, and mode of administration Dosage and Administration Before study drug administration, subjects were to abstain from food and beverages (except still water) for at least 10 hours. Non-carbonated water is permitted up to 1 hour before administration of the study drug.

[0199] Subjects received a single oral dose of 120 mg apalutamide: 2 × 60 mg doses under fasting conditions The study drug was administered in 240 mL of non-carbonated tablet formulation between 8:00 AM and 10:00 AM on Day 1. The test drug is to be taken with water. If necessary, an additional 50 mL of water is permitted. Must be swallowed whole (within 1 minute) without crushing, breaking, dissolving, or crushing Subjects will be given 240 mL of non-carbonated water at least 1 hour after administration. Drinking is permitted after that date.

[0200] Subjects were given a light snack approximately 2 hours after administration and lunch approximately 4 hours after administration of the study drug. The exact date and time of study drug administration will be recorded on source documentation.

[0201] Physical description of the test drug The apalutamide administered in this study was 60 mg of the drug as a spray-dried powder (SDP). Hydroxypropyl methylcellulose acetate succinate ulose-acetate succinate, HPMC AS) polymer in a 1 / 3 ratio (API [active pharmaceutical ingredient] It is formulated as a 60 mg tablet containing 100 mg of the active ingredient (drug ingredient / polymer). The coated oral tablet also contains the following inactive ingredients: colloidal anhydrous silica, Croscarmellose sodium, microcrystalline cellulose, silicified microcrystalline cellulose, stearic acid Magnesium phosphate and coating powder green OPADRY II. Tablet core weight The dosage is 700 mg. The dimensions of the 60 mg tablet formulation are approximately 17 mm x 9 mm.

[0202] Pre-study and concomitant treatment Subjects were not allowed to continue their regular doctor-prescribed intake without obtaining consent from their physician. Do not stop taking the medication.

[0203] For healthy subjects: If the subject is If all prior medications are not discontinued, the investigator may decide that the specific use of prior medications is relevant to the study situation. Male subjects may be included in the study if it can be understood that the condition is not clinically relevant. do.

[0204] Throughout the study, participants were not permitted to take any prescription or nonprescription medications other than the study drug (vaccines, vitamins, and The use of any of these drugs (including herbal supplements) is prohibited, and this point should be discussed with the investigator and the patient before administration. The investigator and the sponsor must first consult with each other before the investigator and the sponsor can consult with each other. If treatment or vaccination is required, it should be initiated. If both the patient and the investigator agree, the study will be allowed to continue.

[0205] Use of acetaminophen or ibuprofen is permitted up to 3 days before administration of study drug. Throughout the study, 500 mg of acetaminophen was administered up to three times daily, and and no more than 3 g per week is permitted for the treatment of headache or other pain. If phenytoin is used, the dose and dosing regimen and reason for use should be recorded on the CRF. Throughout the study, 400 mg of ibuprofen was administered up to three times daily. and up to 1200 mg per 24 hours is permitted for the treatment of headache or other pain. If ibuprofen is used, the dose and dosing regimen and reason for use should be recorded on the CRF. It is necessary.

[0206] For subjects with severe hepatic impairment: Acetaminophen use is prohibited for 3 days after study drug administration. A maximum daily dose of 500 mg of acetaminophen was tolerated throughout the study. Three doses, and up to 3 g per week, are permitted for the treatment of headache or other pain. If acetaminophen is used, the dose and dosing regimen and reason for use should be reported to the CR. It must be recorded in F.

[0207] Subjects with severe hepatic impairment should continue to take their prescribed medications as medically necessary. The acquisition is permitted to continue.

[0208] Subjects with severe hepatic impairment should receive tolerated concomitant medication for at least 2 hours after study drug administration. Patients are advised to maintain their use of the drug. Drugs, e.g., cholestyramine or non-absorbable antacids, should be discontinued for at least 6 hours after study drug administration. It should be administered later.

[0209] Drugs that are strong inhibitors or inducers of CYP2C8 and / or CYP3A4 are being investigated. This is not tolerated and must be discontinued for at least 2 weeks before study drug administration.

[0210] Test evaluation Overview Figures 1A and 1B show the time and event schedule for the screening phase from Day -21 to Day -2. and days -1 to 8 of the open-label phase (Figure 1A), and days 10 to 57 of the open-label phase. The eyes (Figure 1B) are shown. The footnotes for Figures 1A and 1B are as follows: (a) Screen By Day 1 after screening, the subject's condition has changed to the point where the subject no longer meets the eligibility criteria. If any changes are made to the study (including laboratory results or receipt of additional medical records), the subject will be removed from the study. (b) A complete examination at screening, or if not, an abbreviated examination, Examination (minimal cardiovascular, respiratory, and gastrointestinal examination, optionally as indicated by AE / symptoms) (c) - Screening ultrasound obtained within 2 weeks prior to Day 1 (d) Applicable only to subjects with hepatic impairment. (e) Safety. Sexual laboratory testing will be scheduled to be performed under fasting conditions (after a 10-hour fast). Safety If early withdrawal is performed for food-related reasons, safety laboratory studies may not be interpreted as under fasting conditions. (f) If the screening safety assessment is completed within -48 hours of Day -1, repeat The safety assessment on Day -1 must be completed within 48 hours of Day -1. (g) After an overnight fast, the test drug was administered to each subject between 8:00 AM and 10:00 AM. (h) Blood samples will be collected before administration of the study drug. (i) PK blood sample collection Two hours after the PK blood sample collection, a light snack was provided ad libitum. Four hours after the PK blood sample collection, lunch was provided. (j) 10th, 12th, 15th, 22nd, 29th, 36th, 43rd day If the follow-up visits on days 1, 50, or 57 were missed, PK samples were taken within ±1 day. (k) On Day 57 or the day of early withdrawal, an end-of-study assessment will be conducted. (l) Only TSH is required and only for subjects on thyroid replacement therapy. be.

[0211] Pharmacokinetics For the determination of total and unbound apalutamide and N-desmethylapalutamide concentrations, Serial blood samples will be taken pre-dose and >1,344 hours (day 57) post-dose.

[0212] PK analysis was based on individual concentration-time data using actual sampling times. The following plasma PK parameters of apalutamide and N-desmethylapalutamide will be measured as needed. It is measured as follows: max , C max_unb , t max , AUC last , AUC l ast_unb , AUC ∞ , AUC ∞_unb , %AUC ∞、ex , CL / F, CL un b / F, Vd / F, t 1 / 2 , λ z , t last , and C max , AUC last and AUC ∞ Metabolite to parent drug ratio (MPR) for Additional PK parameters may be included if deemed appropriate.

[0213] safety Safety and tolerability were assessed by adverse events (AEs), physical examination, vital signs, and 12-lead ECG. (electrocardiogram, ECG), and clinical laboratory parameters (hematology and serum chemistry) ) will be evaluated throughout the study.

[0214] The verbatim used in the CRF used by the investigator to identify the AEs is Uses the Medical Dictionary for Regulatory Activities (MedDRA) and coded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version All reported AEs with onset during treatment will be graded using the 5.0 (5.0) (i.e., TEAEs and AEs that worsened from baseline) will be included in the analysis. For each, the proportion of subjects experiencing at least one occurrence of a given event varies by treatment group. It can be summarized as follows.

[0215] The majority of blood samples collected in this study for clinical laboratory testing, protein binding, and PK evaluation were Large volume does not exceed 240 mL.

[0216] The following clinical laboratory tests will be performed: screening, serology, urine drug screen, and Hematological panel, serum chemistry panel, testosterone and TS in alcohol testing H.

[0217] Adverse Event Reporting and Severity Criteria Methods for detecting adverse events and serious adverse events: bias when detecting AEs or SAEs Open-label, non-leading questioning of subjects should be used to identify the occurrence of AEs. This is the preferred method for interviewing a patient.

[0218] AE / SAE severity assessment was completed using NCI-CTCAE version 5.0. AEs / SAEs not listed in the NCI CTCAE should be listed in the gray area shown in Table 2. The investigator will grade the condition using the criteria set by the subject. Use clinical judgment when assessing the severity of unexperienced events (e.g., laboratory abnormalities) It should be.

[0219] [Table 2]

[0220] statistical methods Determining sample size Data from studies on subjects with mild and moderate liver impairment versus healthy controls are available. AUC of thamidine last and AUC ∞ ) and C max For each, the total variation of AUC The coefficient of variation (CV) was 27% and 35% of the total CV. AUC 27% (AUC last and AUC ∞ ), there are 8 people in each group. The subject sample size is determined so that the point estimate of the geometric mean ratio between test and control is at a 90% confidence level. is sufficient to fall within (80%, 125%) of the true mean ratio. max Assuming a 35% chance, a sample size of 8 subjects per group would be The point estimate of the geometric mean ratio falls within (75%, 134%) of the true mean ratio at the 90% confidence level. is sufficient.

[0221] Approximately 16 subjects will be enrolled (8 subjects with severe liver impairment and 8 subjects with normal liver function) If a subject does not complete the study, an additional subject in the same category will be It can be registered.

[0222] Pharmacokinetics All subjects included in the PK population have sufficient and interpretable concentration-time data.

[0223] The primary PK parameter of interest was AU for both apalutamide and its active metabolite. C and C max When appropriate, PK parameters are also measured with respect to the unbound concentration. Statistics including arithmetic mean, SD, coefficient of variation, geometric mean, median, minimum, and maximum were Plasma concentrations at each sampling time and all PK parameters for each group Calculate.

[0224] Analysis of variance (ANOVA) models were performed on log-transformed total apalliative care. PK parameter data (AUC ∞ , AUC last , and C max ) applies to. A UC ∞ , AUC last , and C max Geometric mean ratios and associated 90% CIs for The results are then converted back to the original schedule after back-transformation. For exploratory purposes, the P values ​​of unbound apalutamide and N-desmethyl apalutamide are shown. The same analysis is carried out for the K parameter.

[0225] safety The safety population included all subjects who received at least one dose of study drug. Baseline laboratory assessments, 12-lead ECG measurements, and vital signs were performed prior to study drug administration. Safety is defined as the most recent evaluation performed. Safety is measured by the incidence and type of AEs and clinical findings. Screening was performed to include laboratory values, physical examination results, 12-lead ECG changes, and end-of-treatment visits. Vital sign measurements from the training phase will be assessed by testing.

[0226] The examples and embodiments described herein are for illustrative purposes only and are not intended to be limiting unless otherwise indicated and should not be construed as limiting the scope of the invention as claimed. Various modifications or variations are within the spirit and scope of this application and the appended claims. .

Claims

1. Methods for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in human males and administering to a human male in need of such treatment with severe liver damage about 3 times a day. Administering apalutamide at a dose of from 0 mg to about 480 mg per day.

2. 10. The method of claim 1, wherein the male human has normal cardiac condition and function.

3. said normal cardiac condition and function being sinus rhythm, a heart rate of about 50 to about 100 beats per minute; and a QTc interval of about 480 ms or less.

4. The male human has a blood flow of about 45 mL / min / 17.3 m ２ Have the following creatinine clearance: The method according to any one of claims 1 to 3,

5. The method of any one of claims 1 to 4, wherein the male human has stable liver damage. 。

6. 6. The method of claim 1, wherein the human male has a systolic blood pressure of about 90 to about 170 mmHg.

10. The method according to any one of claims 1 to 9.

7. 7. The method of claim 1, wherein the male human has a diastolic blood pressure of less than about 100 mmHg. The method according to any one of claims 1 to 5.

8. 8. The method of claim 1, wherein the male human is receiving a combination therapy for the severe liver damage.

1. The method according to claim 1.

9. The combination therapy includes an antihypertensive agent, a calcium channel blocker, an angiotensin-converting enzyme inhibitor, and inhibitors, angiotensin II receptor antagonists, diuretics, cholesterol-lowering drugs, 10. The method of claim 8, comprising one or more of an oral antidiabetic drug and electrolyte replacement.

10. The male human is administered a potent inhibitor or inducer of CYP2C8 or CYP3A4. The method according to any one of claims 1 to 9, wherein the

11. Administration of apalutamide is effective in treating people with nmCRPC who are not receiving treatment with apalutamide. The method according to any one of claims 1 to 10, which is not associated with an increased risk of adverse events compared to men. How to post.

12. Administration of apalutamide is effective in treating people with nmCRPC who are not receiving treatment with apalutamide. The method according to any one of claims 1 to 10, which is associated with an increased risk of adverse events compared to men. method.

13. The method according to any one of claims 1 to 12, wherein the nmCRPC is high-risk nmCRPC. The method described.

14. The administration of apalutamide is providing increased metastasis-free survival in said human male compared to the metastasis-free survival rate of a population of human males; The method according to any one of claims 1 to 13.

15. The male human has a prostate-specific antigen doubling time (PSADT) of 10 months or less. The method according to any one of claims 1 to 14,

16. 10. The method of claim 1, wherein the male human has undergone at least one prior therapy for the treatment of cancer.

16. The method of any one of 15.

17. the prior therapy for the treatment of cancer is bicalutamide, flutamide, or nilutamide; 17. The method of claim 16.

18. The method of any one of claims 1 to 15, wherein the human male is treatment-naive.

19. 19. Any one of claims 1 to 18, wherein the apalutamide is administered to the male human daily. The method described below.

20. 20. Any one of claims 1 to 19, wherein the apalutamide is administered orally to the male human. The method described below.

21. The apalutamide is orally administered to the male human on a continuous daily dosing schedule.

21. The method according to any one of claims 1 to 20.

22. The apalutamide is administered to the male human at a dose of from about 180 mg per day to about 480 mg per day.

22. The method of any one of claims 1 to 21, wherein the compound is administered orally at a dose of 100 mg / kg.

23. The apalutamide is orally administered to the male human at a dose of about 240 mg per day.

23. The method according to any one of claims 1 to 22.

24. The apalutamide was administered to the human male at a dose of about 60 mg and administered four times daily. The method of any one of claims 1 to 23, wherein the method is administered orally.

25. 23. The method of claim 1, wherein the apalutamide is administered at a dose of about 120 mg per day.

10. The method according to any one of claims 1 to 9.

26. 26. The method according to any one of claims 1 to 25, wherein the apalutamide is formulated as a solid dosage form. The method described.

27. 27. The method of claim 1, wherein the apalutamide is formulated as a tablet. How to do it.

28. The apalutamide is administered in combination with androgen deprivation therapy (ADT).

28. The method of any one of claims 1 to 27.

29. The apalutamide is combined with a gonadotropin-releasing hormone agonist or antagonist. The method according to any one of claims 1 to 28, wherein the compounds are administered in combination.

30. 30. The method according to any one of claims 1 to 29, wherein the apalutamide is used in combination with bilateral orchiectomy. How to post.

31. Methods for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in human males And, determining whether the male human has severe liver damage; - if the male human has severe liver impairment, administering to the male human about 30 mg to 100 mg / day Apalutamide is administered at a dose of about 480 mg per day to treat the nmCRPC. A method comprising:

32. Normal cardiac condition and function is characterized by sinus rhythm, a heart rate of about 50 to about 100 beats per minute, and 32. The method of claim 31, comprising a QTc interval of about 480 ms or less.

33. The male human has a blood flow of about 45 mL / min / 17.3 m ２ Have the following creatinine clearance: The method according to claim 31 or 32,

34. 34. The method of claim 31, wherein the male human has stable liver damage. method.

35. 3. The method of claim 2, wherein the male human has a systolic blood pressure of about 90 to about 170 mmHg.

5. The method according to any one of claims 4 to 4.

36. 36. The method of claim 31, wherein the male human has a diastolic blood pressure of less than about 100 mmHg.

10. The method according to any one of claims 1 to 9.

37. 37. Any of claims 31 to 36, wherein the male human is receiving a combination therapy for the severe liver damage. The method according to any one of claims 1 to 4.

38. The combination therapy includes an antihypertensive agent, a calcium channel blocker, an angiotensin-converting enzyme inhibitor, and inhibitors, angiotensin II receptor antagonists, diuretics, cholesterol-lowering drugs, 38. The method of claim 37, comprising an oral antidiabetic drug and electrolyte replacement.

39. The male human is administered a potent inhibitor or inducer of CYP2C8 or CYP3A4. The method of any one of claims 31 to 38, wherein the method does not

40. If the male human has severe liver impairment, the therapeutically effective amount of apalutamide is adjusted.

40. The method of any one of claims 31 to 39.

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