Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer

Abstract

Described herein are methods of treating non-metastatic castrate-resistant prostate cancer with anti-androgens.

What is claimed is: 
     
       1. A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method comprising administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti-androgen 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,   4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, or   4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide;   wherein said method further comprises administering a gonadotropin releasing hormone (GnRH) agonist.   
     
     
       2. The method of  claim 1 , wherein the non-metastatic castration-resistant prostate cancer is a high risk non-metastatic castration-resistant prostate cancer. 
     
     
       3. The method of  claim 1 , wherein the anti-androgen 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. 
     
     
       4. The method of  claim 3 , wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered daily to the male human. 
     
     
       5. The method of  claim 3 , wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, 7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (ARN-509) is administered orally to the male human at a dose of about 180 mg per day to about 480 mg per day. 
     
     
       6. The method of  claim 3 , wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (ARN-509) is administered orally to the male human at a dose of:
 (a) about 30 mg per day;   (b) about 60 mg per day;   (c) about 90 mg per day;   (d) about 120 mg per day; or   (e) about 240 mg per day.   
     
     
       7. The method of  claim 3 , wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human on a continuous daily dosage schedule. 
     
     
       8. The method of  claim 3 , wherein the GnRH agonist is leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin. 
     
     
       9. The method of  claim 1 , wherein the anti-androgen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide. 
     
     
       10. The method of  claim 9 , wherein the GnRH agonist is leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin. 
     
     
       11. The method of  claim 1 , wherein the anti-androgen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide. 
     
     
       12. The method of  claim 11 , wherein the GnRH agonist is leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin. 
     
     
       13. The method of  claim 1 , wherein the anti-androgen is administered orally to the male human. 
     
     
       14. A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method consisting essentially of administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti-androgen 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,   4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, or   4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide;   wherein said method further comprises administering a gonadotropin releasing hormone (GnRH) agonist.   
     
     
       15. The method of  claim 14 , wherein the anti-androgen 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. 
     
     
       16. The method of  claim 15 , wherein the GnRH agonist is leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin. 
     
     
       17. The method of  claim 15 , wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (ARN-509) is administered orally to the male human at a dose of:
 (a) about 30 mg per day;   (b) about 60 mg per day;   (c) about 90 mg per day;   (d) about 120 mg per day; or   (e) about 240 mg per day.   
     
     
       18. The method of  claim 9 , wherein the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of about 160 mg per day. 
     
     
       19. The method of  claim 3 , wherein 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of about 240 mg per day. 
     
     
       20. The method of  claim 3 , wherein the GnRH agonist is leuprolide. 
     
     
       21. The method of  claim 3 , wherein the GnRH agonist is buserelin. 
     
     
       22. The method of  claim 3 , wherein the GnRH agonist is naferelin. 
     
     
       23. The method of  claim 3 , wherein the GnRH agonist is histrelin. 
     
     
       24. The method of  claim 3 , wherein the GnRH agonist is goserelin. 
     
     
       25. The method of  claim 3 , wherein the GnRH agonist is deslorelin. 
     
     
       26. A method of treating non-metastatic castration-resistant prostate cancer in a male human comprising administering a therapeutically effective amount of an anti-androgen to a male human with a non-metastatic castration-resistant prostate cancer;
 wherein the anti-androgen 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;   wherein the anti-androgen is administered in an amount of about 180 mg per day or 120 mg per day;   and wherein said method further comprises administering a gonadotropin releasing hormone (GnRH) agonist.   
     
     
       27. The method of  claim 26 , wherein the anti-androgen is administered in an amount of about 180 mg per day. 
     
     
       28. The method of  claim 26 , wherein the anti-androgen is administered in an amount of about 120 mg per day. 
     
     
       29. The method of  claim 26 , wherein the male human was previously treated at 240 mg per day and required dose reduction. 
     
     
       30. The method of  claim 26 , wherein the male human was previously treated at 240 mg per day and required dose interruption. 
     
     
       31. The method of  claim 26 , wherein the non-metastatic castration-resistant prostate cancer is a high risk non-metastatic castration-resistant prostate cancer. 
     
     
       32. The method of  claim 31 , wherein the male human with the high risk non-metastatic castration-resistant prostate cancer has a prostate-specific antigen doubling time (PSADT) that is less than or equal to 10 months. 
     
     
       33. The method of  claim 28 , wherein the male human has experienced 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with the last PSA>2 ng/ml. 
     
     
       34. The method of  claim 26 , wherein the male human is further treated to maintain castrate levels of testosterone of less than 50 ng/dL. 
     
     
       35. The method of  claim 26 , wherein the anti-androgen is administered daily to the male human. 
     
     
       36. The method of  claim 26 , wherein the anti-androgen is administered orally to the male human. 
     
     
       37. The method of  claim 26 , wherein the anti-androgen is administered to the male human orally and on a continuous daily dosing schedule. 
     
     
       38. The method of  claim 26 , wherein the male human has previously been treated with either orchiectomy or continuous androgen deprivation therapy (ADT). 
     
     
       39. The method of  claim 38 , wherein the continuous androgen deprivation therapy comprises administration of a gonadotropin-releasing hormone (GnRH) agonist or antagonist. 
     
     
       40. The method of  claim 39 , wherein the continuous androgen deprivation therapy comprises administration of a gonadotropin-releasing hormone agonist; and wherein the gonadotropin-releasing hormone is leuprolide, buserelin, nafarelin, histrelin, goserelin, or deslorelin. 
     
     
       41. A method of treating non-metastatic castration-resistant prostate cancer in a male human consisting essentially of administering a therapeutically effective amount of an anti-androgen to a male human with a non-metastatic castration-resistant prostate cancer;
 wherein the anti-androgen 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;   wherein the anti-androgen is administered in an amount of about 180 mg per day or 120 mg per day;   and wherein said method further comprises administering a gonadotropin releasing hormone (GnRH) agonist.   
     
     
       42. The method of  claim 41 , wherein the anti-androgen is administered in an amount of about 180 mg per day. 
     
     
       43. The method of  claim 41 , wherein the anti-androgen is administered in an amount of about 120 mg per day. 
     
     
       44. The method of  claim 41 , wherein the male human was previously treated at 240 mg per day and required dose reduction. 
     
     
       45. The method of  claim 41 , wherein the non-metastatic castration-resistant prostate cancer is a high risk non-metastatic castration-resistant prostate cancer. 
     
     
       46. The method of  claim 45 , wherein the male human with the high risk non-metastatic castration-resistant prostate cancer has a prostate-specific antigen doubling time (PSADT) that is less than or equal to 10 months. 
     
     
       47. The method of  claim 45 , wherein the male human has experienced 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with the last PSA>2 ng/mL. 
     
     
       48. The method of  claim 41 , wherein the male human is further treated to maintain castrate levels of testosterone of less than 50 ng/dL. 
     
     
       49. The method of  claim 41 , wherein the anti-androgen is administered daily to the male human. 
     
     
       50. The method of  claim 41 , wherein the anti-androgen is administered orally to the male human. 
     
     
       51. The method of  claim 41 , wherein the anti-androgen is administered to the male human orally and on a continuous daily dosing schedule. 
     
     
       52. The method of  claim 41 , wherein the male human has previously been treated with either orchiectomy or continuous androgen deprivation therapy (ADT). 
     
     
       53. The method of  claim 52 , wherein the continuous androgen deprivation therapy comprises administration of a gonadotropin-releasing hormone (GnRH) agonist or antagonist. 
     
     
       54. The method of  claim 53 , wherein the continuous androgen deprivation therapy comprises administration of a gonadotropin-releasing hormone agonist; and wherein the gonadotropin-releasing hormone is leuprolide, buserelin, nafarelin, histrelin, goserelin, or deslorelin. 
     
     
       55. A method of treating non-metastatic castration-resistant prostate cancer in a male human comprising administering a therapeutically effective amount of an anti-androgen to a male human with a non-metastatic castration-resistant prostate cancer;
 wherein the anti-androgen 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;   wherein the anti-androgen is administered in an amount of about 180 mg per day;   and wherein said method further comprises administering a gonadotropin releasing hormone (GnRH) agonist.   
     
     
       56. A method of treating non-metastatic castration-resistant prostate cancer in a male human consisting essentially of administering a therapeutically effective amount of an anti-androgen to a male human with a non-metastatic castration-resistant prostate cancer;
 wherein the anti-androgen 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;   wherein the anti-androgen is administered in an amount of about 180 mg per day;   and wherein said method further comprises administering a gonadotropin releasing hormone (GnRH) agonist.