Androgen Receptor Inhibitors For The Treatment Of Non-Metastatic Castration-Resistant Prostate Cancer In Subjects With Severe Hepatic Impairment

Abstract

Described herein are methods of treating non-metastatic castration-resistant prostate cancer in subjects with severe hepatic impairment with androgen receptor inhibitors, including but not limited to, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

What is claimed: 
     
         1 . A method for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in a male human comprising administering enzalutamide at a dose of about 160 mg per day to a male human in need of such treatment who has severe hepatic impairment. 
     
     
         2 . The method of  claim 1 , wherein the male human has normal cardiac condition and function. 
     
     
         3 . The method of  claim 2 , wherein the normal cardiac condition and function comprises sinus rhythm, a heart rate between about 50 and about 100 beats per minutes, and a QTc interval of less than or equal to about 480 ms. 
     
     
         4 . The method of any one of the preceding claims, wherein the male human has a creatinine clearance of less than or equal to about 45 mL/min/17.3 m 2 . 
     
     
         5 . The method of  claim 1 , wherein the male human has stable hepatic impairment. 
     
     
         6 . The method of  claim 1 , wherein the male human has a blood pressure of between about 90 and about 170 mmHg systolic. 
     
     
         7 . The method of  claim 1 , wherein the male human has a blood pressure of less than about 100 mmHg diastolic. 
     
     
         8 . The method of  claim 1 , the male human receives concomitant therapy for the severe hepatic impairment. 
     
     
         9 . The method of  claim 8 , wherein the concomitant therapy comprises one or more of antihypertensive agents, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor-antagonists, diuretics, cholesterol-lowering drugs, oral antidiabetics, and electrolyte substitution. 
     
     
         10 . The method of  claim 1 , wherein the male human is not administered a strong inhibitor or inducer of CYP2C8 or CYP3A4. 
     
     
         11 . The method of  claim 1 , wherein administration of enzalutamide is accompanied by an increased risk of adverse events relative to a male human with nmCRPC who is not receiving treatment with enzalutamide. 
     
     
         12 . The method of  claim 1 , wherein the nmCRPC is a high-risk nmCRPC. 
     
     
         13 . The method of  claim 1 , wherein administration of the enzalutamide provides an increase in the metastasis-free survival of the male human relative to the metastasis-free survival rate of a population of male humans with nmCRPC who are not receiving treatment with enzalutamide. 
     
     
         14 . The method of  claim 1 , wherein the male human has a prostate-specific antigen doubling time (PSADT) that is less than or equal to 10 months. 
     
     
         15 . The method of  claim 1 , wherein the male human has received at least one prior therapy for the treatment of cancer. 
     
     
         16 . The method of  claim 15 , wherein the prior therapy for the treatment of cancer is bicalutamide, flutamide or nilutamide. 
     
     
         17 . The method of  claim 1 , wherein the male human is treatment naïve. 
     
     
         18 . The method of  claim 1 , wherein the enzalutamide is administered daily to the male human. 
     
     
         19 . The method of  claim 1 , wherein the enzalutamide is administered orally to the male human. 
     
     
         20 . The method of  claim 1 , wherein the enzalutamide is administered orally to the male human on a continuous daily dosing schedule. 
     
     
         21 . The method of  claim 1 , wherein the enzalutamide is formulated as a solid dosage form. 
     
     
         22 . The method of  claim 1 , wherein the enzalutamide is formulated as a tablet. 
     
     
         23 . The method of  claim 1 , wherein the enzalutamide is administered in combination with androgen deprivation therapy (ADT). 
     
     
         24 . The method of  claim 1 , wherein the enzalutamide is administered in combination with a gonadotropin-releasing hormone agonist or antagonist. 
     
     
         25 . The method of  claim 1 , wherein the enzalutamide is used concomitant with bilateral orchiectomy. 
     
     
         26 . A method for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in a male human comprising:
 determining if the male human has severe hepatic impairment; and   if the male human has severe hepatic impairment, administering to the male human enzalutamide at a dose of about of about 160 mg per day to treat the nmCRPC.   
     
     
         27 . The method of  claim 26 , wherein the normal cardiac condition and function comprises sinus rhythm, a heart rate between about 50 and about 100 beats per minutes, and a QTc interval of less than or equal to about 480 ms. 
     
     
         28 . The method of  claim 26 , wherein the male human has a creatinine clearance of less than or equal to about 45 mL/min/17.3 m 2 . 
     
     
         29 . The method of  claim 26 , wherein the male human has stable hepatic impairment. 
     
     
         30 . The method of  claim 26 , wherein the male human has a blood pressure of between about 90 and about 170 mmHg systolic. 
     
     
         31 . The method of  claim 26 , wherein the male human has a blood pressure of less than about 100 mmHg diastolic. 
     
     
         32 . The method of  claim 26 , wherein the male human receives concomitant therapy for the severe hepatic impairment. 
     
     
         33 . The method of  claim 32 , wherein the concomitant therapy comprises antihypertensive agents, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor-antagonists, diuretics, cholesterol-lowering drugs, oral antidiabetics, and electrolyte substitution. 
     
     
         34 . The method of  claim 26 , wherein the male human is not administered a strong inhibitor of inducer of CYP2C8 or CYP3A4.