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A61p5/28 (2006.01) ) ( (51) International Patent Classification: Declarations under Rule 4.17: A61K 31/4155 (2006.01) A61P5/28 (2006.01) — as to applicant's entitlement to apply for and be granted a A61K 31/4166 (2006.01) A61P 35/00 (2006.01) patent (Rule 4.17(H)) A61K 31/4439 (2006.01) — as to the applicant's entitlement to claim the priority of the (21) International Application Number: earlier application (Rule 4.17(iii)) PCT/IB2020/050752 Published: (22) International Filing Date: — with international search report (Art. 21(3)) 30 January 2020 (30.01.2020) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (25) Filing Language: English amendments (Rule 48.2(h)) (26) Publication Language: English — in black and white; the international application as filed contained color or greyscale and is available for download (30) Priority Data: from PATENTSCOPE 62/798,836 30 January 2019 (30.01.2019) US 62/803,096 08 February 2019 (08.02.2019) US 62/822,3 12 22 March 2019 (22.03.2019) US 62/833,371 12 April 2019 (12.04.2019) US 62/836,920 22 April 2019 (22.04.2019) US 62/901,694 17 September 2019 (17.09.2019) US (71) Applicant: ARAGON PHARMACEUTICALS, INC. [US/US]; 10990 Wilshire Blvd, Suite 300, Los Angeles, California 90024 (US). (72) Inventor: YU, Margaret K.; 10990 Wilshire Blvd, Suite 300, Los Angeles, California 90024 (US). (74) Agent: SHIRTZ, Joseph F. et al.; Johnson & Johnson, One Johnson & Johnson Plaza, New Brunswick, New Jer¬ sey 08933 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: ANTI-ANDROGENS FOR THE TREATMENT OF METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER (57) Abstract: Described herein are methods of treating metastatic castration-sensitive prostate cancer with anti-androgens, includ¬ ing 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- methyl- benzamide. ANTI-ANDROGENS FOR THE TREATMENT OF METASTATIC CASTRATION- SENSITIVE PROSTATE CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. provisional patent application no. U.S. provisional patent application no. 62/901,694, filed on September 17, 2019; 62/836,920, filed April 22, 2019; U.S. provisional patent application no. 62/833,371, filed April 12, 2019; U.S. provisional patent application no. 62/822,312, filed on March 22, 2019; 62/803,096, filed February 8, 2019; and U.S. provisional application no. 62/798,836, filed on January 30, 2019; all of which are incorporated by reference herein in their families. TECHNICAL FIELD Disclosed herein are methods of treating metastatic castration-sensitive prostate cancer with anti-androgens, 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 . BACKGROUND Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, accounting for 14% (903,500) of the total new cancer cases and 6% (258,400) of the total cancer deaths in males worldwide. The course of prostate cancer from diagnosis to death is best categorized as a series of clinical stages based on the extent of disease, hormonal status, and absence or presence of detectable metastases: localized disease, rising levels of prostate-specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and clinical metastases in the non-castrate or castrate stage. Although surgery, radiation, or a combination of both can be curative for patients with localized disease, a significant proportion of these patients have recurrent disease as evidenced by a rising level of PSA, which can lead to the development of metastases, especially in the high-risk group - a transition to the lethal stage of the disease. Based on current guidelines, androgen deprivation therapy (ADT) with or without docetaxel is considered the appropriate active control therapy for the patients with metastatic hormone-sensitive prostate cancer. However, there is a clear unmet medical need for altemative treatment options in mCSPC. Treatments that can delay disease progression and associated morbidities would be of significant clinical benefit in this patient population. The disclosed methods are directed to these and other important needs. SUMMARY Described herein are methods of treating metastatic castration-sensitive prostate cancer in a male human comprising, consisting of, or consisting essentially of administering a therapeutically effective amount of an anti-androgen to a male human with metastatic castration-sensitive prostate cancer. In these methods, the anti-androgen can be: 4-[7-(6- cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro- N-methylbenzamide, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, 4-[7-[4-cyano-3- (trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N- methylbenzamide or N-{(2S)-1- [3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}- 5-(l-hydroxyethyl)-1H-pyrazole-3-carboxamide. In some embodiments, administration of the anti-androgen provides an increase in overall survival of the male human relative to the overall survival rate of a comparative population of male humans with the metastatic castration-sensitive prostate cancer, said comparative population having been administered a placebo in combination with an androgen deprivation therapy. In other embodiments, the comparative population is untreated. In further embodiments, administration of the anti- androgen provides an increase in progression-free survival of the male human relative to the progression-free survival rate of a comparative population of male humans with the metastatic castration-sensitive prostate cancer, said comparative population having been administered a placebo in combination with an androgen deprivation therapy. In other embodiments, the comparative population is untreated. In some embodiments, the male human has received at least one prior therapy for the treatment of cancer prior to the administration of the anti-androgen, wherein the prior therapy for the treatment of cancer is radiation, surgical intervention or docetaxel therapy. In some embodiments, the male human is treatment naive. In some embodiments, 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. In further embodiments, the anti-androgen generally and 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)- 8-oxo-6-thioxo-5,7-diazaspiro[3 4]oct-5-yl]-2-fluoro-N-methylbenzamide more specifically is administered daily to the male human. In still further embodiments, the anti-androgen generally and 4-[7-(6-cyano-5-trifluoromethylpyridin-3 -yl)-8-oxo-6-thioxo-5 ,7- diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide more specifically is administered orally to the male human. In some embodiments, the anti-androgen generally and 4-[7-(6- cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro- N-methylbenzamide more specifically is administered orally to the male human on a continuous daily dosing schedule. In further embodiments, the anti-androgen generally and 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2- fluoro-N-methylbenzamide more specifically is administered orally to the male human at a dose of about 30 mg per day to about 480 mg per day. In still further embodiments, the anti- androgen generally and 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide more specifically is administered orally to the male human at a dose of about 180 mg per day to about 480 mg per day. In certain embodiments, the anti-androgen generally and 4-[7-(6-cyano-5- trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 -fluoro-N- methylbenzamide more specifically 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 (d) about 240 mg per day.
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