US 2014O199236A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0199236A1 CHEN et al. (43) Pub. Date: Jul. 17, 2014

(54) ANDROGEN RECEPTORMODULATOR AND A63L/337 (2006.01) USES THEREOF A613 L/4439 (2006.01) A638/09 (2006.01) (71) Applicant: ARAGON PHARMACEUTICALS, (52) U.S. Cl. INC., SAN DIEGO, CA (US) CPC ...... C07D401/04 (2013.01); A61 K3I/4439 (2013.01); A61 K3I/5377 (2013.01); A61 K (72) Inventors: ISAN CHEN, SAN DIEGO, CA (US); 31/436 (2013.01); A61 K3I/58 (2013.01); JEFFREY H. HAGER, SAN DIEGO, A61K38/09 (2013.01); A61K.39/39558 CA (US); EDNACHOW MANEVAL, (2013.01); A61 K5I/025 (2013.01); A61 K SAN DIEGO, CA (US); MARK R. 5 1/1096 (2013.01); A61 K3I/337 (2013.01); HERBERT, SAN DIEGO, CA (US); A61K 31/4025 (2013.01) NICHOLAS D. SMITH, SAN DIEGO, USPC ...... 424/1.49; 514/338: 514/232.2: 514/291; CA (US) 514/171; 514/10.4; 424/142.1; 424/1.61 (73) Assignee: ARAGON PHARMACEUTICALS, (57)57 ABSTRACT INC., SAN DIEGO, CA (US) Described herein is the androgen receptor modulator of for mula (I) (21) Appl. No.: 14/151,106

(22) Filed: Jan. 9, 2014 (I)) Related U.S. Application Data (60) Provisional application No. 61/752,842, filed on Jan. 15, 2013. Publication Classification pH (51) Int. Cl. NH CO7D40 L/04 (2006.01) F A 6LX3/5377 (2006.01) O A6 IK3I/436 (2006.01) A6 IK3I/58 (2006.01) in the treatment of prostate cancer in combination with other A6 IK3I/4025 (2006.01) therapeutic options and in the treatment of diseases or condi A 6LX39/395 (2006.01) tions that are amenable to treatment with the androgen recep A6 IK5I/02 (2006.01) tor modulator, as well as pharmaceutical compositions and A6 IK5I/It (2006.01) medicaments that include Such compound. US 2014/O 199236 A1 Jul. 17, 2014

ANDROGEN RECEPTORMODULATOR AND

USES THEREOF (I)

CROSS REFERENCE TO RELATED APPLICATIONS 0001. This application claims the benefit of priority to U.S. Patent Application Ser. No. 61/752,842, filed Jan. 15, 2013, the contents of which are incorporated by reference CH herein in their entirety for all purposes. NH

FIELD OF THE INVENTION 0002. Described herein is the use of the androgen receptor modulator 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0007. In another aspect, described herein is a method of oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth decreasing prostate-specific antigen levels in a male human ylbenzamide in the treatment of prostate cancer, breast can with advanced prostate cancer comprising administering cer, androgen dependent hirsutism, androgenic alopecia, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- uterine fibroids, leiomyoma, endometrial carcinoma or thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben endometriosis, alone or in combination with other therapeutic Zamide at a dose of about 30 mg per day to about 480 mg per agents. day to the male human with castration-sensitive prostate can cer, castration-resistant prostate cancer, or high-risk localized prostate cancer. In some embodiments, the prostate-specific BACKGROUND OF THE INVENTION antigen levels in the male human are decreased by at least 50% from baseline after 3 months of administering 4-7-(6- 0003. The androgen receptor (“AR”) is a ligand-activated cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- transcriptional regulatory protein that mediates induction of a diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide on a variety of biological effects through its interaction with endogenous androgens. Endogenous androgens include Ste continuous daily dosing schedule. roids such as testosterone and dihydrotestosterone. Testoster 0008. In one aspect, described herein is a method of one is converted to dihydrotestosterone by the enzyme 5 increasing the metastasis free survival (MFS) in a male alpha-reductase in many tissues. human with advanced prostate cancer comprising adminis tering 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo 0004. The actions of androgens with androgen receptors 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl have been implicated in a number of diseases or conditions, benzamide at a dose of about 30 mg per day to about 480 mg Such as prostate cancer, breast cancer, androgen dependent per day to the male human with advanced prostate cancer. In hirsutism, androgenic alopecia, uterine fibroids, leiomyoma, another aspect, described herein is a method of providing endometrial carcinoma or endometriosis. The androgen survival benefit to a male human with advanced prostate receptor modulator 4-7-(6-cyano-5-trifluoromethylpyridin cancer comprising administering 4-7-(6-cyano-5-trifluo 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 N-methylbenzamide finds use in the treatment of these dis oct-5-yl)-2-fluoro-N-methylbenzamide at a dose of about 30 eases or conditions in which androgen receptors play a role. mg per day to about 480 mg per day to the male human with advanced prostate cancer. In yet another aspect, described SUMMARY OF THE INVENTION herein is a method of providing a delay in symptoms related to disease progression in a male human with advanced pros 0005. In one aspect, described herein is a method of treat tate cancer comprising administering 4-7-(6-cyano-5-trif ing advanced prostate cancer in a male human comprising luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. administering 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- 4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose of about 8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- 30 mg per day to about 480 mg per day to the male human methylbenzamide at a dose of about 30 mg per day to about with advanced prostate cancer. In some embodiments, the 480 mg per day to the male human with advanced prostate advanced prostate is cancer castration-sensitive prostate can cancer. In some embodiments, the advanced prostate is cancer cer, castration-resistant prostate cancer, or high-risk localized castration-sensitive prostate cancer, castration-resistant pros prostate cancer. In some embodiments, the castration-resis tate cancer, or high-risk localized prostate cancer. In some tant prostate cancer is metastatic castration-resistant prostate embodiments, the castration-resistant prostate cancer is cancer. In some embodiments, the metastatic castration-re metastatic castration-resistant prostate cancer. In some sistant prostate cancer is chemotherapy naive metastatic cas embodiments, the metastatic castration-resistant prostate tration-resistant prostate cancer or post-abiraterone acetate cancer is chemotherapy naive metastatic castration-resistant treated metastatic castration-resistant prostate cancer. prostate cancer or post-abiraterone acetate treated metastatic 0009. In another aspect, described herein is a method of castration-resistant prostate cancer. treating breast cancer, androgen dependent hirsutism, andro 0006 4-7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8- genic alopecia, uterine fibroids, leiomyoma, endometrial car oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth cinoma or endometriosis in a human comprising administer ylbenzamide may be represented by the structure of Formula ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- (I), and may be used or available as Such or as a pharmaceu thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- tically acceptable salt thereof methylbenzamide at a dose of about 30 mg per day to about US 2014/O 199236 A1 Jul. 17, 2014

480 mg per day to a human with breast cancer, androgen about 20 mg per day. In some embodiments, everolimus is dependent hirsutism, androgenic alopecia, uterine fibroids, administered at a dose of about 5 mg per day or about 10 mg leiomyoma, endometrial carcinoma or endometriosis. per day. 0010. In some embodiments, 4-7-(6-cyano-5-trifluorom 0016. In yet another aspect, described herein is a method ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- of treating prostate cancer in a male human comprising yl)-2-fluoro-N-methylbenzamide is administered orally to administering 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- the human in the form of soft-gel capsules. 8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2-fluoro-N- 0011. In some embodiments, 4-7-(6-cyano-5-trifluorom methylbenzamide at a dose of about 30 mg per day to about ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 480 mg per day to a male human with metastatic castration yl)-2-fluoro-N-methylbenzamide is administered orally to resistant prostate cancer, non-metastatic castration-resistant the human in the form of Soft-gel capsules at a dose of about prostate cancer, metastatic castration-sensitive prostate can 180 mg per day to about 480 mg per day. cer, non-metastatic castration-sensitive prostate cancer or 0012. In some embodiments, 4-7-(6-cyano-5-trifluorom high-risk localized prostate cancer in combination with a ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- CYP17 inhibitor. In some embodiments, the method of treat yl)-2-fluoro-N-methylbenzamide is administered orally to ing prostate cancer further comprises administering a thera the human in the form of Soft-gel capsules at a dose of about peutically effective amount of a gonadotropin-releasing hor 180 mg per day, about 240 mg per day, about 300 mg per day, mone agonist or antagonist to the male human. In some about 390 mg per day, or about 480 mg per day. embodiments, the CYP17 inhibitor is abiraterone acetate 0013. In some embodiments, 4-7-(6-cyano-5-trifluorom (Zytiga), TAK-700 (orteronel), TOK-001 (galeterone) or ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- VT-464. In some embodiments, 4-7-(6-cyano-5-trifluorom yl)-2-fluoro-N-methylbenzamide is administered orally to ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- the human in the form of Soft-gel capsules at a dose of about yl)-2-fluoro-N-methylbenzamide is administered orally at a 240 mg per day. dose of about 120 mg per day to about 240 mg per day. In 0014. In some embodiments, 4-7-(6-cyano-5-trifluorom some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- yl)-2-fluoro-N-methylbenzamide is administered orally to fluoro-N-methylbenzamide is administered orally at a dose of the human on a continuous daily dosing schedule. about 240 mg per day. In some embodiments, 4-7-(6-cyano 0015. In one aspect, described herein is a method of treat 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza ing prostate cancer in a male human comprising administer spiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- tered orally in the form of a softgel capsule. In some thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- embodiments, the CYP17 inhibitor is abiraterone acetate methylbenzamide at a dose of about 30 mg per day to about (Zytiga). In some embodiments, abiraterone acetate (Zytiga) 480 mg per day to a male human with metastatic castration is administered at a dose of about 500 mg per day to about resistant prostate cancer, non-metastatic castration-resistant 1000 mg per day. In some embodiments, abiraterone acetate prostate cancer, metastatic castration-sensitive prostate can (Zytiga) is administered at a dose of about 1000 mg per day. cer, non-metastatic castration-sensitive prostate cancer or In some embodiments, abiraterone acetate is administered in high-risk localized prostate cancer in combination with a combination with prednisone. In some embodiments, abi phosphoinositide 3-kinase (PI3K) inhibitor, TORC inhibitor, raterone acetate is administered once a day and prednisone is or dual PI3K/TORC inhibitor. In some embodiments, the administered twice a day. In some embodiments, the CYP17 method of treating prostate cancer further comprises admin inhibitor is TAK-700 (orteronel). In some embodiments, istering atherapeutically effective amount of agonadotropin TAK-700 (orteronel) is administered at a dose of about 300 releasing hormone agonist or antagonist to the male human. mg twice per day to about 600 mg twice per day. In some In some embodiments, the phosphoinositide 3-kinase (PI3K) embodiments, TAK-700 (orteronel) is administered at a dose inhibitor, TORC inhibitor, or dual PI3K/TORC inhibitor is of about 300 mg twice per day to about 600 mg twice per day, everolimus, BEZ-235, BKM120, BGT226, BYL-719, together with prednisone at about 5 mg twice per day GDC0068, GDC-0980, GDCO941, GDC0032, MK-2206, 0017. In one aspect, described herein is a method of treat OSI-027, CC-223, AZD8055, SAR245408, SAR245409, ing prostate cancer in a male human comprising administer PF0469 1502, WYE125132, GSK2126458, GSK-2636771, ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- BAY806946, PF-05212384, SF1126, PX866, AMG319, thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- ZSTK474, Cal 101, PWT33597, LY-317615 (enzastaurin methylbenzamide at a dose of about 30 mg per day to about hydrochloride), CU-906, or CUDC-907. In some embodi 480 mg per day to a male human with metastatic castration ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo resistant prostate cancer, non-metastatic castration-resistant 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl prostate cancer, metastatic castration-sensitive prostate can benzamide is administered orally at a dose of about 120 mg cer, non-metastatic castration-sensitive prostate cancer or per day to about 240 mg per day. In some embodiments, high-risk localized prostate cancer in combination with a 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- gonadotropin-releasing hormone agonist or antagonist. thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben Gonadotropin-releasing hormone (GnRH) is also known as Zamide is administered orally at a dose of about 240 mg per Luteinizing-hormone-releasing hormone (LHRH). day. In some embodiments, 4-7-(6-cyano-5-trifluorometh 0018. In some embodiments, the gonadotropin-releasing ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- hormone agonist or antagonist is Lupron, Zoladex (Goser yl)-2-fluoro-N-methylbenzamide is administered orally in elin), Degarelix, Ozarelix, ABT-620 (Elagolix), TAK-385 the form of a softgel capsule. In some embodiments, the (Relugolix), EP-100 or KLH-2109. In some embodiments, TORC inhibitor is everolimus. In some embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- everolimus is administered at a dose of about 5 mg per day to thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben US 2014/O 199236 A1 Jul. 17, 2014

Zamide is administered orally at a dose of about 120 mg per 480 mg per day to a male human with metastatic castration day to about 240 mg per day. In some embodiments, 4-7-(6- resistant prostate cancer, non-metastatic castration-resistant cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- prostate cancer, metastatic castration-sensitive prostate can diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is cer, non-metastatic castration-sensitive prostate cancer or administered orally at a dose of about 240 mg per day. In some high-risk localized prostate cancer in combination with a embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- radiation therapy. In some embodiments, the method of treat yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- ing prostate cancer further comprises administering a thera methylbenzamide is administered orally in the form of a peutically effective amount of a gonadotropin-releasing hor softgel capsule. In some embodiments, the gonadotropin mone agonist or antagonist to the male human. In some releasing hormone agonist or antagonist is Lupron. In some embodiments, the radiation therapy is Alpharadin, ''Lu embodiments, Lupron is administered as a depot injection at J591, external beam radiation therapy (including Proton a dose of about 7.5 mg every 4 weeks, or 22.5 mg every 3 beam), or brachytherapy. In some embodiments, 4-7-(6-cy months, or about 30 mg every 4 months, or about 45 mg every ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia 6 months. In some embodiments, the gonadotropin-releasing Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is hormone agonist or antagonist is Zoladex (Goserelin). In administered orally at a dose of about 120 mg per day to about Some embodiments, Zoladex (Goserelin) is administered as a 240 mg per day. In some embodiments, 4-7-(6-cyano-5- Subcutaneous implantata dose of about 3.6 mg every 4 weeks trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro or about 10.8 mg every 12 weeks. In some embodiments, the 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered gonadotropin-releasing hormone agonist or antagonist is orally at a dose of about 240 mg per day. In some embodi Degarelix. In some embodiments, Degarelix is administered ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo as a Subcutaneous injection at a dose of about 240 mg fol 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl lowed by about 80 mg administered every 4 weeks. benzamide is administered orally in the form of a softgel 0019. In one aspect, described herein is a method of treat capsule. In some embodiments, the radiation therapy is ing prostate cancer in a male human comprising administer Alpharadin. In some embodiments, Alpharadin is adminis ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- tered by intravenous infusion at a dose of about 25 to about 50 thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- kBq/kg every 4 weeks. In some embodiments, the radiation methylbenzamide at a dose of about 30 mg per day to about therapy is 77Lu-J591. In some embodiments, '77Lu-J591 is 480 mg per day to a male human with metastatic castration administered by intravenous infusion at a dose of about 30 resistant prostate cancer, non-metastatic castration-resistant mCi/m2 to about 70 mCi/m2. prostate cancer, metastatic castration-sensitive prostate can 0022. In one aspect, described herein is a method of treat cer, non-metastatic castration-sensitive prostate cancer or ing prostate cancer in a male human comprising administer high-risk localized prostate cancer in combination with an ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- osteoprotective agent. In some embodiments, the method of thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- treating prostate cancer further comprises administering a methylbenzamide at a dose of about 30 mg per day to about therapeutically effective amount of a gonadotropin-releasing 480 mg per day to a male human with post-abiraterone acetate hormone agonist or antagonist to the male human. treated metastatic castration-resistant prostate cancer, meta 0020. In some embodiments, the osteoprotective agent is static castration-resistant prostate cancer, non-metastatic cas Denosumab, AMG-0007, CEP-37251, ALX-0141, tration-resistant prostate cancer, metastatic castration-sensi Zoledronic acid, Alendronate Sodium (Fosamax), Pamidr tive prostate cancer, non-metastatic castration-sensitive onate disodium (Aredia), Neridronic acid (Nerixia), Mino prostate cancer or high-risk localized prostate cancer in com dronic acid (Recalbon) or Risedronate sodium (Actonel). In bination with a kinase inhibitor. In some embodiments, the some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri method of treating prostate cancer further comprises admin din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- istering atherapeutically effective amount of agonadotropin fluoro-N-methylbenzamide is administered orally at a dose of releasing hormone agonist or antagonist to the male human. about 120 mg per day to about 240 mg per day. In some In some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- fluoro-N-methylbenzamide is administered orally at a dose of methylbenzamide is administered orally at a dose of about about 120 mg per day to about 240 mg per day. In some 240 mg per day. In some embodiments, 4-7-(6-cyano-5- embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2-fluoro-N- 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered methylbenzamide is administered orally at a dose of about orally in the form of a softgel capsule. In some embodiments, 240 mg per day. In some embodiments, 4-7-(6-cyano-5- the osteoprotective agent is Denosumab. In some embodi trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro ments, Denosumab is administered by Subcutaneous injec 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered tion at a dose of about 60 mg to about 120 mg every 4 weeks orally in the form of a softgel capsule. In some embodiments, to every 6 months. In some embodiments, the osteoprotective the kinase inhibitor targets angiogenesis or bone metastases. agent is Zoledronic acid. In some embodiments, Zoledronic In some embodiments, the kinase inhibitor is a MET or acid is administered by intravenous infusionata dose of about VEGFR kinase inhibitor. In some embodiments, the kinase 4 mg every 4 weeks to every 12 weeks. inhibitoris Cabozantinib (XL184), PF-2341066 (Crizotinib), 0021. In one aspect, described herein is a method of treat ARQ-197 (Tivantinib), MK-2461, JNJ-38877605, ing prostate cancer in a male human comprising administer MK-8033, INCB-28060, BMS-777607, AMG-208, ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- LY-280.1653, EMD-1214063, EMD-1204831, AMG-337, thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- HMPL-504 (Volitinib), SAR-125844, LY2875358, methylbenzamide at a dose of about 30 mg per day to about ABR-215050 (Tasquinimod), CHIR-258 (Dovitinib), EXEL US 2014/O 199236 A1 Jul. 17, 2014

7647, OSI-930, BIBF-1120, BAY-73-4506 (Regorafenib), PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is BMS-582664 (Brivanib), JNJ-26483327, AZD-2171 (Cedi BMS-936.558. In some embodiments, the PD-1 inhibitor is ranib), Sorafenib, Aflibercept, Enzastaurin, AG-013736 BMS-93.6558 and is administered by intravenous infusion at (Axitinib), OSI-632, or GSK-786.034 (Pazopanib). In some a dose of about 1.0 mg/kg to about 10 mg/kg on days 1, 15 and embodiments, the kinase inhibitor is Cabozantinib. In some 29 of 6-week cycles. In some embodiments, 4-7-(6-cyano embodiments, Cabozantinib is administered orally at a dose 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza of about 40 mg per day to about 100 mg per day. In some spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis embodiments, the kinase inhibitor is an EGFR, MEK, or SRC tered in combination with Provenge. In some embodiments, 3 kinase inhibitor. In some embodiments, the kinase inhibitoris doses of Provenge are administered doses at approximately 2 Erlotinib, Cetuximab, Gefitinib, Canertinib, Panitumumab, weeks interval. In some embodiments, 4-7-(6-cyano-5-trif Nimotuzumab, Lapatinib, Vandetanib, Afatinib, MP-412, luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. AEE-788, Neratinib, XL-647, AC-480, Dacomitinib, AZD 4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered in 8931, CUDC-101, AP-26113, CO-1686, Trametinib, Selu combination with Prostvac. In some embodiments, Prostvac metinib, MEK-162, Refametinib, TAK-733, RO-5 126766, is administered by Subcutaneous injection. BI-847325, AZD6244, GSK1 120212, PF-5208763 (Bosu 0024. In one aspect, described herein is a method of treat tinib), or AZD-0530 (Saracatinib). In some embodiments, the ing prostate cancer in a male human comprising administer kinase inhibitor is Erlotinib. In some embodiments, Erlotinib ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- is administered orally at a dose of about 100 mg to about 150 thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- mg. In some embodiments, the kinase inhibitor is Gefitinib. In methylbenzamide at a dose of about 30 mg per day to about some embodiments, Gefitinib is administered orally at a dose 480 mg per day to a male human with metastatic castration of about 250 mg. In some embodiments, the kinase inhibitor resistant prostate cancer, or high-risk localized prostate can is Trametinib. In some embodiments, Trametinib is adminis cer in combination with a taxane or tubulin inhibitor. In some tered orally at a dose of about 1 mg to about 2 mg. In some embodiments, the method of treating prostate cancer further embodiments, the kinase inhibitor is a AKT, RAF, FGFR, or comprises administering a therapeutically effective amount CDK476 kinase inhibitor. In some embodiments, the kinase ofagonadotropin-releasing hormone agonist orantagonist to inhibitor is GDC0068, MK-2206, AT7867, GSK2110183, the male human. In some embodiments, 4-7-(6-cyano-5- GSK2141795, GSK690693, Vemurafenib (PLX4032/ trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro RG7204), GSK21 18436, Dabrafenib (GSK208436), 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered LGX818, RAF265, LY2780301, Dovitinib (TKI258), orally at a dose of about 120 mg per day to about 240 mg per BGJ398, AZD4547, PD-033,2991 or LEE011. day. In some embodiments, 4-7-(6-cyano-5-trifluorometh 0023. In one aspect, described herein is a method of treat ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5- ing prostate cancer in a male human comprising administer yl)-2-fluoro-N-methylbenzamide is administered orally at a ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- dose of about 240 mg per day. In some embodiments, 4-7- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, methylbenzamide at a dose of about 30 mg per day to about 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is 480 mg per day to a male human with metastatic castration administered orally in the form of a softgel capsule. In some resistant prostate cancer, non-metastatic castration-resistant embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- prostate cancer, metastatic castration-sensitive prostate can yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2-fluoro-N- cer, non-metastatic castration-sensitive prostate cancer or methylbenzamide is administered in combination with Doc high-risk localized prostate cancer in combination with etaxel. In some embodiments, Docetaxel is administered by Provenge, Prostvac, Ipilimumab, or a PD-1 inhibitor. In some intravenous infusion at a dose of about 35 mg/m to about 75 embodiments, the method of treating prostate cancer further mg/m every 3 weeks. In some embodiments, 4-7-(6-cyano comprises administering a therapeutically effective amount 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza ofagonadotropin-releasing hormone agonist orantagonist to spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis the male human. In some embodiments, 4-7-(6-cyano-5- tered in combination with Cabazitaxel. In some trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro embodiments, Cabazitaxel is administered by intravenous 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered infusionata dose of about 13 mg/m to about 25 mg/m every orally at a dose of about 120 mg per day to about 240 mg per 3 weeks. day. In some embodiments, 4-7-(6-cyano-5-trifluorometh 0025. In one aspect, described herein is a method of treat ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- ing prostate cancer in a male human comprising administer yl)-2-fluoro-N-methylbenzamide is administered orally at a ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- dose of about 240 mg per day. In some embodiments, 4-7- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, methylbenzamide at a dose of about 30 mg per day to about 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is 480 mg per day to a male human with metastatic castration administered orally in the form of a softgel capsule. In some resistant prostate cancer, non-metastatic castration-resistant embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- prostate cancer, metastatic castration-sensitive prostate can yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- cer, non-metastatic castration-sensitive prostate cancer or methylbenzamide is administered in combination with Ipili high-risk localized prostate cancer in combination with an mumab. In some embodiments, Ipilimumab is administered anti-STEAP-1 antibody drug conjugate. In some embodi by intravenous infusion at a dose of about 1.5 mg/Kg to about ments, the method of treating prostate cancer further com 3.0 mg/kg IV every 3 weeks for a total of 4 doses. In some prises administering a therapeutically effective amount of a embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- gonadotropin-releasing hormone agonist or antagonist to the yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- male human. In some embodiments, 4-7-(6-cyano-5-trifluo methylbenzamide is administered in combination with a romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 US 2014/O 199236 A1 Jul. 17, 2014

oct-5-yl)-2-fluoro-N-methylbenzamide is administered Zamide in a softgel capsule. In some embodiments, the non orally at a dose of about 120 mg per day to about 240 mg per aqueous, lipid-based solution of 4-7-(6-cyano-5- day. In some embodiments, 4-7-(6-cyano-5-trifluorometh trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide comprises: yl)-2-fluoro-N-methylbenzamide is administered orally at a 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- dose of about 240 mg per day. In some embodiments, 4-7- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, Zamide, vitamin Ed-C.-tocopheryl polyethylene glycol 1000 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is succinate NF (Vitamin E TPGS), polyethylene glycol 400 administered orally in the form of a softgel capsule. In some NF/EP (PEG 400), glycerol monocaprylocaprate EP and embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- caprylocaproyl macroglycerides EP/NF. In some embodi yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- ments, the nonaqueous, lipid-based solution of 4-7-(6-cy methylbenzamide is administered in combination with an ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia anti-STEAP-1 antibody drug conjugate. In some embodi Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo comprises about 3% of 4-7-(6-cyano-5-trifluoromethylpyri 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- benzamide is administered in combination with RG7450 fluoro-N-methylbenzamide. In some embodiments, the soft (DSTP3086S). gel capsule shell comprises gelatin NF/EP, a 50:50 sorbitol/ 0026. In one aspect, described herein is a method of treat glycerin blend USP/EP, and purified water USP/EP. In some ing prostate cancer in a male human comprising administer embodiments, a single unit dosage of the pharmaceutical ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- composition comprises about 30 mg of 4-7-(6-cyano-5-trif thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. methylbenzamide at a dose of about 30 mg per day to about 4 oct-5-yl)-2-fluoro-N-methylbenzamide. 480 mg per day to a male human with metastatic castration 0028. In any of the methods of treatment embodiments resistant prostate cancer, non-metastatic castration-resistant described herein, the methods of treatment further comprises prostate cancer, metastatic castration-sensitive prostate can administering a gonadotropin-releasing hormone (GnRH) cer, non-metastatic castration-sensitive prostate cancer or agonist orantagonist. In some embodiments, the GnRHago high-risk localized prostate cancer in combination with a heat nist orantagonist is leuprolide, buserelin, nafarelin, histrelin, shock protein 90 (HSP90) or heat shock protein 27 (HSP27) goserelin, or deslorelin. pathway modulator. In some embodiments, the method of 0029. In any of the aforementioned aspects the effective treating prostate cancer further comprises administering a amount of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- therapeutically effective amount of a gonadotropin-releasing oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth hormone agonist or antagonist to the male human. In some ylbenzamide is: (a) systemically administered to the male embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- human; and/or (b) administered orally to the male human; yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- and/or (c) intravenously administered to the male human; methylbenzamide is administered orally at a dose of about and/or (d) administered by injection to the male human. 120 mg per day to about 240 mg per day. In some embodi 0030. In any of the aforementioned aspects, the effective ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo amount of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth benzamide is administered orally at a dose of about 240 mg ylbenzamide is administered (i) once a day; or (ii) multiple per day. In some embodiments, 4-7-(6-cyano-5-trifluorom times over the span of one day. In some embodiments, the ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- effective amount of 4-7-(6-cyano-5-trifluoromethylpyridin yl)-2-fluoro-N-methylbenzamide is administered orally in 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro the form of a softgel capsule. In some embodiments, 4-7-(6- N-methylbenzamide is administered once a day, twice a day, cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- three times a day or four times a day. In some embodiments, diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is the effective amount of 4-7-(6-cyano-5-trifluoromethylpyri administered in combination with OGX-011 (Custirsen), din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- OGX-427, AUY922, HSP990, PF-04928473, PF-04929113 fluoro-N-methylbenzamide is administered every other day, (SNX-5422), Retaspimycin or AT 13387. In some embodi twice a week, once a week, or every two weeks. ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo 0031. In any of the aforementioned aspects the effective 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl amount of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- benzamide is administered in combination with OGX-011 oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth (Custirsen). In some embodiments, OGX-011 (Custirsen) is ylbenzamide is administered continuously or intermittently. administered by intravenous infusion at a dose of about 320 In some embodiments, the effective amount of 4-7-(6-cyano mg to about 640 mg every week. In some embodiments, 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben tered continuously. In some embodiments, the effective Zamide is administered in combination with OGX-427. In amount of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- some embodiments, OGX-427 is administered by intrave oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth nous infusion at a loading dose of about 300 mg to about 600 ylbenzamide is administered daily. mg followed by about 500 mg to about 1000 mg every week. 0032. In some embodiments, 4-7-(6-cyano-5-trifluorom 0027. In one aspect, described herein is a pharmaceutical ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- composition comprising a nonaqueous, lipid-based solution yl)-2-fluoro-N-methylbenzamide is orally administered. of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- 0033. In some embodiments, 4-7-(6-cyano-5-trifluorom thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- US 2014/O 199236 A1 Jul. 17, 2014

yl)-2-fluoro-N-methylbenzamide is administered orally to DETAILED DESCRIPTION OF THE INVENTION the human on a continuous daily dosing schedule. 0037 Androgen receptor (AR) is a member of the steroid 0034. In some embodiments, described herein is a method and nuclear receptor Superfamily. Among this large family of of treating cancer in a mammal comprising administering to proteins, only five vertebrate steroid receptors are known and the mammal a therapeutically effective amount of 4-7-(6- include the androgen receptor, estrogen receptor, progester cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- one receptor, glucocorticoid receptor, and mineralocorticoid diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. In receptor. AR is a soluble protein that functions as an intrac Some embodiments, the cancer is a hormone dependent can ellular transcriptional factor. AR function is regulated by the cer. In some embodiments, the hormone dependent cancer is binding of androgens, which initiates sequential conforma an androgen receptor dependent cancer. In some embodi tional changes of the receptor that affect receptor-protein ments, the cancer is advanced prostate cancer. In some interactions and receptor-DNA interactions. embodiments, the cancer is hormone refractory prostate can 0038 AR is mainly expressed in androgen target tissues, cer. In some embodiments, the cancer is castration sensitive Such as the prostate, skeletal muscle, liver, and central ner prostate cancer. In some embodiments, the cancer is castra vous system (CNS), with the highest expression level tion resistant prostate cancer. In some embodiments, the can observed in the prostate, adrenal gland, and epididymis. AR cer is high risk localized prostate cancer. In some embodi can be activated by the binding of endogenous androgens, ments, the cancer is androgen receptor positive breast cancer. including testosterone and 5C.-dihydrotestosterone (5C.- In some embodiments, the method of treating cancer further DHT). comprises administering to the mammal at least one addi 0039. The androgen receptor (AR), located on Xq11-12, is tional therapeutic agent. In some embodiments, the additional a 110 kD nuclear receptor that, upon activation by androgens, therapeutic agent is an anti-cancer agent. In some embodi mediates transcription of target genes that modulate growth ments, the one or more additional therapeutically active and differentiation of prostate epithelial cells. Similar to the agents other than 4-7-(6-cyano-5-trifluoromethylpyridin-3- other steroid receptors, unbound AR is mainly located in the yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- cytoplasm and associated with a complex of heat shock pro methylbenzamide is selected from: TORC inhibitors, PI3K teins (HSPs) through interactions with the ligand-binding inhibitors, CYP17 inhibitors, GNRHagonists or antagonists, domain. Upon agonist binding, AR goes through a series of osteoprotective agents, Syk inhibitors; RANKL inhibitors, conformational changes: the heat shock proteins dissociate MET inhibitors, VEGFR inhibitors, EGFR inhibitors, FGFR, from AR, and the transformed AR undergoes dimerization, MEK inhibitors, Src inhibitors, AKT inhibitors, RAF inhibi phosphorylation, and translocation to the nucleus, which is tors, CDK4 inhibitors, CDK6 inhibitors, mTOR inhibitors; mediated by the nuclear localization signal. Translocated and antibodies (e.g., rituxan), corticosteroids, anti-emetic receptor then binds to the androgen response element (ARE). agents, analgesics, taxanes, tubulin inhibitors, anti-inflam which is characterized by the six-nucleotide half-site consen matories, HSP90 inhibitors, histone deacetylase (HDAC) sus sequence 5'-TGTTCT-3' spaced by three random nucle inhibitors or any other chemotherapeutic agent. otides and is located in the promoter or enhancer region of AR 0035 Articles of manufacture, which include packaging gene targets. Recruitment of other transcription co-regulators material, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- (including co-activators and co-repressors) and transcrip oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth tional machinery further ensures the transactivation of AR ylbenzamide within the packaging material, and a label that regulated gene expression. All of these processes are initiated indicates that the 4-7-(6-cyano-5-trifluoromethylpyridin-3- by the ligand-induced conformational changes in the ligand yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- binding domain. methylbenzamide or composition thereof, or pharmaceuti 0040 AR signaling is crucial for the development and cally acceptable salt, pharmaceutically active metabolite, is maintenance of male reproductive organs including the pros used for reducing, diminishing or eliminating the effects of tate gland, as genetic males harboring loss of function AR androgen receptors, or for the treatment, prevention or ame mutations and mice engineered with AR defects do not lioration of one or more symptoms of a disease or condition develop prostates or prostate cancer. This dependence of that would benefit from a reduction or elimination of andro prostate cells on AR signaling continues even upon neoplastic gen receptor activity, are provided. In some embodiments, transformation. Androgen depletion (such as using GnRH Such diseases or conditions include, but are not limited to, agonists) continues to be the mainstay of prostate cancer metastatic castration-resistant prostate cancer, non-meta treatment. However androgen depletion is usually effective static castration-resistant prostate cancer, metastatic castra for a limited duration and prostate cancerevolves to regain the tion-sensitive prostate cancer, non-metastatic castration-sen ability to grow despite low levels of circulating androgens. sitive prostate cancer, high-risk localized prostate cancer, Castration resistant prostate cancer (CRPC) is a lethal phe breast cancer, androgen dependent hirsutism, androgenic notype and almost all of patients will die from prostate cancer. alopecia, uterine fibroids, leiomyoma, endometrial carci Interestingly, while a small minority of CRPC does bypass noma or endometriosis. the requirement for AR signaling, the vast majority of CRPC, 0036. Other objects, features and advantages of the com though frequently termed "androgen independent prostate pound, methods and compositions described herein will cancer or “hormone refractory prostate cancer, retains its become apparent from the following detailed description. It lineage dependence on AR signaling. should be understood, however, that the detailed description 0041 Prostate cancer is the second most common cause of and the specific examples, while indicating specific embodi cancer death in men in the US, and approximately one in ments, are given by way of illustration only, since various every six American men will be diagnosed with the disease changes and modifications within the spirit and scope of the during his lifetime. Treatment aimed at eradicating the tumor instant disclosure will become apparent to those skilled in the is unsuccessful in 30% of men, who develop recurrent disease art from this detailed description. that is usually manifest first as a rise in plasma prostate US 2014/O 199236 A1 Jul. 17, 2014

specific antigen (PSA) followed by spread to distant sites. 0046 Prostate Cancer Stages Given that prostate cancer cells depend on androgen receptor 0047. In the early stages of prostate cancer, the cancer is (AR) for their proliferation and survival, these men are treated localized to the prostate. In these early stages, treatment typi with agents that block production of testosterone (e.g. GnRH cally involes either Surgical removal of the prostate or radia agonists), alone or in combination with anti-androgens (e.g. tion therapy to the prostate or observation only with no active bicalutamide), which antagonize the effect of any residual intervention therapy in Some patients. In the early stages testosterone on AR. The approach is effective as evidenced by where the prostate cancer is localized and requires interven a drop in PSA and regression of visible tumor (if present) in tion, Surgery or radiation therapy are curative by eradicating Some patients; however, this is followed by regrowth as a the cancerous cells. About 30% of the time these procedures castration resistant prostate cancer (CRPC) to which most fail, and the prostate cancer continues to progress, as typically patients eventually succumb. Recent studies on the molecular evidenced by a rising PSA level. Men whose prostate cancer basis of CRPC have demonstrated that CRPC continues to has progressed following these early treatment strategies are depend on AR signaling and that a key mechanism of said to have advanced or recurrent prostate cancer. acquired resistance is an elevated level of AR protein (Nat. 0048 Because prostate cancer cells depend on the andro Med, 2004, 10, 33-39). AR targeting agents with activity in gen receptor (AR) for their proliferation and survival, men with advanced prostate cancer are treated with agents that castration sensitive and castration resistant resistant prostate block the production of testosterone (eg. GnRH agonists), cancer have great promise in treating this lethal disease. alone or in combination with anti-androgens (eg. bicaluta 0042. The course of prostate cancer from diagnosis to mide), which antagonize the effect of any residual testoster death is best categorized as a series of clinical states based on one on AR. These treatments reduce serum testosterone to the extent of disease, hormonal status, and absence or pres castrate levels, which generally slows disease progression for ence of detectable metastases: localized disease, rising levels a period of time. The approach is effective as evidenced by a of prostate-specific antigen (PSA) after radiation therapy or drop in PSA and the regression of visible tumors in some Surgery with no detectable metastases, and clinical patients. Eventually, however, this is followed by regrowth metastases in the non-castrate or castrate state. Although Sur referred to as castration-resistant prostate cancer (CRPC), to gery, radiation, or a combination of both can be curative for which most patients eventually succumb. patients with localized disease, a significant proportion of 0049 Castration-resistant prostate cancer (CRPC) is cat these patients have recurrent disease as evidenced by a rising egorized as non-metastatic or metastatic, depending on level of PSA, which can lead to the development of whether or not the prostate cancer has metastasized to other metastases, especially in the high risk group—a transition to parts of the body. the lethal phenotype of the disease. 0050. In some embodiments, prior to treatment with a 0043 Androgen depletion is the standard treatment with a second-generation anti-androgen (e.g. 4-7-(6-cyano-5-trif generally predictable outcome: decline in PSA, a period of luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. stability in which the tumor does not proliferate, followed by 4 oct-5-yl)-2-fluoro-N-methylbenzamide) men with non rising PSA and regrowth as castration-resistant disease. metastatic CRPC are characterized as having the following: Molecular profiling studies of castration-resistance prostate 0051 1. Histologically or cytologically confirmed cancers commonly show increased androgen receptor (AR) adenocarcinoma of the prostate, with high risk for devel expression, which can occur through AR gene amplification opment of metastases. or other mechanisms. 0.052 2. Castration-resistant prostate cancer demon strated during continuousandrogen deprivation therapy 0044 Anti-androgens are useful for the treatment of pros (ADT)/post orchiectomy. For example defined as 3 con tate cancer during its early stages. However, prostate cancer secutive rises of PSA, 1 week apart, resulting in two 50% often advances to a hormone-refractory state in which the increases over the nadir, with the last PSA>2 ng/mL, disease progresses in the presence of continued androgen with castrated levels of testosterone (<50 ng/dL (1.72 ablation or anti-androgen therapy. Instances of antiandrogen nmol/L). withdrawal syndrome have also been reported after pro 0053. 3. Absence of distant metastasis by bone scan, CT longed treatment with anti-androgens. Antiandrogen with or MRI scans. drawal syndrome is commonly observed clinically and is 0054. In some embodiments, prior to treatment with a defined interms of the tumor regression or symptomatic relief second-generation anti-androgen (e.g. 4-7-(6-cyano-5-trif observed upon cessation of antiandrogen therapy. AR muta luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. tions that result in receptor promiscuity and the ability of 4 oct-5-yl)-2-fluoro-N-methylbenzamide) men with meta these anti-androgens to exhibit agonist activity might at least static CRPC are characterized as having the following: partially account for this phenomenon. For example, 0.055 1. Histologically or cytologically confirmed hydroxyflutamide and bicalutamide act as AR agonists in adenocarcinoma of the prostate, with progressive meta T877A and W741L/W741CAR mutants, respectively. static disease based on either PSA or radiographic evi 0045. In the setting of prostate cancer cells that were ren dence of progression on bone Scan, CT or MRI scans. dered castration resistant via overexpression of AR, it has 0056 2. Castration-resistant prostate cancer demon been demonstrated that certain anti-androgen compounds, strated during continuousandrogen deprivation therapy Such as bicalutamide, have a mixed antagonist/agonist profile (ADT)/post orchiectomy. For example defined as 3 con (Science, 2009 May 8: 324(5928): 787-90). This agonist secutive rises of PSA, 1 week apart, resulting in two 50% activity helps to explain a clinical observation, called the increases over the nadir, with the last PSA>2 ng/mL, anti-androgen withdrawal syndrome, whereby about 30% of with castrated levels of testosterone (<50 ng/dL (1.72 men who progress on ARantagonists experience a decrease in nmol/L). serum PSA when therapy is discontinued (J Clin Oncol, 1993. 0057. In some embodiments, prior to treatment with a 11 (8): p. 1566-72). second-generation anti-androgen (e.g. 4-7-(6-cyano-5-trif US 2014/O 199236 A1 Jul. 17, 2014

luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 0072. As used herein, the term 'AR antagonist' or AR 4 oct-5-yl)-2-fluoro-N-methylbenzamide) men with post inhibitor' are used interchangeably herein and refer to an abiraterone acetate treated metastatic CRPC are agent that inhibits or reduces at least one activity of an AR characterized as having the following: polypeptide. Exemplary AR activities include, but are not 0.058 1. Histologically or cytologically confirmed limited to, co-activator binding, DNA binding, ligand bind adenocarcinoma of the prostate, with progressive meta ing, or nuclear translocation. static disease based on either PSA or radiographic evi 0073. As used herein, a “full antagonist” refers to an dence of progression on bone, CT or MRI scan, follow antagonist which, at an effective concentration, essentially ing at least 6 months of treatment with abiraterone completely inhibits an activity of an AR polypeptide. As used acetate herein, a partial antagonist” refers an antagonist that is 0059 2. Castration-resistant prostate cancer demon capable of partially inhibiting an activity of an AR polypep strated during continuousandrogen deprivation therapy tide, but that, even at a highest concentration is not a full (ADT)/post orchiectomy. For example defined as 3 con antagonist. By essentially completely is meant at least about secutive rises of PSA, 1 week apart, resulting in two 50% 80%, at least about 90%, at least about 95%, at least about increases over the nadir, with the last PSA>2 ng/mL, 96%, at least about 97%, at least about 98% at least about with castrated levels of testosterone (<50 ng/dL (1.72 99%, or greater inhibition of the activity of an AR polypep nmol/L). tide. 0060. In some embodiments, prior to treatment with a 0074 As used herein, the term “first-generation anti-an second-generation anti-androgen (e.g. 4-7-(6-cyano-5-trif drogen' refers to an agent that exhibits antagonist activity luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. against a wild-type AR polypeptide. However, first-genera 4 oct-5-yl)-2-fluoro-N-methylbenzamide) men with meta tion anti-androgens differ from second-generation anti-an static castration-sensitive prostate cancer are characterized as drogens in that first-generation anti-androgens can poten having the following: tially act as agonists in castration resistant prostate cancers 0061 1. Histologically or cytologically confirmed (CRPC). Exemplary first-generation anti-androgens include, adenocarcinoma of the prostate, with metastatic disease but are not limited to, flutamide, nilutamide and bicalutamide. based on radiographic evidence on bone Scan, CT or 0075. As used herein, the term “second-generation anti MRI scans. androgen' refers to an agent that exhibits full antagonist 0062. 2. Prostate cancer which is still responsive to activity against a wild-type AR polypeptide. Second-genera androgen deprivation therapy (ADT). tion anti-androgens differ from first-generation anti-andro 0063. In some embodiments, prior to treatment with a gens in that second-generation anti-androgens act as full second-generation anti-androgen (e.g. 4-7-(6-cyano-5-trif antagonists in cells expressing elevated levels of AR, Such as luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. for example, in castration resistant prostate cancers (CRPC). 4 oct-5-yl)-2-fluoro-N-methylbenzamide) men with non Exemplary second-generation anti-androgens include 4-7- metastatic castration-sensitive prostate cancer are (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, characterized as having the following: 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide 0064 1. Histologically or cytologically confirmed (also known as ARN-509; CAS No. 956104-40-8): 4-(3-(4- adenocarcinoma of the prostate, with high risk for devel cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- opment of metastases. thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide 0065 2. Absence of distant metastasis by bone scan, CT (also known as MDV3100 or enzalutamide: CAS No: or MRI scans. 915087-33-1) and RD162 (CAS No. 915087-27-3). In some 0.066 3. Prostate cancer which is still responsive to embodiments, a second-generation anti-androgen binds to an androgen deprivation therapy (ADT). AR polypeptide at or near the ligand binding site of the AR 0067. In some embodiments, prior to treatment with a polypeptide. second-generation anti-androgen (e.g. 4-7-(6-cyano-5-trif 0076. In some embodiments, an anti-androgen contem luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. plated in the methods described herein inhibits AR nuclear 4 oct-5-yl)-2-fluoro-N-methylbenzamide) men with high translocation, DNA binding to androgen response elements, risk localized prostate cancer are characterized as having the and coactivator recruitment. In some embodiments, an anti following: androgen contemplated in the methods described herein 0068 1. Absence of distant metastasis by bone scan, CT exhibits no agonist activity in AR-overexpressing prostate or MRI scans. cancer cells. 0069 2. Local-regional prostate cancer which is at high 0077 4-7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8- risk for disease recurrence after local treatment with oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Surgery or radiation therapy. ylbenzamide (I) is a second-generation anti-androgen that 0070 Anti-Androgens binds directly to the ligand-binding domain of AR, impairing 0071. As used herein, the term “anti-androgen refers to a nuclear translocation, AR binding to DNA and AR target gene group of hormone receptor antagonist compounds that are modulation, thereby inhibiting tumor growth and promoting capable of preventing or inhibiting the biologic effects of apoptosis. 4-7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8- androgens on normally responsive tissues in the body. In oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Some embodiments, an anti-androgen is a small molecule. In ylbenzamide binds AR with greater affinity than bicaluta Some embodiments, an anti-androgen is an AR antagonist. In mide, and induces partial or complete tumor regression in Some embodiments, an anti-androgen is an AR full antago non-castrate hormone-sensitive and bicalutamide-resistant nist. In some embodiments, an anti-androgen is a first-gen human prostate cancer Xenograft models (Clegget al. Cancer eration anti-androgen. In some embodiments, an anti-andro Res Mar. 15, 201272; 1494). 4-7-(6-Cyano-5-trifluorometh gen is a second-generation anti-androgen. ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5- US 2014/O 199236 A1 Jul. 17, 2014

yl)-2-fluoro-N-methylbenzamide lacks the partial agonist non-metastatic castration-resistant prostate cancer in a activity seen with bicalutamide in the context of AR overex human. In some embodiments, the treatment of non-meta pression. static castration-resistant prostate cancer in the human com 0078 Disclosed herein is the use of 4-7-(6-cyano-5-trif prises at least one additional therapeutic agent in addition to luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben metastatic castration-resistant prostate cancer in a human. In Zamide (i.e. combination therapy). Some embodiments, the treatment of metastatic castration I0085 Disclosed herein is the use of 4-7-(6-cyano-5-trif resistant prostate cancer in the human comprises at least one luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. additional therapeutic agent in addition to 4-7-(6-cyano-5- 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro metastatic castration-sensitive prostate cancer in a human. In 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. combina Some embodiments, the treatment of metastatic castration tion therapy). sensitive prostate cancer in the human comprises at least one 0079 Disclosed herein is the use of 4-7-(6-cyano-5-trif additional therapeutic agent in addition to 4-7-(6-cyano-5- luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. combina chemotherapy naive metastatic castration-resistant prostate tion therapy). cancer in a human. In some embodiments, the treatment of I0086 Disclosed herein is the use of 4-7-(6-cyano-5-trif chemotherapy naive metastatic castration-resistant prostate luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. cancer in the human comprises at least one additional thera 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of peutic agent in addition to 4-7-(6-cyano-5-trifluorometh non-metastatic castration-sensitive prostate cancer in a ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- human. In some embodiments, the treatment of non-meta yl)-2-fluoro-N-methylbenzamide (i.e. combination therapy). static castration-sensitive prostate cancer in the human com 0080 Disclosed herein is the use of 4-7-(6-cyano-5-trif prises at least one additional therapeutic agent in addition to luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben post-abiraterone acetate treated metastatic castration-resis Zamide (i.e. combination therapy). tant prostate cancer in a human. In some embodiments, the treatment of post-abiraterone acetate treated metastatic cas I0087 Disclosed herein is the use of 4-7-(6-cyano-5-trif tration-resistant prostate cancer in the human comprises at luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. least one additional therapeutic agent in addition to 4-7-(6- 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- breast cancer in a human. In some embodiments, the treat ment of breast cancer in the human comprises at least one diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. additional therapeutic agent in addition to 4-7-(6-cyano-5- combination therapy). trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 0081 Disclosed herein is the use of 4-7-(6-cyano-5-trif luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. combina 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of tion therapy). castration-sensitive prostate cancer in a human. In some I0088 Disclosed herein is the use of 4-7-(6-cyano-5-trif embodiments, the treatment of castration-sensitive prostate luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. cancer in the human comprises at least one additional thera 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of peutic agent in addition to 4-7-(6-cyano-5-trifluorometh androgen dependent hirsutism in a human. In some embodi ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- ments, the treatment of androgen dependent hirsutism in the yl)-2-fluoro-N-methylbenzamide (i.e. combination therapy). human comprises at least one additional therapeutic agent in 0082 Disclosed herein is the use of 4-7-(6-cyano-5-trif addition to 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of ylbenzamide (i.e. combination therapy). castration-resistant prostate cancer in a human. In some I0089 Disclosed herein is the use of 4-7-(6-cyano-5-trif embodiments, the treatment of castration-resistant prostate luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. cancer in the human comprises at least one additional thera 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of peutic agent in addition to 4-7-(6-cyano-5-trifluorometh androgenic alopecia in a human. In some embodiments, the ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- treatment of androgenic alopecia in the human comprises at yl)-2-fluoro-N-methylbenzamide (i.e. combination therapy). least one additional therapeutic agent in addition to 4-7-(6- 0083 Disclosed herein is the use of 4-7-(6-cyano-5-trif cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of combination therapy). high-risk localized prostate cancer in a human. In some 0090 Disclosed herein is the use of 4-7-(6-cyano-5-trif embodiments, the treatment of high-risk localized prostate luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. cancer in the human comprises at least one additional thera 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of peutic agent in addition to 4-7-(6-cyano-5-trifluorometh uterine fibroids in a human. In some embodiments, the treat ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- ment of uterine fibroids in the human comprises at least one yl)-2-fluoro-N-methylbenzamide (i.e. combination therapy). additional therapeutic agent in addition to 4-7-(6-cyano-5- 0084 Disclosed herein is the use of 4-7-(6-cyano-5-trif trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. combina 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of tion therapy). US 2014/O 199236 A1 Jul. 17, 2014

0091 Disclosed herein is the use of 4-7-(6-cyano-5-trif patients who had 90% decline in PSA was 55%, confirming luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. the durability of response to 4-7-(6-cyano-5-trifluorometh 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5- leiomyoma in a human. In some embodiments, the treatment yl)-2-fluoro-N-methylbenzamide. The median time to PSA of leiomyoma in the human comprises at least one additional progression was not reached in this oberserved time period. therapeutic agent in addition to 4-7-(6-cyano-5-trifluorom 0097 4-7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8- ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth yl)-2-fluoro-N-methylbenzamide (i.e. combination therapy). ylbenzamide is Suited as monotherapy and as combination 0092 Disclosed herein is the use of 4-7-(6-cyano-5-trif therapy for advanced prostate cancer, as well as other diseases luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. or conditions described herein. 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of endometrial carcinoma in a human. In some embodiments, CERTAIN TERMINOLOGY the treatment of endometrial carcinoma in the human com prises at least one additional therapeutic agent in addition to 0098. The term “cancer as used herein refers to an abnor 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- mal growth of cells which tend to proliferate in an uncon thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben trolled way and, in Some cases, to metastasize (spread). Zamide (i.e. combination therapy). (0099. The term “prostate cancer as used herein refers to 0093. Disclosed herein is the use of 4-7-(6-cyano-5-trif histologically or cytologically confirmed adenocarcinoma of luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. the prostate. 4 oct-5-yl)-2-fluoro-N-methylbenzamide in the treatment of 0100. The term “androgen-deprivation therapy (ADT) endometriosis in a human. In some embodiments, the treat refers to the reduction of androgen levels in a prostate cancer ment of endometriosis in the human comprises at least one patient to castrated levels of testosterone (<50 ng/dL). Such additional therapeutic agent in addition to 4-7-(6-cyano-5- treatments can include orchiectomy or the use of gonadotro trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro pin-releasing hormone agonists or antagonists. 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (i.e. combina 0101 The term “locally advanced prostate cancer refers tion therapy). to prostate cancer where all actively cancerous cells appear to 0094. In a Phase II clinical trial of male humans with high be confined to the prostate and the associated organs or neigh risk non-metastatic CRPC, treatment-naive metastatic CRPC bor organs (e.g. seminal vesicle, bladder neck and rectal and metastatic CRPC that progressed after prior treatment wall). with abiraterone acetate (Zytiga), oral administration of 240 mg of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo 0102 The term “high-risk localized prostate cancer' 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl refers to locally advanced prostate cancer that has a probabil ity of developing metastases or recurrent disease after pri benzamide on a continuous daily dosing schedule was very mary therapy with curative intent. In some embodiments, well tolerated and resulted in robust and durable PSA high risk for development of metastases is defined as prostate responses, as well as evidence of objective responses. A total specific antigen doubling time (PSADT)s.20 months, s19 of 25 patients with chemotherapy and abiraterone acetate months, s18 months, s17 months, s16 months, s15 months, naive metastatic CRPC who had progressed on standard s14 months, s13 months, s12 months, or s11 months, s10 androgen deprivation therapy (treatment-naïve (TN) cohort) months, s9 months, s8 months, s7 months, so months, s5 and 21 patients who progressed after treatment with abirater months, s4 months, s3 months, s2 months, or s1 month. In one acetate acetate (PA cohort) were orally administered 240 Some embodiments, high risk for development of metastases mg of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo is defined as prostate specificantigen doublingtime (PSADT) 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl s10 months. In some embodiments, high risk for develop benzamide on a continuous daily dosing schedule. ment of metastases is defined as having a high Gleason score 0095. The primary objective was to assess antitumor activ or bulky tumor. ity and PSA kinetics as defined by the Prostate Cancer Clini cal Trials Working Group (PCWG2) criteria. Preliminary 0103) The term “castration-sensitive prostate cancer' results demonstrated 12-week PSA declines of 50% or more refers to cancer that is responsive to androgen-deprivation from baseline in 88% and 29% of the TN and PA cohorts, therapy (ADT) either as localized disease, biochemical respectively. The median time to PSA progression was not relapse or in the metastatic setting. reached for the TN cohort during the preliminary 12-week 0104. The term “metastatic castration-sensitive prostate period, and was 16 weeks in the PA cohort. In addition, the cancer refers to cancer that has spread (metastasized) to the objective response rate (by RECIST) was 63% in the TN bone, lymph nodes or other parts of the body in a male, and patients presenting with measurable disease at baseline, fur that is responsive to androgen-deprivation therapy (ADT). ther confirming the antitumor activity of 4-7-(6-cyano-5- 0105. The term “non-metastatic castration-sensitive pros trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro tate cancer refers to cancer that has not spread (metastasized) 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. in a male, and that is responsive to androgen-deprivation 0096. A total of 47 patients with non-metastatic CRPC therapy (ADT). In some embodiments, non-metastatic cas were orally administered 240 mg of 4-7-(6-cyano-5-trifluo tration-sensitive prostate cancer is assessed with bone scan romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 and computed tomography (CT) or magnetic resonance oct-5-yl)-2-fluoro-N-methylbenzamide on a continuous daily imaging (MRI) scans. dosing schedule. At 12 weeks of treatment, 91% of the 01.06 The term “CRPC as used herein refers to castra patients had a >50% decline in PSA as compared to baseline. tion-resistant prostate cancer. CRPC is prostate cancer that At 24 weeks, the percentage of patients who had a 50% continues to grow despite the Suppression of male hormones decline in PSA remained at 91% and the percentage of that fuel the growth of prostate cancer cells. US 2014/O 199236 A1 Jul. 17, 2014

0107 The term “metastatic castration-resistant prostate amount of the anti-androgen that after administration for 3 cancer refers to castration-resistant prostate cancer that has months to a male human with prostate cancer provides a metastasized to other parts of the human body. PSA50 or PSA90 or demonstrates a robust (such as >90%) 0108. The term “NM-CRPC as used herein refers to non AR blockade (e.g. by FDHT-PET). In some embodiments, an metastatic castration-resistant prostate cancer. In some effective amount of an anti-androgen is the amount of the embodiments, NM-CRPC is assessed with bone scan and anti-androgen that after administration for 6 months to a male computed tomography (CT) or magnetic resonance imaging human with prostate cancer provides a PSA50 or PSA90. In (MRI) scans. Some embodiments, an effective amount of an anti-androgen 0109 The term “chemotherapy naive metastatic castra is the amount of the anti-androgen that after administration tion-resistant prostate cancer refers to metastatic castration for 6 months to a male human with prostate cancer delays resistant prostate cancer that has not been previously treated progression of the prostate cancer. In some embodiments, an with a chemotherapeutic agent. effective amount of an anti-androgen is the amount of the 0110. The term “post-abiraterone acetate treated meta anti-androgen that after administration for 6 months to a male static castration-resistant prostate cancer refers to metastatic human with prostate cancer increases the Survival rate of the castration-resistant prostate cancer that has already been male human. In some embodiments, the anti-androgen is treated with abiraterone acetate. administered on a continuous daily dosing schedule. An 0111. The term “high risk NM-CRPC as used herein appropriate “effective” amount in any individual case may be refers to probability of a man with NM-CRPC developing determined using techniques, such as a dose escalation study. metastases. In some embodiments, high risk for development 0115 The term “FDHT-PET refers to 18F-163-fluoro of metastases is defined as prostate specific antigen doubling 5C.-dihydrotestosterone Positron Emission Tomography and time (PSADT)s.20 months, s19 months, s18 months, s17 is a technique that uses a tracerbased on dihydrotestosterone, months, s16 months, s15 months, s14 months, s13 months, and allows for a visual assessment of ligand binding to the s12 months, or s 11 months, s10 months, s9 months, s8 androgen receptor in a patient. It may be used to evaluate months, s7 months, so months, ss months, s4 months, s3 pharmacodynamics of an androgen receptor directed therapy months, s2 months, or s1 month. In some embodiments, high risk for development of metastases is defined as prostate 0116. The term “continuous daily dosing schedule” refers specific antigen doubling time (PSADT)s 10 months. In some to the administration of a particular therapeutic agent without embodiments, high risk for development of metastases is any drug holidays from the particular therapeutic agent. In defined as having local-regional recurrence (e.g. primary some embodiments, a continuous daily dosing schedule of a tumor bed, bladder neck, anastomotic area, pelvic lymph particular therapeutic agent comprises administration of a nodes). particular therapeutic agent everyday at roughly the same 0112. The terms “co-administration” or the like, as used time each day. herein, are meant to encompass administration of the selected 0117. The terms “treat,” “treating” or “treatment,” as used therapeutic agents to a single patient, and are intended to herein, include alleviating, abating or ameliorating at least include treatment regimens in which the agents are adminis one symptom of a disease disease or condition, preventing tered by the same or different route of administration or at the additional symptoms, inhibiting the disease or condition, e.g., same or different time. arresting the development of the disease or condition, reliev 0113. The term “pharmaceutical combination” as used ing the disease or condition, causing regression of the disease herein, means a product that results from the mixing or com or condition, delaying progression of condition, relieving a bining of more than one active ingredient and includes both condition caused by the disease or condition, or stopping the fixed and non-fixed combinations of the active ingredients. symptoms of the disease or condition either prophylactically The term “fixed combination' means that the active ingredi and/or therapeutically. In some embodiments, in the context ents, e.g. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- of administering an anti-androgen to a male human with oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth prostate cancer, treating comprises any one, or a combination, ylbenzamide and a co-agent, are both administered to a of the following: providing a PSA50 or PSA90 in men with patient simultaneously in the form of a single entity or dos prostate cancer as compared to placebo at 3 months; provid age. The term “non-fixed combination” means that the active ing a PSA50 or PSA90 in men with prostate cancer as com ingredients, e.g. 4-7-(6-cyano-5-trifluoromethylpyridin-3- pared to placebo at 6 months; demonstrating Superiority in the yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- metastasis-free survivial (MFS) of men with prostate cancer methylbenzamide and a co-agent, are administered to a as compared to placebo (i.e. not administering a second patient as separate entities either simultaneously, concur generation anti-androgen); increasing the overall Survisial rently or sequentially with no specific intervening time limits, (OS) of men with prostate cancer as compared to placebo. wherein such administration provides effective levels of the increasing the time to metastasis (TTM) in men with prostate two compounds in the body of the patient. The latter also cancer as compared to placebo, increasing the progression applies to cocktail therapy, e.g. the administration of three or free survival (PFS) in men with prostate cancer as compared more active ingredients. to placebo: increasing the time to PSA progression (TTPP) in 0114. The terms “effective amount’ or “therapeutically men with prostate cancer as compared to placebo, increasing effective amount, as used herein, refer to a sufficient amount the health-related quality of life and prostate cancer-specific of an anti-androgen being administered which will relieve to symptoms in men with prostate cancer as compared to pla Some extent one or more of the symptoms of the disease or cebo. In some embodiments, the prostate cancer is metastatic condition being treated. The result can be reduction and/or castration-resistant prostate cancer, non-metastatic castra alleviation of the signs, symptoms, or causes of a disease, or tion-resistant prostate cancer, metastatic castration-sensitive any other desired alteration of a biological system. For prostate cancer, non-metastatic castration-sensitive prostate example, an effective amount of an anti-androgen is the cancer or high-risk localized prostate cancer. US 2014/O 199236 A1 Jul. 17, 2014

0118. The term “metastasis-free survival or “MFS the severity of the disease, the age and relative health of the refers to the percentage of Subjects in a study who have Subject, the potency of the therapeutic agent used and other survived without cancer spread for a defined period of time or factors. death. MFS is usually reported as time from the beginning of I0127. The term “acceptable' with respect to a formula enrollment, randomization or treatment in the study. MFS is tion, composition or ingredient, as used herein, means having reported for an individual or a study population. In the context no persistent detrimental effect on the general health of the of treatment of CRPC with an anti-androgen, an increase in male human being treated. the metastasis-free survival is the additional time that is I0128. As described herein, 4-7-(6-cyano-5-trifluorom observed without cancer having spread or death, whichever ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- occurs first, as compared to treatment with placebo. In some yl)-2-fluoro-N-methylbenzamide is orally administered to a embodiments, the increase in the metastasis-free Survival is human. In some embodiments, 4-7-(6-cyano-5-trifluorom about 1 month, about 2 months, about 3 months, about 4 ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- months, about 5 months, about 6 months, about 7 months, yl)-2-fluoro-N-methylbenzamide is orally administered to a about 8 months, about 10 months, about 11 months, about 12 human in the form of a capsule. In some embodiments, the months, about 13 months, about 14 months, about 15 months, capsule is a softgel capsule. The pharmaceutical composi about 16 months, about 17 months, about 18 months, about 19 tions described herein allow for systemic administration 4-7- months, about 20 months, or greater than 20 months. (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, 0119 The term “placebo' as used herein means adminis 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. tration of a pharmaceutical composition that does not include I0129. Softgel (also called softgelatin or soft elastic) cap a second-generation anti-androgen. In the context of treat Sules consist of one-piece hermetically-sealed soft shells. In ment of CRPC, men that are administered an anti-androgen or Some embodiments, softgelatin capsules are prepared by add placebo will need to continue to maintain castrated levels of ing a plasticizer, Such as glycerin or polyhydric alcohol (e.g., testosterone by either coadministration of a GnRH agonist/ Sorbitol), to gelatin. The plasticizer makes gelatin elastic. antagonist or orchiectomy. Softgelatin capsules come in various shapes such as spheri 0120. The term “Survival benefit’ as used herein means an cal, elliptical, and oblong. They can contain non-aqueous increase in Survival of the patient from time of randomization liquids or Suspensions. on the trial of administered drug to death. In some embodi 0.130. In some embodiments, a softgel capsule comprises ments, the survival benefit is about 1, about 2, about 3, about component(s) from Component #1 and Component #2: 4, about 5, about 6, about 7, about 8, about 9, about 10, about 0131 Component #1: Softgel Capsule Shell—Examples 15, about 20, about 25, about 30, about 35, about 40, about 45, include, but are not limited to, gelatin, starch, and carrag about 50, about 55, about 60, about 80, about 100 months or CCa: greater than 100 months. I0132 Component #2: Softgel Capsule Plasticizer Ex 0121 The term “delay in symptoms related to disease amples include, but are not limited to, Sorbitol, glycerin, progression” as used herein means an increase in time in the xylose, maltitol, and polyethylene glycol (PEG). development of symptoms Such as pain, urinary obstruction I0133. In some embodiments, the softgel capsule shell and quality of life considerations from the time of random comprises gelatin NF/EP, a 50:50 sorbitol/glycerin blend ization on the trial of administered drug. USP/EP, and purified water USP/EP. 0122 The term randomization as it refers to a clinical I0134. In some embodiments, the outer shell comprises trial refers to the time when the patient is confirmed eligible optional ingredients such as color additives or flavor addi for the clinical trial and gets assigned to a treatment arm. tives. (0123. The terms “kit' and “article of manufacture are 0.135 There are three types of inner fill materials for soft used as synonyms. gel capsules: neat Substance, solution fill and Suspension fill. 0.124. The term “subject' and “patient' and “human are 0.136 Neat substance is suited for oily liquids. used interchangeably. 0.137 Solution fill comprises an active dissolved in a car rier. Carriers include, but are not limited to, oils (such as Routes of Administration and Pharmaceutical Compositions soybean oil and Miglyol 812 (neutral oil, triglycerides of 0.125. Therapuetic agents described herein are adminis medium chain fatty acids)), polyethylene glycols (e.g. PEG tered in any suitable manner or suitable formulation. Suitable 400-600), any other solvent which doesn’t degrade or solu routes of administration of the therapeutic agents include, but bilize the gelatin shell (dimethyl isosorbide, surfactants, are not limited to, oral and parenteral (e.g., intravenous, Sub diethylene glycol monoethly ether). Optional ingredients cutaneous, intramuscular). All formulations are in dosages include, but are not limited to, water or alcohol (up to 10% Suitable for administration to a human. A Summary of phar w/w, if needed for solubility), glycerin (1 to 4% w/w to retard maceutical compositions can be found, for example, in Rem the migration of the glycerin out of the shell into the fill), ington: The Science and Practice of Pharmacy, Nineteenth Ed polyvinylpyrrolidone (up to 10% w/w used in combination (Easton, Pa.; Mack Publishing Company, 1995); Hoover, with PEG, can increase drug solubility, and also improve John E., Remington's Pharmaceutical Sciences, Mack Pub stability by inhibiting drug recrystallization). lishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, 0.138. Suspension Fill comprises an active dispersed in a L., Eds. Pharmaceutical Dosage Forms, Marcel Decker, New carrier. Carriers include, but are not limited to, oily mixtures, York, N.Y., 1980; and Pharmaceutical Dosage Forms and polyethylene glycols, and glycerides. Oily mixtures include, Drug Delivery Systems, Seventh Ed. (Lippincott Williams & but are not limited to, traditional oily mixtures such as Soy Wilkins 1999), herein incorporated by reference for such bean oil with beeswax (4-10% w/w) and lecithin (2-4% w/w); disclosure. gelified oil (e.g. Geloil(R) SC), a ready to use system com 0126 Atherapeutically effective amount of the therapeu posed of soybean oil, a suspending agent, and a wetting agent. tic agents that are administered can vary widely depending on Polyethylene glycol includes, but is not limited to, PEG 800

US 2014/O 199236 A1 Jul. 17, 2014

Zamide and 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 3-yl)-1-(3-fluoro-4-(methylcarbamoyl)phenyl)ureido)-cy oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-N- clobutanecarboxylic acid. In some embodiments, described is methylbenzamide. a pharmaceutical composition comprising 1-(3-(6-cyano-5- 0148. In one aspect, described herein is a softgel pharma (trifluoromethyl)pyridin-3-yl)-1-(3-fluoro-4-(methylcar ceutical composition comprising a softgel capsule that is bamoyl)phenyl)ureido)-cyclobutanecarboxylic acid, or a filled with a nonaqueous, lipid-based solution comprising pharmaceutically acceptable salt thereof. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- 0157. In another aspect, described is the compound 4-(7- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben (6-cyano-5-(difluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5, Zamide and 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 7-diazaspiro[3.4 octan-5-yl)-2-fluoro-N-methylbenzamide. thioxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- In some embodiments, described is a pharmaceutically methylbenzamide. acceptable salt of 4-(7-(6-cyano-5-(difluoromethyl)pyridin 0149. In one aspect, described herein is a softgel pharma 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 octan-5-yl)-2- ceutical composition comprising a softgel capsule that is fluoro-N-methylbenzamide. In some embodiments, filled with a nonaqueous, lipid-based solution comprising described is a pharmaceutical composition comprising 4-(7- 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- (6-cyano-5-(difluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5, thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben 7-diazaspiro[3.4 octan-5-yl)-2-fluoro-N-methylbenzamide, Zamide and methyl 4-(7-(6-cyano-5-(trifluoromethyl)pyri or a pharmaceutically acceptable salt thereof. din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 octan-5-yl)-2- 0158. In any of the embodiments described herein, 4-7- fluorobenzoate. (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, 0150. In one aspect, described herein is a softgel pharma 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is ceutical composition comprising a softgel capsule that is replaced with 1-(3-(6-cyano-5-(trifluoromethyl)pyridin-3- filled with a nonaqueous, lipid-based solution comprising yl)-1-(3-fluoro-4-(methylcarbamoyl)phenyl)ureido)-cy 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- clobutanecarboxylic acid, or a pharmaceutically acceptable thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben salt thereof. Zamide and 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)- 0159. In any of the embodiments described herein, 4-7- 8-oxo-6-thioxo-5,7-diazaspiro 3.4 octan-5-yl)-2- (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, fluorobenzoic acid. 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is 0151. In one aspect, described herein is a softgel pharma replaced with 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3- ceutical composition comprising a softgel capsule that is yl)-6,8-dioxo-5,7-diazaspiro3.4 octan-5-yl)-2-fluoro-N- filled with a nonaqueous, lipid-based solution comprising methylbenzamide, or a pharmaceutically acceptable salt 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- thereof. thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben 0160. In any of the embodiments described herein, 4-7- Zamide and 4-(7-(6-cyano-5-(difluoromethyl)pyridin-3-yl)- (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, 8-oxo-6-thioxo-5,7-diazaspiro 3.4 octan-5-yl)-2-fluoro-N- 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is methylbenzamide. replaced with 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3- 0152. In one aspect, described herein is a softgel pharma yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 octan-5-yl)-2-fluo ceutical composition comprising a softgel capsule that is robenzamide, or a pharmaceutically acceptable salt thereof. filled with a nonaqueous, lipid-based solution comprising 0.161. In any of the embodiments described herein, 4-7- 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is Zamide and 1-((4-(methylcarbamoyl)phenyl)amino)cyclobu replaced with 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3- tanecarboxylic acid. yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 octan-5-yl)-2-fluo 0153. In one aspect, described herein is a softgel pharma robenzoic acid, or a pharmaceutically acceptable salt thereof. ceutical composition comprising a softgel capsule that is 0162. In any of the embodiments described herein, 4-7- filled with a nonaqueous, lipid-based solution comprising (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben replaced with 4-(7-(6-cyano-5-(difluoromethyl)pyridin-3- Zamide and 1-(3-fluoro-4-(methylcarbamoyl)phenylamino) yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 octan-5-yl)-2-fluoro cyclobutanecarboxylic acid. N-methylbenzamide, or a pharmaceutically acceptable salt 0154 These formulations are manufactured by conven thereof. tional formulation techniques. There are several procedures to prepare softgelatin capsules, such as the plate process, the Methods of Dosing and Treatment Regimens rotary die process, and reciprocating die process. In some 0163. In one aspect, 4-7-(6-cyano-5-trifluoromethylpyri embodiments, softgel capsules of 4-7-(6-cyano-5-trifluo din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 fluoro-N-methylbenzamide is administered daily to humans oct-5-yl)-2-fluoro-N-methylbenzamide are prepared as out in need of therapy with 4-7-(6-cyano-5-trifluoromethylpyri lined in the Examples. din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- O155 All formulations for oral administration are in dos fluoro-N-methylbenzamide. In some embodiments, 4-7-(6- ages Suitable for Such administration. cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- 0156. In one aspect, described is the compound 1-(3-(6- diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(3-fluoro-4-(me orally administered to the humans. In some embodiments, thylcarbamoyl)phenyl)ureido)-cyclobutanecarboxylic acid. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- In some embodiments, described is a pharmaceutically thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben acceptable salt of 1-(3-(6-cyano-5-(trifluoromethyl)pyridin Zamide is administered once-a-day. In some embodiments, US 2014/O 199236 A1 Jul. 17, 2014

4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- fluoro-N-methylbenzamide is administered orally to the thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben human at a dose of about 240 mg per day. In some embodi Zamide is administered twice-a-day. In some embodiments, ments, greater than 240 mg per day of 4-7-(6-cyano-5-trif 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben 4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered to Zamide is administered three times-a-day. In some embodi the human. In some embodiments, 4-7-(6-cyano-5-trifluo ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- oct-5-yl)-2-fluoro-N-methylbenzamide is administered methylbenzamide is administered every other day. In some orally to the human on a continuous daily dosing schedule. embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- 0166 In some embodiments, the amount of 4-7-(6-cy yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia methylbenzamide is administered twice a week. In some Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is embodiments, 4-7-(6-cyano-5-trifluoromethylpyridin-3- administered once-a-day. In some other embodiments, the yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- amount of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- methylbenzamide is administered weekly. In some embodi oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ments, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo ylbenzamide is administered twice-a-day. 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- 0167. In certain embodiments wherein improvement in methylbenzamide is administered every other week. the status of the disease or condition in the human is not 0164. In general, doses of a 4-7-(6-cyano-5-trifluorom observed, the daily dose of 4-(3-(4-cyano-3-(trifluoromethyl) ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2- yl)-2-fluoro-N-methylbenzamide employed for treatment of fluoro-N-methylbenzamide is increased. In some embodi the diseases or conditions described herein in humans are ments, a once-a-day dosing schedule is changed to a twice typically in the range of 10 mg to 1000 mg per day. In one a-day dosing schedule. In some embodiments, a three times a embodiment, the desired dose is conveniently presented in a day dosing schedule is employed to increase the amount of single dose or in divided doses administered simultaneously 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- (or over a short period of time) or at appropriate intervals, for oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenza example as two, three, four or more Sub-doses per day. In mide that is administered. some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri 0.168. In some embodiments, the amount of 4-(3-(4-cy din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl-2- ano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- fluoro-N-methylbenzamide is conveniently presented in thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide that divided doses that are administered simultaneously (or over a is given to the human varies depending upon factors such as, short period of time) once a day. In some embodiments, but not limited to, condition and severity of the disease or 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- condition, and the identity (e.g., weight) of the human, and thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben the particular additional therapeutic agents that are adminis Zamide is conveniently presented in divided doses that are tered (if applicable). administered in equal portions twice-a-day. Combination Therapies 0.165. In some embodiments, 4-7-(6-cyano-5-trifluorom ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 0169. In certain instances, it is appropriate to administer a yl)-2-fluoro-N-methylbenzamide is administered daily to the second generation anti-androgen (e.g. 4-7-(6-cyano-5-trif human. In some embodiments, 4-7-(6-cyano-5-trifluorom luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 4 oct-5-yl)-2-fluoro-N-methylbenzamide), in combination yl)-2-fluoro-N-methylbenzamide is administered orally to with another therapeutic agent. the human. In some embodiments, 4-7-(6-cyano-5-trifluo 0170 In one specific embodiment, the second generation romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 anti-androgen is co-administered with an additional thera oct-5-yl)-2-fluoro-N-methylbenzamide is administered peutic agent, wherein the Seond generation anti-androgen and orally to the human at a dose of about 30 mg per day to about the additional therapeutic agent modulate different aspects of 960 mg per day. In some embodiments, 4-7-(6-cyano-5- the disease or condition being treated, thereby providing a trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro greater overall benefit than administration of either therapeu 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered tic agent alone. orally to the human at a dose of about 30 mg per day to about 0171 In any case, regardless of the disease, disorder or 480 mg per day. In some embodiments, 4-7-(6-cyano-5- condition being treated, the overall benefit experienced by the trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro patient may simply be additive of the two therapeutic agents 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered or the patient may experience a synergistic benefit. orally to the humanata dose of about 180 mg per day to about 0172. It is understood that the dosage regimen to treat, 480 mg per day. In some embodiments, 4-7-(6-cyano-5- prevent, or ameliorate the condition(s) for which relief is trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro sought, is modified in accordance with a variety of factors. 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is administered These factors include the disease, disorder or condition from orally to the human at a dose of about 30 mg per day, about 60 which the Subject Suffers, as well as the age, weight, sex, diet, mg per day, about 90 mg per day, about 120 mg per day, about and medical condition of the Subject. Thus, in Some instances, 180 mg per day, about 240 mg per day, about 300 mg per day, the dosage regimen actually employed varies and, in some about 390 mg per day, about 480 mg per day, about 600 mg embodiments, deviates from the dosage regimens set forth per day, about 780 mg per day, or about 960 mg per day. In herein. some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri 0173. In combination therapies, the multiple therapeutic din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- agents (one of which is one of the compounds described US 2014/O 199236 A1 Jul. 17, 2014

herein) are administered in any order or even simultaneously. GSK2126458, BAY306946, PF-05212384, SF1126, PX866, Combination therapies are not to be limited to the use of only AMG319, ZSTK474, Cal 101, PWT33597, LY-317615 (En two agents; the use of multiple therapeutic combinations is Zastaurin hydrochloride), CU-906, CUDC-907, Abi, also envisioned. TAK700, TOK-001 (Galeterone), VT-464, Lupron, Zoladex 0174. In some embodiments, methods for treatment of (Goserelin-LHRH agonist), Degarelix (GNRH antagonist), prostate cancer descrinbed herein comprise administration of Ozarelix, ABT-620 (Elagolix), TAK-385 (Relugolix), TAK a second generation anti-androgen to a human in combination 448, EP-100, KLH-2109, Denosumab (RANKL Ab), Zolen with at least one additional therapeutic agent. In some dronic acid (bisphosphonate), OCIF (OPG), AMG-0007, embodiments, the cancer is advanced prostate cancer. In a CEP-37251, ALX-0141, Alendronate sodium (Fosamax), further embodiment, the cancer is castration-sensitive. In a Pamidronate sodium (Aredia), Neridronic acid (Nerixia), further embodiment, the cancer is castration-resistant pros Minodronic acid (Recalbon), Risedronate sodium (Actonel), tate cancer. In a further embodiment, the cancer is high-risk Alpharadin, 177Lu-J59 (PSMA monoclonal Ab J591-radio localized prostate cancer. In some embodiments, the combi immunoconjugate), External beam radiation therapy, brachy nation therapy is targeted toward patients identified with cas therapy, Cabozantinib (XL184.) Met/VEGR2, PF-2341066 tration-resistant prostate cancer (CRPC) that exhibits intrin (Crizotinib), ARQ-197 (Tivantinib), MK-2461, JNJ sic or acquired resistance to abiraterone acetate and/or MDV 38877605, MK-8033, INCB-28060, BMS-777607, AMG 31 OO. 208, LY-280.1653, EMD-1214063, EMD-1204831, AMG 0.175. In some embodiments, 4-7-(6-cyano-5-trifluorom 337, HM-5016504 (Volitinib), SAR-125844, LY2875358, ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- ABR-215050 (Tasquinimod), CHIR-258 (Dovitinib), EXEL yl)-2-fluoro-N-methylbenzamide is used to treat prostate can 7647, OSI-930, BIBF-1120, BAY-73-4506, BAY-73-4506, cer in a human in combination with another therapeutic agent. BMS-582664 (Brivanib), RO-4929097, JNJ-26483327, In one embodiment, the prostate cancer is metastatic castra AZD-2 171 (Cediranib), Sorafenib, Aflibercept, Enzastaurin, tion-resistant prostate cancer, non-metastatic castration-re AG-013736 (Axitinib), GSK-78.6034 (Pazopanib), sistant prostate cancer, metastatic castration-sensitive pros GSK-786034 (Pazopanib), AP-23573, BMS-354825 (Dasat tate cancer, non-metastatic castration-sensitive prostate inib), Provenge, Prostvac-VF, Ipilimumab, CTLA4 inhibi cancer or high-risk localized prostate cancer. Given the cen tors, PD-1 inhibitors, ChK inhibitors, Docetaxel, Cabazi tral role of AR in prostate cancer development and progres taxel, taxanes, tubulin inhibitors, Anti-STEAP1 ADC, sion, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- STEAP-1, Tarceva (EGFR1), Trametinib (MEK inhibitor thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N- GSK), Cetuximab, Gefitinib, Canertinib, Panitumumab, methylbenzamide is useful in the treatment of advanced Nimotuzumab, OSI-632, Lapatinib, Vandetanib, Afatinib, prostate cancer, either alone or in combination with other MP-412, AEE-788, Neratinib, XL-647, AC-480, Dacomi agents that can modulate other critical pathways in prostate tinib, AZD-8931, CUDC-101, AP-26113, CO-1686, Selume cancer, including but not limited to those that target IGF1R, tinib, MEK-162, Refametinib, TAK-733, RO-5126766, the PI3K/AKT/mTOR axis, or HSP90. BI-847325, AZD6244, GSK1 120212, PF-5208763 (Bosu 0176). In some embodiments, 4-7-(6-cyano-5-trifluorom tinib), AZD-0530 (Saracatinib), OGX-11 (Custirsen, anti ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- clusterin), OGX-427 (Anti-HSP27), AUY922, HSP990, yl)-2-fluoro-N-methylbenzamide or a pharmaceutical com AT13387, GDC0068, MK-2206, AT7867, GSK2110183, position thereof is administered in combination with an GSK2141795, GSK690693, PLX4032/RG7204, additional therapeutic agent including but not limited to: GSK21 18436, GSK208436, LGX818, RAF265, PI3K inhibitors, TORC inhibitors, CYP17 inhibitors, GNRH/ LY2780301, LY2584702, Dovitinib (TKI258), BGJ398, LHRH agonists/antagonists, osteoprotective agents, radia AZD4547, PD-0332991 or LEE011; or combinations tion, kinase inhibitors (e.g. MET, VEGFR, EGFR, MEK, thereof. SRC, AKT, RAF, FGFR, CDK4/6), immunotherapy, taxanes, 0179. In certain instances, it is appropriate to administer a tubulin inhibitors, STEAP-1 anti-body drug conjugate (ADC), second generation anti-androgen (e.g. 4-7-(6-cyano-5-trif HSP90/HSP27 pathway modulators. luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 0177. In certain instances, it is appropriate to administer a 4 oct-5-yl)-2-fluoro-N-methylbenzamide), in combination second generation anti-androgen (e.g. 4-7-(6-cyano-5-trif with an anti-estrogen (e.g., tamoxifen), an anti-androgen luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. (e.g., bicalutamide, flutamide), gonadotropin releasing hor 4 oct-5-yl)-2-fluoro-N-methylbenzamide), in combination mone analog (e.g., leuprolide). with a TORC inhibitor, PI3K inhibitor, CYP17 inhibitor, 0180. In certain instances, it is appropriate to administer a GNRH agonist or antagonist, osteoprotective agent, Syk second generation anti-androgen (e.g. 4-7-(6-cyano-5-trif inhibitor, RANKL inhibitor, MET inhibitor, VEGFR inhibi luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. tor, EGFR inhibitor, FGFR inhibitor, MEK inhibitor, Src 4 oct-5-yl)-2-fluoro-N-methylbenzamide), in combination inhibitor, AKT inhibitor, RAF inhibitor, CDK4 inhibitor, or with anti-emetic agents to treat nausea or emesis, which may CDK6 inhibitor. result from the use of the second generation anti-androgen, 0178. In certain instances, it is appropriate to administer a anti-cancer agent(s) and/or radiation therapy. Anti-emetic second generation anti-androgen (e.g. 4-7-(6-cyano-5-trif agents include, but are not limited to: neurokinin-1 receptor luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. antagonists, 5HT3 receptorantagonists (such as ondansetron, 4 oct-5-yl)-2-fluoro-N-methylbenzamide), in combination granisetron, tropisetron, Palomosetron, and Zatisetron), with abiraterone acetate, Everolimus, GDC-0980, GDC GABA receptor agonists (such as baclofen), corticosteroids 0068, (GDC-0980+GDC-0068), GSK-2636771, BEZ-235, (such as dexamethasone, prednisone, prednisolone, or oth BKM120, BGT226, BYL-719, GDC0941, GDC0032, ers), dopamine antagonists (such as, but not limited to, dom INK1117, MK-2206, OSI-027, CC-223, AZD8055, peridone, droperidol, haloperidol, chlorpromazine, promet SAR245408, SAR245409, PF0469 1502, WYE125132, hazine, prochlorperazine, metoclopramide), antihistamines US 2014/O 199236 A1 Jul. 17, 2014

(H1 histamine receptor antagonists, such as but not limited to, post-abiraterone acetate treated metastatic castration-resis cyclizine, diphenhydramine, dimenhydrinate, meclizine, tant prostate cancer, metastatic castration-resistant prostate promethazine, hydroxy Zine), cannabinoids (such as but not cancer, non-metastatic castration-resistant prostate cancer, limited to, cannabis, marinol, dronabinol), and others (such metastatic castration-sensitive prostate cancer, non-meta as, but not limited to, trimethobenzamide: ginger, emetrol, static castration-sensitive prostate cancer or high-risk local propofol). ized prostate cancer in combination with a phosphoinositide 0181 Combination with a PI3K/TORC Inhibitor 3-kinase (PI3K) inhibitor, TORC inhibitor, or dual PI3K/ 0182. In some embodiments, patients with prostate may TORC inhibitor. In some embodiments, the second genera exhibit intrinsic or acquired resistance to 2nd generation anti tion anti-androgen is MDV-3100 or 4-7-(6-cyano-5-trifluo hormonal therapies such as abiraterone acetate, MDV-3100& romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- oct-5-yl)-2-fluoro-N-methylbenzamide. In SO thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben embodiments, the second generation anti-androgen is MDV Zamide. In both intrinsic and acquired endocrine resistance, 3100. In some embodiments, the second generation anti signaling via other critical pathways is thought to be a key androgen is 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- determinant of the resistant phenotype. Deregulation of the oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N- PI3K pathway (e.g. PTEN deletion) is one of the most preva methylbenzamide. lent alterations found in prostate cancer. Recently, activation 0186. In one aspect, described herein is a method of treat of the PI3K pathway has been shown to confer intrinsic ing prostate cancer in a male human comprising administer resistance to hormonal therapy in the PTEN KO model of ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- prostate cancer (Carveretal. “Reciprocal feedback regulation thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- of PI3K and androgen receptor signaling in PTEN-deficient methylbenzamide at a dose of about 30 mg per day to about prostate cancer.” Cancer Cell. 2011 May 17: 19(5):575-86: 480 mg per day to a male human with post-abiraterone acetate Mulholland et at “Cell autonomous role of PTEN in regulat treated metastatic castration-resistant prostate cancer, meta ing castration-resistant prostate cancer growth. Cancer Cell. static castration-resistant prostate cancer, non-metastatic cas 2011 Jun. 14, 19(6):792-804). In some embodiments, com tration-resistant prostate cancer, metastatic castration-sensi bination of Complete Androgen Blockade (CAB) (GNRH+ tive prostate cancer, non-metastatic castration-sensitive 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- prostate cancer or high-risk localized prostate cancer in com thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- bination with a phosphoinositide 3-kinase (PI3K) inhibitor, methylbenzamide)+PI3K pathway inhibition in CRPC TORC inhibitor, or dual PI3K/TORC inhibitor. In some patients has the potential to overcome both intrinsic and embodiments, the method of treating prostate cancer further extrinsic resistance to 2nd generation hormonal therapies. comprises administering a therapeutically effective amount 0183 In some embodiments, overexpression of wild type ofagonadotropin-releasing hormone agonist orantagonist to androgen receptor 3-5 fold in the LNCaP (LNCaP/AR) cell the male human. line confers a castration resistant phenotype both in vitro and 0187. In some embodiments, the phosphoinositide 3-ki in vivo. In some embodiments, it was observed that 4-7-(6- nase (PI3K) inhibitor, TORC inhibitor, or dual PI3K/TORC cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- inhibitor is everolimus, BEZ-235, BKM120, BGT226, BYL diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at 719, GDC0068, GDC-0980, GDC0941, GDC0032, doses from 10-30 mg/kg/day causes nearly full regression of MK-2206, OSI-027, CC-223, AZD8055, SAR245408, all treated LNCaP/AR tumors, whereas a dose of 1 mg/kg/day SAR245409, PF04691502, WYE125132, GSK2126458, results in a mean response of tumor stasis. In some embodi GSK-2636771, BAY306946, PF-05212384, SF1126, PX866, ments, treatment with PI3K inhibitors SAR245408 or AMG319, ZSTK474, Cal 101, PWT33597, LY-317615 (en BKM120 or the TORC1 inhibitor everoliomus (all at or near Zastaurin hydrochloride), CU-906, or CUDC-907. their respective maximally efficacious dose) exhibit a range 0188 In some embodiments, the TORC inhibitor is of efficacy from tumor growth inhibition to tumor stasis. In everolimus. In some embodiments, everolimus is adminis Some embodiments, combining 4-7-(6-cyano-5-trifluorom tered at a dose of about 5 mg per day to about 20 mg per day. ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- In some embodiments, everolimus is administered at a dose of yl)-2-fluoro-N-methylbenzamide 1 mg/kg/day+PI3K path about 5 mg per day or about 10 mg per day. way inhibition via the compounds noted above, resulted in 0189 In some embodiments, 4-7-(6-cyano-5-trifluorom increased efficacy (tumor regeression) compared to either ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- agent alone. yl)-2-fluoro-N-methylbenzamide is administered orally at a 0184. In some embodiments, in the PTEN KO genetically dose of about 120 mg per day to about 240 mg per day. In engineered mouse model of prostate cancer, combined andro some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri gen blockage or CAB (castration+MDV3100 or castration+ din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- fluoro-N-methylbenzamide is administered orally at a dose of thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- about 240 mg per day. In some embodiments, 4-7-(6-cyano methylbenzamide) exhibits minimal efficacy. In some 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza embodiments, monotherapy with pan-PI3K pathway inhibi spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis tion with BEZ-235 also has minimal anti-tumor activity. In tered orally in the form of a softgel capsule. contrast, in some embodiments the combination of CAB with 0.190 Combination with a CYP17 Inhibitor BEZ-235 resulted in significant reduction in tumor volume in 0191 In some embodiments, incomplete target or path all animals treated. way Suppression can result in less than optimal therapeutic 0185. In one aspect, described herein is a method of treat response. One way to overcome this and maximize treatment ing prostate cancer in a male human comprising administer outcomes is inhibit multiple nodes within a given pathway. In ing a second generation anti-androgen to a male human with Some embodiments, hormonal treatment in prostate cancer US 2014/O 199236 A1 Jul. 17, 2014 include a GNRH agonist (e.g. Lupron) in combination with fluoro-N-methylbenzamide is administered orally at a dose of an anti-androgen (bicalutamide, MDV3100 or 4-7-(6-cyano about 240 mg per day. In some embodiments, 4-7-(6-cyano 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide). In some spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis embodiments, further Suppression of androgen levels to tered orally in the form of a softgel capsule. below castrate levels comprises the combination of a CYP17 0200 Combination with a GnRH Agonist or Antagonist inhibitor with a GNRHagonist and an anti-androgen. 0201 In one aspect, described herein is a method of treat 0.192 In one aspect, described herein is a method of treat ing prostate cancer in a male human comprising administer ing prostate cancer in a male human comprising administer ing a second generation anti-androgen to a male human with ing a second generation anti-androgen to a male human with metastatic castration-resistant prostate cancer, non-meta metastatic castration-resistant prostate cancer, non-meta static castration-resistant prostate cancer, metastatic castra static castration-resistant prostate cancer, metastatic castra tion-sensitive prostate cancer, non-metastatic castration-sen tion-sensitive prostate cancer, non-metastatic castration-sen sitive prostate cancer or high-risk localized prostate cancer in sitive prostate cancer or high-risk localized prostate cancer in combination with a gonadotropin-releasing hormone agonist combination with a CYP17 inhibitor. In some embodiments, or antagonist. In some embodiments, the second generation the second generation anti-androgen is MDV-3100 or 4-7- anti-androgen is MDV-3100 or 4-7-(6-cyano-5-trifluorom (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. In yl)-2-fluoro-N-methylbenzamide. In some embodiments, the Some embodiments, the second generation anti-androgen is second generation anti-androgen is MDV-3100. In some MDV-3100. In some embodiments, the second generation embodiments, the second generation anti-androgen is 4-7- anti-androgen is 4-7-(6-cyano-5-trifluoromethylpyridin-3- (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. methylbenzamide. 0202 In one aspect, described herein is a method of treat 0193 In some embodiments, described herein is a method ing prostate cancer in a male human comprising administer of treating prostate cancer in a male human comprising ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- administering 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- 8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- methylbenzamide at a dose of about 30 mg per day to about methylbenzamide at a dose of about 30 mg per day to about 480 mg per day to a male human with metastatic castration 480 mg per day to a male human with metastatic castration resistant prostate cancer, non-metastatic castration-resistant resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate can prostate cancer, metastatic castration-sensitive prostate can cer, non-metastatic castration-sensitive prostate cancer or cer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in combination with a high-risk localized prostate cancer in combination with a gonadotropin-releasing hormone agonist or antagonist. CYP17 inhibitor. 0194 In some embodiments, the method of treating pros 0203 Gonadotropin-releasing hormone (GnRH) is also tate cancer further comprises administering a therapeutically known as Luteinizing-hormone-releasing hormone (LHRH). effective amount of a gonadotropin-releasing hormone ago 0204. In some embodiments, the gonadotropin-releasing nist or antagonist to the male human. hormone agonist or antagonist is Lupron, Zoladex (Goser (0195 In some embodiments, the CYP17 inhibitor is abi elin), Degarelix, Ozarelix, ABT-620 (Elagolix), TAK-385 raterone acetate (Zytiga), TAK-700 (orteronel), TOK-001 (Relugolix), EP-100 or KLH-2109. (galeterone) or VT-464. 0205. In some embodiments, the gonadotropin-releasing 0196. In some embodiments, the CYP17 inhibitor is abi hormone agonist or antagonist is Lupron. In some embodi raterone acetate (Zytiga). In some embodiments, abiraterone ments, Lupron is administered as a depot injection at a dose of acetate (Zytiga) is administered at a dose of about 500 mg per about 7.5 mg every 4 weeks, or 22.5 mg every 3 months, or day to about 1000 mg per day. In some embodiments, abi about 30 mg every 4 months, or about 45 mg every 6 months. raterone acetate (Zytiga) is administered at a dose of about 0206. In some embodiments, the gonadotropin-releasing 1000 mg per day. In some embodiments, abiraterone acetate hormone agonist or antagonist is Zoladex (Goserelin). In is administered in combination with prednisone. In some Some embodiments, Zoladex (Goserelin) is administered as a embodiments, abiraterone acetate is administered once a day Subcutaneous implantata dose of about 3.6 mg every 4 weeks and prednisone is administered twice a day. or about 10.8 mg every 12 weeks. 0197). In some embodiments, the CYP17 inhibitoris TAK 0207. In some embodiments, the gonadotropin-releasing 700 (orteronel). In some embodiments, TAK-700 (orteronel) hormone agonist orantagonist is Degarelix. In some embodi is administered at a dose of about 300 mg twice per day to ments, Degarelix is administered as a Subcutaneous injection about 600 mg twice per day. at a dose of about 240 mg followed by about 80 mg admin (0198 In some embodiments, TAK-700 (orteronel) is istered every 4 weeks. administered at a dose of about 300 mg twice per day to about 0208. In some embodiments, 4-7-(6-cyano-5-trifluorom 600mg twice per day, together with prednisone at about 5 mg ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- twice per day. yl)-2-fluoro-N-methylbenzamide is administered orally at a 0199. In some embodiments, 4-7-(6-cyano-5-trifluorom dose of about 120 mg per day to about 240 mg per day. In ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri yl)-2-fluoro-N-methylbenzamide is administered orally at a din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- dose of about 120 mg per day to about 240 mg per day. In fluoro-N-methylbenzamide is administered orally at a dose of some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri about 240 mg per day. In some embodiments, 4-7-(6-cyano din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza US 2014/O 199236 A1 Jul. 17, 2014 spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis yl)-2-fluoro-N-methylbenzamide is administered orally at a tered orally in the form of a softgel capsule. dose of about 120 mg per day to about 240 mg per day. In 0209 Combination with an Osteoprotective Agent some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri 0210 Skeletal morbidity via bone metastases is a major din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- cause of death in patients with castration resistance prostate fluoro-N-methylbenzamide is administered orally at a dose of cancer. In addition, long term androgen deprivation therapy about 240 mg per day. In some embodiments, 4-7-(6-cyano results in loss of bone mineral density and increase in poten 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza tial fractures. In some embodiments, osteoprotective agents spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis prevent/delay skeletal events in men on androgen deprivation tered orally in the form of a softgel capsule. therapy (ADT) and have the potential to prevent/delay skel 0218 Combination with Radiation Therapy etal events in men on ADT+4-7-(6-cyano-5-trifluorometh 0219 Radiation induces tumor cell death via DNA dam ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- age Subsequent induction of apoptosis. Induction of apoptosis yl)-2-fluoro-N-methylbenzamide. Osteoclasts, through in prostatic epithelium and prostate cancer cells through inhi paracrine effects, can influence the growth of bone mets. In bition of the androgen receptor signaling pathway is well Some embodiments, combining a second generation anti-an established in both pre-clinical models and in patients. droigen with an osteoprotective agent may prevent formation Recently, it has been shown that the androgen receptor may of bones metastases and/or the growth of already established regulate DNA repair mechanisms and thus combination of bone metastases. radiation and AR inhibition has the potential to increase DNA 0211. In one aspect, described herein is a method of treat damage mediated apoptosis and thus anti-tumor efficacy. ing prostate cancer in a male human comprising administer 0220. A technique for delivering radiation to cancer cells ing a second generation anti-androgen to a male human with is to place radioactive implants directly in a tumor or body metastatic castration-resistant prostate cancer, non-meta cavity. This is called internal radiotherapy (brachytherapy, static castration-resistant prostate cancer, metastatic castra interstitial irradiation, and intracavitary irradiation are types tion-sensitive prostate cancer, non-metastatic castration-sen of internal radiotherapy). Using internal radiotherapy, the sitive prostate cancer or high-risk localized prostate cancer in radiation dose is concentrated in a small area. combination with an osteoprotective agent. In some embodi 0221) The term “radiotherapy’ or “ionizing radiation' ments, the second generation anti-androgen is MDV-3100 or include all forms of radiation, including but not limited to C. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- B, and Y radiation and ultraviolet light. thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylben 0222 Another way of delivering radiation is by use of Zamide. In some embodiments, the second generation anti radiopharmaceuticals. Radiopharmaceuticals induce tumor androgen is MDV-3100. In some embodiments, the second cell death via DNA damage and subsequent induction of generation anti-androgen is 4-7-(6-cyano-5-trifluorometh apoptosis. Alpharadin (Radium-223 Chloride) is an alpha ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- particle emitter that acts as calcium mimic and thus has pro yl)-2-fluoro-N-methylbenzamide. pensity to home to bone and thus close proximity to bone 0212. In one aspect, described herein is a method of treat metastases. It has been shown to prolong Survival in castra ing prostate cancer in a male human comprising administer tion resistant prostate cancer patients in a recently completed ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- Phase 3 study. 'Lu-J591 is a deimmunized monoclonal thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- antibody specific to the extracellular domain of prostate spe methylbenzamide at a dose of about 30 mg per day to about cific membrane antigen (PSMA) conjugated to the radiometal 480 mg per day to a male human with metastatic castration '''Lutium (beta emitter). The restricted expression pattern of resistant prostate cancer, non-metastatic castration-resistant PSMA results in selective delivery of '77Lutium to prostate prostate cancer, metastatic castration-sensitive prostate can cancer cells and thus in theory increased efficacy and cer, non-metastatic castration-sensitive prostate cancer or decreased side effects. high-risk localized prostate cancer with an osteoprotective 0223 Androgen receptor signaling provides prostate can agent. cer cells with Survival signals necessary for primary and 0213. In some embodiments, the method of treating pros metastatic tumor growth. Anti-androgen therapy has been tate cancer further comprises administering a therapeutically shown to increase tumor apoptosis in preclinical models of effective amount of a gonadotropin-releasing hormone ago CRPC and exhibit anti-tumor efficacy in man. Decrease in nist or antagonist to the male human. Survival signaling via anti-androgen treatment will lower 0214. In some embodiments, the osteoprotective agent is apoptotic threshold, increasing cell death inducing effects of Denosumab, AMG-0007, CEP-37251, ALX-0141, radiopharmaceuticals. In some embodiments, combining an Zoledronic acid, Alendronate Sodium (Fosamax), Pamidr anti-androgen with 'Lu-J591 has an added benefit in that onate disodium (Aredia), Neridronic acid (Nerixia), Mino PSMA is under negative transcriptional control of the andro dronic acid (Recalbon) or Risedronate sodium (Actonel). gen receptor (in the absence of androgen PSMA levels 0215. In some embodiments, the osteoprotective agent is increase). Thus, treatment of prostate cancer with a second Denosumab. In some embodiments, Denosumab is adminis generation anti-androgen will increase PSMA protein levels tered by Subcutaneous injection at a dose of about 60 mg to resulting in more 'Lu-J591 binding per cell and thus poten about 120 mg every 4 weeks to every 6 months. tially increasing radiation induced cell death. 0216. In some embodiments, the osteoprotective agent is 0224. In one aspect, described herein is a method of treat Zoledronic acid. In some embodiments, Zoledronic acid is ing prostate cancer in a male human comprising administer administered by intravenous infusion at a dose of about 4 mg ing a second generation anti-androgen to a male human with every 4 weeks to every 12 weeks. metastatic castration-resistant prostate cancer, non-meta 0217. In some embodiments, 4-7-(6-cyano-5-trifluorom static castration-resistant prostate cancer, metastatic castra ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- tion-sensitive prostate cancer, non-metastatic castration-sen US 2014/O 199236 A1 Jul. 17, 2014 20 sitive prostate cancer or high-risk localized prostate cancer in ing in the tumor, and VEGFR2 in the tumor endothelium, combination with a radiation therapy. In some embodiments, potentially resulting in robust inhibition of both formation of the second generation anti-androgen is MDV-3100 or 4-7- prostate cancer associated bone metastases as well as growth (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, of established bone metastases 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. In 0234. In one aspect, described herein is a method of treat Some embodiments, the second generation anti-androgen is ing prostate cancer in a male human comprising administer MDV-3100. In some embodiments, the second generation ing a second generation anti-androgen to a male human with anti-androgen is 4-7-(6-cyano-5-trifluoromethylpyridin-3- post-abiraterone acetate treated metastatic castration-resis yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- tant prostate cancer, metastatic castration-resistant prostate methylbenzamide. cancer, non-metastatic castration-resistant prostate cancer, 0225. In one aspect, described herein is a method of treat metastatic castration-sensitive prostate cancer, non-meta ing prostate cancer in a male human comprising administer static castration-sensitive prostate cancer or high-risk local ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- ized prostate cancer in combination with a kinase inhibitor. In thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- Some embodiments, the second generation anti-androgen is methylbenzamide at a dose of about 30 mg per day to about MDV-3100 or 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- 480 mg per day to a male human with metastatic castration 8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2-fluoro-N- resistant prostate cancer, non-metastatic castration-resistant methylbenzamide. In some embodiments, the second genera prostate cancer, metastatic castration-sensitive prostate can tion anti-androgen is MDV-3100. In some embodiments, the cer, non-metastatic castration-sensitive prostate cancer or second generation anti-androgen is 4-7-(6-cyano-5-trifluo high-risk localized prostate cancer in combination with a romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 radiation therapy. oct-5-yl)-2-fluoro-N-methylbenzamide. 0226. In some embodiments, the method of treating pros 0235. In one aspect, described herein is a method of treat tate cancer further comprises administering a therapeutically ing prostate cancer in a male human comprising administer effective amount of a gonadotropin-releasing hormone ago ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- nist or antagonist to the male human. thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- 0227. In some embodiments, the radiation therapy is methylbenzamide at a dose of about 30 mg per day to about Alpharadin, ''Lu-J591, external beam radiation therapy (in 480 mg per day to a male human with post-abiraterone acetate cluding Proton beam), or brachytherapy. treated metastatic castration-resistant prostate cancer, meta 0228. In some embodiments, the radiation therapy is static castration-resistant prostate cancer, non-metastatic cas Alpharadin. In some embodiments, Alpharadin is adminis tration-resistant prostate cancer, metastatic castration-sensi tered by intravenous infusion at a dose of about 25 to about 50 tive prostate cancer, non-metastatic castration-sensitive kBq/kg every 4 weeks. prostate cancer or high-risk localized prostate cancer in com 0229. In some embodiments, the radiation therapy is '''Lu-J591. In some embodiments, ''Lu-J591 is adminis bination with a kinase inhibitor. tered by intravenous infusion at a dose of about 30 mCi/m2 to 0236. In some embodiments, the method of treating pros about 70 mCi/m2. tate cancer further comprises administering a therapeutically 0230. In some embodiments, 4-7-(6-cyano-5-trifluorom effective amount of a gonadotropin-releasing hormone ago ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- nist or antagonist to the male human. yl)-2-fluoro-N-methylbenzamide is administered orally at a 0237. In some embodiments, the kinase inhibitor targets dose of about 120 mg per day to about 240 mg per day. In angiogenesis or bone metastases. In some embodiments, the some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri kinase inhibitoris a MET or VEGFR kinase inhibitor. In some din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- embodiments, the kinase inhibitor is Cabozantinib (XL184), fluoro-N-methylbenzamide is administered orally at a dose of PF-2341066 (Crizotinib), ARQ-197 (Tivantinib), MK-2461, about 240 mg per day. In some embodiments, 4-7-(6-cyano JNJ-38877605, MK-8033, INCB-28060, BMS-777607, 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza AMG-208, LY-280.1653, EMD-1214063, EMD-1204831, spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis AMG-337, HMPL-504 (Volitinib), SAR-125844, tered orally in the form of a softgel capsule. LY2875358, ABR-215050 (Tasquinimod), CHIR-258 (Dovi 0231 Combination with a Kinase Inhibitor tinib), EXEL-7647, OSI-930, BIBF-1120, BAY-73-4506 0232 Growth factor signaling pathways such as EGFR (Regorafenib), BMS-582664 (Brivanib), JNJ-26483327, and RAS/RAF/Mek are mediators of tumor cell growth and AZD-2 171 (Cediranib), Sorafenib, Aflibercept, Enzastaurin, Survival. In some embodiments, these pathways are deregu AG-013736 (Axitinib), OSI-632, or GSK-786034 (Pazo lated in prostate cancer (or at least a Subset) and function in panib). In some embodiments, the kinase inhibitor is Cabo parallel to androgen receptor signaling to promote disease Zantinib. In some embodiments, Cabozantinib is adminis progression. In some embodiments, simultaneous inhibition tered orally at a dose of about 40 mg per day to about 100 mg of AR signaling and growth factor signaling increases effi per day. cacy of treatment across the spectrum of prostate cancer 0238. In some embodiments, the kinase inhibitor is an disease. EGFR, MEK, or SRC kinase inhibitor. In some embodiments, 0233 Metastasis to the bone in prostate cancer patients is the kinase inhibitor is Erlotinib, Cetuximab, Gefitinib, Can associated with significant pain and mortality. cMet is ertinib, Panitumumab, Nimotuzumab, Lapatinib, Vandetanib, involved in both tumor cell growth, survival and metastasis Afatinib, MP-412, AEE-788, Neratinib, XL-647, AC-480, and VEGFR2 signaling promotes tumor angiogenesis. In Dacomitinib, AZD-8931, CUDC-101, AP-26113, CO-1686, Some embodiments, combining a second generation anti-an Trametinib, Selumetinib, MEK-162, Refametinib, TAK-733, drogen with a suitable kinase inhibtor will simultaneously RO-5 126766, BI-847325, AZD6244, GSK1120212, inhibit the activity of the androgen receptor and cMet signal PF-5208763 (Bosutinib), or AZD-0530 (Saracatinib). US 2014/O 199236 A1 Jul. 17, 2014

0239. In some embodiments, the kinase inhibitor is Erlo ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- tinib. In some embodiments, Erlotinib is administered orally thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- at a dose of about 100 mg to about 150 mg. methylbenzamide at a dose of about 30 mg per day to about 0240. In some embodiments, the kinase inhibitor is Gefi 480 mg per day to a male human with metastatic castration tinib. In some embodiments, Gefitinib is administered orally resistant prostate cancer, non-metastatic castration-resistant at a dose of about 250 mg. prostate cancer, metastatic castration-sensitive prostate can 0241. In some embodiments, the kinase inhibitor is cer, non-metastatic castration-sensitive prostate cancer or Trametinib. In some embodiments, Trametinib is adminis high-risk localized prostate cancer in combination with tered orally at a dose of about 1 mg to about 2 mg. Provenge, Prostvac, Ipilimumab, or a PD-1 inhibitor. 0242. In some embodiments, the kinase inhibitorisa AKT, 0248. In some embodiments, the method of treating pros RAF, FGFR, or CDK476 kinase inhibitor. In some embodi tate cancer further comprises administering a therapeutically ments, the kinase inhibitor is GDC0068, MK-2206, AT7867, effective amount of a gonadotropin-releasing hormone ago GSK2110183, GSK2141795, GSK690693, Vemurafenib nist or antagonist to the male human. (PLX4032/RG7204), GSK21 18436, Dabrafenib 0249. In some embodiments, 4-7-(6-cyano-5-trifluorom (GSK208436), LGX818, RAF265, LY2780301, Dovitinib ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- (TKI258), BGJ398, AZD4547, PD-0332991 or LEE011. yl)-2-fluoro-N-methylbenzamide is administered in combi 0243 In some embodiments, 4-7-(6-cyano-5-trifluorom nation with Ipilimumab. In some embodiments, Ipilimumab ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- is administered by intravenous infusion at a dose of about 1.5 yl)-2-fluoro-N-methylbenzamide is administered orally at a mg/Kg to about 3.0 mg/kg IV every 3 weeks for a total of 4 dose of about 120 mg per day to about 240 mg per day. In doses. some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri 0250 In some embodiments, 4-7-(6-cyano-5-trifluorom din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- fluoro-N-methylbenzamide is administered orally at a dose of yl)-2-fluoro-N-methylbenzamide is administered in combi about 240 mg per day. In some embodiments, 4-7-(6-cyano nation with PD-1 inhibitor. In some embodiments, the PD-1 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza inhibitor is BMS-936.558. In some embodiments, the PD-1 spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis inhibitor is BMS-93.6558 and is administered by intravenous tered orally in the form of a softgel capsule. infusion at a dose of about 1.0 mg/kg to about 10 mg/kg on 0244 Combination with Immunotherapy days 1, 15 and 29 of 6-week cycles. 0245 Augmentation of cytotoxic T-cell responses is the (0251. In some embodiments, 4-7-(6-cyano-5-trifluorom cornerstone of most immunotherapies. Androgen ablation ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- has been shown to result in modulation of immune function yl)-2-fluoro-N-methylbenzamide is administered in combi which in turn could further augment tumor targeted immune nation with Provenge. In some embodiments, 3 doses of therapy. These effects include, but are not limited to: Provenge are administered doses at approximately 2 weeks Increased CD4+ T cell infiltration into the prostate gland; interval. Increased in CD8+ T cell and macrophage number in the 0252. In some embodiments, 4-7-(6-cyano-5-trifluorom prostate gland; Increased thymic production of T cells and ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- overall enhancement of immunotherapy in various animal yl)-2-fluoro-N-methylbenzamide is administered in combi models. In some embodiments, combination of a second gen nation with Prostvac. In some embodiments, Prostvac is eration anti-androgen (on top of androgen ablation) could administered by Subcutaneous injection. further increase the androgen ablation induced immunologi 0253) In some embodiments, 4-7-(6-cyano-5-trifluorom cal effects increasing the efficacy of the immunotherapy. In ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- addition, given that immunotherapies function via the cyto yl)-2-fluoro-N-methylbenzamide is administered orally at a toxic T cell response resulting in induction of tumor cell dose of about 120 mg per day to about 240 mg per day. In apoptosis, the proapoptotic activity of a second generation some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri anti-androgen should lower the apoptotic threshold of the din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- immunotherapy based T-cell responses fluoro-N-methylbenzamide is administered orally at a dose of 0246. In one aspect, described herein is a method of treat about 240 mg per day. In some embodiments, 4-7-(6-cyano ing prostate cancer in a male human comprising administer 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza ing a second generation anti-androgen to a male human with spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis metastatic castration-resistant prostate cancer, non-meta tered orally in the form of a softgel capsule. static castration-resistant prostate cancer, metastatic castra 0254 Combination with a Taxane or Tubulin Inhibitor tion-sensitive prostate cancer, non-metastatic castration-sen 0255 Taxanes such as Docetaxel and Cabazitaxel are anti sitive prostate cancer or high-risk localized prostate cancer in mitotic drugs that inhibit tumor cell proliferation and also combination with Provenge, Prostvac, Ipilimumab, or a PD-1 induce tumor cell apoptosis. In some embodiments, the com inhibitor. In some embodiments, the second generation anti bination of a second generation anti-androgen with a taxane androgen is MDV-3100 or 4-7-(6-cyano-5-trifluorometh or tubulin inhibitor increases increases apoptotic and antipro ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- liferative response in CRPC resulting in an increase in anti yl)-2-fluoro-N-methylbenzamide. In some embodiments, the tumor response to the therapy. second generation anti-androgen is MDV-3100. In some 0256 In one aspect, described herein is a method of treat embodiments, the second generation anti-androgen is 4-7- ing prostate cancer in a male human comprising administer (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, ing a second generation anti-androgen to a male human with 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. metastatic castration-resistant prostate cancer, or high-risk 0247. In one aspect, described herein is a method of treat localized prostate cancer in combination with a taxane or ing prostate cancer in a male human comprising administer tubulin inhibitor. In some embodiments, the second genera US 2014/O 199236 A1 Jul. 17, 2014 22 tion anti-androgen is MDV-3100 or 4-7-(6-cyano-5-trifluo romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. oct-5-yl)-2-fluoro-N-methylbenzamide. In SO 0265. In one aspect, described herein is a method of treat embodiments, the second generation anti-androgen is MDV ing prostate cancer in a male human comprising administer 3100. In some embodiments, the second generation anti ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- androgen is 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N- methylbenzamide at a dose of about 30 mg per day to about methylbenzamide. 480 mg per day to a male human with metastatic castration 0257. In one aspect, described herein is a method of treat resistant prostate cancer, non-metastatic castration-resistant ing prostate cancer in a male human comprising administer prostate cancer, metastatic castration-sensitive prostate can ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- cer, non-metastatic castration-sensitive prostate cancer or thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- high-risk localized prostate cancer in combination with an methylbenzamide at a dose of about 30 mg per day to about anti-STEAP-1 antibody drug conjugate. 480 mg per day to a male human with metastatic castration 0266. In some embodiments, 4-7-(6-cyano-5-trifluorom resistant prostate cancer, or high-risk localized prostate can ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- cer in combination with a taxane or tubulin inhibitor. yl)-2-fluoro-N-methylbenzamide is administered in combi 0258. In some embodiments, 4-7-(6-cyano-5-trifluorom nation with an anti-STEAP-1 antibody drug conjugate. In ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri yl)-2-fluoro-N-methylbenzamide is administered in combi din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- nation with Docetaxel. In some embodiments, Docetaxel is fluoro-N-methylbenzamide is administered in combination administered by intravenous infusion at a dose of about 35 with RG7450 (DSTP3086S). mg/m to about 75 mg/m every 3 weeks. 0267 In some embodiments, the method of treating pros 0259. In some embodiments, 4-7-(6-cyano-5-trifluorom tate cancer further comprises administering a therapeutically ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- effective amount of a gonadotropin-releasing hormone ago yl)-2-fluoro-N-methylbenzamide is administered in combi nist or antagonist to the male human. nation with Cabazitaxel. In some embodiments, Cabazitaxel 0268. In some embodiments, 4-7-(6-cyano-5-trifluorom is administered by intravenous infusion at a dose of about 13 ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- mg/m to about 25 mg/m every 3 weeks. yl)-2-fluoro-N-methylbenzamide is administered orally at a 0260. In some embodiments, the method of treating pros dose of about 120 mg per day to about 240 mg per day. In tate cancer further comprises administering a therapeutically some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri effective amount of a gonadotropin-releasing hormone ago din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- nist or antagonist to the male human. fluoro-N-methylbenzamide is administered orally at a dose of 0261. In some embodiments, 4-7-(6-cyano-5-trifluorom about 240 mg per day. In some embodiments, 4-7-(6-cyano ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza yl)-2-fluoro-N-methylbenzamide is administered orally at a spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis dose of about 120 mg per day to about 240 mg per day. In tered orally in the form of a softgel capsule. some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri 0269 Combination with a HSP Inhibitor din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- 0270. The heat shock protein family is a critical regulator fluoro-N-methylbenzamide is administered orally at a dose of tumor cell growth and Survival via its regulation of client about 240 mg per day. In some embodiments, 4-7-(6-cyano protein function. These client proteins include oncoproteins 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza such as HER2 and Rafas well the androgen receptor (AR), all spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis of which are key drivers of prostate cancer growth and Sur tered orally in the form of a softgel capsule. vival. 0262 Combination with an Anti-STEAP-1 Antibody 0271 In some embodiments, combination therapy of a Drug Conjugate HSP90/HSP27 (OGX-427) inhibitor with a second genera 0263. An anti-STEAP1 antibody drug conjugate (ADC) tion anti-androgen results in inhibition of the AR signaling selectively delivers an anti-mitotic agent to prostate cells pathway at 2 distinct nodes and thus has potential to increase expressing STEAP1. This results in a tumor selective increase therapeutic outcomes across the spectrum of CRPC. in tumor cell apoptosis. 0272. In one aspect, described herein is a method of treat 0264. In one aspect, described herein is a method of treat ing prostate cancer in a male human comprising administer ing prostate cancer in a male human comprising administer ing a second generation anti-androgen to a male human with ing a second generation anti-androgen to a male human with metastatic castration-resistant prostate cancer, non-meta metastatic castration-resistant prostate cancer, non-meta static castration-resistant prostate cancer, metastatic castra static castration-resistant prostate cancer, metastatic castra tion-sensitive prostate cancer, non-metastatic castration-sen tion-sensitive prostate cancer, non-metastatic castration-sen sitive prostate cancer or high-risk localized prostate cancer in sitive prostate cancer or high-risk localized prostate cancer in combination with a heat shock protein 90 (HSP90) or heat combination with an anti-STEAP-1 antibody drug conjugate. shock protein 27 (HSP27) pathway modulator. In some In some embodiments, the second generation anti-androgen embodiments, the second generation anti-androgen is MDV is MDV3100 or 4-7-(6-cyano-5-trifluoromethylpyridin-3- 3100 or 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth methylbenzamide. In some embodiments, the second genera ylbenzamide. In some embodiments, the second generation tion anti-androgen is MDV-3100. In some embodiments, the anti-androgen is MDV-3100. In some embodiments, the sec second generation anti-androgen is 4-7-(6-cyano-5-trifluo ond generation anti-androgen is 4-7-(6-cyano-5-trifluorom US 2014/O 199236 A1 Jul. 17, 2014 ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- comprises the use of a selective estrogen receptor modulator yl)-2-fluoro-N-methylbenzamide. (SERM) (e.g. tamoxifen), aromatase inhibitor (e.g. anastro 0273. In one aspect, described herein is a method of treat Zole (Arimidex), letrozole (Femara) and exemestane (Aroma ing prostate cancer in a male human comprising administer sin)), or fulvestrant (Faslodex). In some embodiments, the at ing 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- least one additional treatment option comprises Surgery to thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- remove the ovaries or medications to stop the ovaries from methylbenzamide at a dose of about 30 mg per day to about making estrogen. In some embodiments, the at least one 480 mg per day to a male human with metastatic castration additional treatment option comprises the use of trastuzumab resistant prostate cancer, non-metastatic castration-resistant (Herceptin), lapatinib (Tykerb), or bevacizumab (Avastin). In prostate cancer, metastatic castration-sensitive prostate can Some embodiments, the at least one additional treatment cer, non-metastatic castration-sensitive prostate cancer or option comprises the use of bone-building drugs to prevent high-risk localized prostate cancer in combination with a heat breast cancer recurrence (e.g. Zoledronic acid (Reclast, shock protein 90 (HSP90) or heat shock protein 27 (HSP27) Zometa)). pathway modulator. 0281. In one aspect, disclosed herein is the use of 4-7-(6- 0274. In some embodiments, 4-7-(6-cyano-5-trifluorom cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide in the yl)-2-fluoro-N-methylbenzamide is administered in combi treatment of uterine fibroids in a human in combination with nation with OGX-011 (Custirsen), OGX-427, AUY922, at least one additional treatment option for the uterine HSP990, PF-04928473, PF-04929113 (SNX-5422), Retaspi fibroids. In some embodiments, the at least one additional mycin or AT13387. treatment option comprises the use of a gonadotropin-releas 0275. In some embodiments, 4-7-(6-cyano-5-trifluorom ing hormone (GnRH) agonist or antagonist, a progestin-re ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- leasing intrauterine device (IUD), an androgen, nonsteroidal yl)-2-fluoro-N-methylbenzamide is administered in combi anti-inflammatory drug (NSAIDs), a hysterectomy, or a myo nation with OGX-011 (Custirsen). In some embodiments, mectomy. OGX-011 (Custirsen) is administered by intravenous infu 0282. In one aspect, disclosed herein is the use of 4-7-(6- sion at a dose of about 320 mg to about 640 mg every week. cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- 0276. In some embodiments, 4-7-(6-cyano-5-trifluorom diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide in the ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- treatment of endometriosis in a human in combination with at yl)-2-fluoro-N-methylbenzamide is administered in combi least one additional treatment option for the endometriosis. In nation with OGX-427. In some embodiments, OGX-427 is Some embodiments, the at least one additional treatment administered by intravenous infusion at a loading dose of option comprises the use of pain medications, and/or hor about 300 mg to about 600 mg followed by about 500 mg to mone therapies. In some embodiments, hormone therapies about 1000 mg every week. comprise hormonal contraceptives, gonadotropin-releasing 0277. In some embodiments, the method of treating pros hormone (Gn-RH) agonists and antagonists, DanaZol. tate cancer further comprises administering a therapeutically medroxyprogesterone (Depo-Provera) and aromatase inhibi effective amount of a gonadotropin-releasing hormone ago tOrS. nist or antagonist to the male human. 0278. In some embodiments, 4-7-(6-cyano-5-trifluorom Kits/Articles of Manufacture ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 0283 For use in the therapeutic methods of use described yl)-2-fluoro-N-methylbenzamide is administered orally at a herein, kits and articles of manufacture are also described dose of about 120 mg per day to about 240 mg per day. In herein. Such kits include a package or container that is com some embodiments, 4-7-(6-cyano-5-trifluoromethylpyri partmentalized to receive one or more dosages of the phar din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- maceutical compositions disclosed herein. Suitable contain fluoro-N-methylbenzamide is administered orally at a dose of ers include, for example, bottles. In one embodiment, the about 240 mg per day. In some embodiments, 4-7-(6-cyano containers are formed from a variety of materials such as 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza glass or plastic. spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is adminis 0284. The articles of manufacture provided herein contain tered orally in the form of a softgel capsule. packaging materials. Packaging materials for use in packag (0279. Other Combination Strategies ing pharmaceutical products include, e.g., U.S. Pat. Nos. 0280. In one aspect, disclosed herein is the use of 4-7-(6- 5,323,907, 5,052,558 and 5,033,252. Examples of pharma cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- ceutical packaging materials include, but are not limited to, diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide in the blister packs, bottles, tubes, bags, containers, bottles, and any treatment of breast cancer in a human in combination with at packaging material Suitable for a selected formulation and least one additional treatment option for the breast cancer. In intended mode of administration and treatment. Some embodiments, the at least one additional treatment 0285. A kit typically includes labels listing contents and/ option comprises breast cancer Surgery. In some embodi or instructions for use, and package inserts with instructions ments, breast cancer Surgery comprises lumpectomy, mastec for use. A set of instructions will also typically be included. tomy, sentinel node biopsy, or axillary node dissection. In 0286. In one embodiment, a label is on or associated with Some embodiments, the at least one additional treatment the container. In one embodiment, a label is on a container option comprises radiation therapy. In some embodiments, when letters, numbers or other characters forming the label radiation comprises external beam radiation or brachy are attached, molded oretched into the container itself a label therapy. In some embodiments, the at least one additional is associated with a container when it is present within a treatment option comprises hormone therapy (i.e. hormone receptacle or carrier that also holds the container, e.g., as a blocking therapy). In some embodiments, hormone therapy package insert. In one embodiment, a label is used to indicate US 2014/O 199236 A1 Jul. 17, 2014 24 that the contents are to be used for a specific therapeutic embodiments, it can guide as to the minimal dose level that application. The label also indicates directions for use of the will result in a robustandrogen blockade by a second genera contents, such as in the methods described herein. tion anti-androgen (e.g. 4-7-(6-cyano-5-trifluoromethylpy 0287. In certain embodiments, the pharmaceutical com ridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- positions are presented in a pack or dispenser device which fluoro-N-methylbenzamide). contains one or more unit dosage forms containing a com 0291 Similar to CTCs, changes in PSA kinetics during pound provided herein. The pack, for example, contains treatment of prostate cancer may be a prognostic factor for metal or plastic foil. Such as a blister pack. In one embodi clinical benefit. Men with metastatic prostate cancer with ment, the pack or dispenser device is accompanied by instruc PSA levels of 4 ng/ml or less after 7 months on hormonal tions for administration. In one embodiment, the pack or therapy have been shown to have longer survival and 30% dispenser is also accompanied with a notice associated with PSA decline at 3 months of chemotherapy has been associ the container in form prescribed by a governmental agency ated with better survival. regulating the manufacture, use, or sale of pharmaceuticals, 0292. The following listing of embodiments in intended to which notice is reflective of approval by the agency of the complement, rather than displace or Supersede, the previous form of the drug for human or veterinary administration. Such descriptions. notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the Embodiment 1 approved product insert. In one embodiment, compositions 0293. A method of treating advanced prostate cancer in a containing a compound provided hereinformulated in a com male human comprising administering 4-7-(6-cyano-5-trif patible pharmaceutical carrier are also prepared, placed in an luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. appropriate container, and labeled for treatment of an indi 4 oct-5-yl)-2-fluoro-N-methylbenzamide (I), or a pharma cated condition. ceutically acceptable salt thereof, at a dose of about 30 mg per day to about 480 mg per day to a male human with castration Biomarkers sensitive prostate cancer, castration-resistant prostate cancer, 0288. In some embodiments, efficacy of treatment with a or high-risk localized prostate cancer. second generation anti-androgen (e.g. 4-7-(6-cyano-5-trif luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.

4 oct-5-yl)-2-fluoro-N-methylbenzamide) is assessed by (I) monitoring any one of the following: circulating tumor cells (CTCs); 18F-fluorodihydrotestosterone-positron emission tomography (FDHT-PET); PSA kinetics: AR target gene modulation in primary tumor (neoadjuvent/presurgical stud ies), tumor biopsies and in CTCs; Ki67, TUNEL and other markers of proliferation and apoptosis in primary tumor (neo adjuvent/presurgical studies), tumor biopsies and in CTCs; CH3 transmembrane protease, serine 2 (TMPRSS2)-v-ets erythro NH blastosis virus E26 oncogene homolog (ERG) fusion (TM PRSS2:ERG fusion); or any of the preceding in primary tumor upon radical prostatectomy or in CT-guided biopsies. 0289. In some embodiments, enumeration of circulating tumor cells (CTCs) themselves are a biomarker and maybe predictive of outcome. The number of CTC at baseline and Embodiment 2 change over time from unfavorable (>5 CTCs/7.5 ml of 0294 The method of Embodiment 1, wherein the castra blood) to favorable (<5 CTCs/7.5 ml of blood) has been tion-resistant prostate cancer is metastatic castration-resis shown to be correlated with statistically improved survival in tant prostate cancer. patient with metastatic CRPC. The number of CTCs at base line has also been associated with risk of death. The higher the Embodiment 3 number of CTCs at baseline correlates with higher risk of dying from prostate cancer. In some embodiments, using 0295. The method of Embodiment 2, wherein the meta CTC's to determine PTEN/PI3K, PHLPP1, or AR status, is static castration-resistant prostate cancer is chemotherapy used to stratify patients as well as an indication of outcome. In naive metastatic castration-resistant prostate cancer or post Some embodiments, interrogating CTCs for genetic alter abiraterone acetate treated metastatic castration-resistant ations is feasible. In some embodiments, assessing PTEN/ prostate cancer. PI3K and or AR status at baseline has the potential to person alize treatment plan for a patient with metastatic prostate Embodiment 4 cancer by designing a proper combination therapy (e.g. with 0296. A method of decreasing prostate-specific antigen PI3K inhibitor in patients with PTEN loss in the tumor) or levels in a male human with advanced prostate cancer com choosing other treatment for patients with AR alterations that prising administering 4-7-(6-cyano-5-trifluoromethylpyri render them unlikely to respond to the a second generation din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2- anti-androgen (e.g. 4-7-(6-cyano-5-trifluoromethylpyridin fluoro-N-methylbenzamide, or a pharmaceutically 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro acceptable salt thereof, at a dose of about 30 mg per day to N-methylbenzamide). about 480 mg per day to the male human with castration 0290 FDHT-PET has been shown to be a useful pharma sensitive prostate cancer, castration-resistant prostate cancer, codynamic biomarker for antiandrogen drugs. In some or high-risk localized prostate cancer. US 2014/O 199236 A1 Jul. 17, 2014

Embodiment 5 ylbenzamide, or a pharmaceutically acceptable salt thereof, is 0297. The method of Embodiment 4, wherein the prostate administered orally to the human on a continuous daily dos specific antigen levels in the male human are decreased by at ing schedule. least 50% from baseline after 3 months of administering 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- Embodiment 12 thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben 0304. A method of treating prostate cancer in a male Zamide, or a pharmaceutically acceptable salt thereof, on a human comprising administering 4-7-(6-cyano-5-trifluo continuous daily dosing schedule. romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti Embodiment 6 cally acceptable salt thereof, at a dose of about 30 mg per day 0298. A method of treating breast cancer, androgen depen to about 480 mg per day to a male human with post-abirater dent hirsutism, androgenic alopecia, uterine fibroids, lei one acetate treated metastatic castration-resistant prostate omyoma, endometrial carcinoma or endometriosis in a cancer, metastatic castration-resistant prostate cancer, non human comprising administering 4-7-(6-cyano-5-trifluo metastatic castration-resistant prostate cancer, metastatic cas romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 tration-sensitive prostate cancer, non-metastatic castration oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti sensitive prostate cancer or high-risk localized prostate cally acceptable salt thereof, at a dose of about 30 mg per day cancer in combination with a phosphoinositide 3-kinase to about 480 mg per day to a human with breast cancer, (PI3K) inhibitor, TORC inhibitor, or dual PI3K/TORC androgen dependent hirsutism, androgenic alopecia, uterine inhibitor. fibroids, leiomyoma, endometrial carcinoma or endometrio S1S. Embodiment 13

Embodiment 7 0305 The method of Embodiment 12, further comprising administering a therapeutically effective amount of a gona 0299. The method of any one of Embodiments 1 to 6, dotropin-releasing hormone agonist orantagonist to the male wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- human. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is Embodiment 14 administered orally to the human in the form of soft-gel capsules. 0306 The method of Embodiment 12 or Embodiment 13, wherein the phosphoinositide 3-kinase (PI3K) inhibitor, Embodiment 8 TORC inhibitor, or dual PI3K/TORC inhibitor is everolimus, 0300. The method of any one of Embodiments 1 to 7, BEZ-235, BKM120, BGT226, BYL-719, GDC0068, GDC wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- O980, GDCO941, GDC0032, MK-2206, OSI-027, CC-223, oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth AZD8055, SAR245408, SAR245409, PF0469 1502, ylbenzamide, or a pharmaceutically acceptable salt thereof, is WYE125132, GSK2126458, GSK-2636771, BAY306946, administered orally to the human in the form of soft-gel PF-05212384, SF1126, PX866, AMG319, ZSTK474, capsules at a dose of about 180 mg per day to about 480 mg Cal 101, PWT33597, LY-317615 (enzastaurin hydrochlo per day. ride), CU-906, or CUDC-907. Embodiment 9 Embodiment 15 0301 The method of any one of Embodiments 1 to 8, 0307 The method of any one of Embodiments 12 to 14, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally to the human in the form of soft-gel administered orally at a dose of about 120 mg per day to about capsules at a dose of about 180 mg per day, about 240 mg per 240 mg per day. day, about 300 mg per day, about 390 mg per day, or about 480 mg per day. Embodiment 16 Embodiment 10 (0308. The method of any one of Embodiments 12 to 15, 0302) The method of any one of Embodiments 1 to 8, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 240 mg per day. administered orally to the human in the form of soft-gel capsules at a dose of about 240 mg per day. Embodiment 17 (0309 The method of any one of Embodiments 12 to 16, Embodiment 11 wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0303. The method of any one of Embodiments 7 to 10, oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- ylbenzamide, or a pharmaceutically acceptable salt thereof, is oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth administered orally in the form of a softgel capsule. US 2014/O 199236 A1 Jul. 17, 2014 26

Embodiment 18 Embodiment 27 0310. The method of any one of Embodiments 12 to 17, 0319. The method of any one of Embodiment 21 to 26, wherein the TORC inhibitor is everolimus. wherein the CYP17 inhibitor is abiraterone acetate (Zytiga). Embodiment 19 Embodiment 28 0311. The method of Embodiment 18, wherein everolimus 0320. The method of Embodiment 27, wherein abirater is administered at a dose of about 5 mg per day to about 20 mg one acetate (Zytiga) is administered at a dose of about 500 mg per day. per day to about 1000 mg per day together with prednisone at a dose of about 5 mg twice per day. Embodiment 20 0312 The method of Embodiment 18, wherein everolimus Embodiment 29 is administered at a dose of about 5 mg per day or about 10 mg per day. 0321. The method of Embodiment 28, wherein abirater one acetate (Zytiga) is administered at a dose of about 1000 Embodiment 21 mg per day. 0313 A method of treating prostate cancer in a male Embodiment 30 human comprising administering 4-7-(6-cyano-5-trifluo romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 0322 The method of any one of Embodiment 21 to 26, oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti wherein the CYP17 inhibitor is TAK-700 (orteronel). cally acceptable salt thereof, at a dose of about 30 mg per day to about 480 mg per day to a male human with metastatic Embodiment 31 castration-resistant prostate cancer, non-metastatic castra tion-resistant prostate cancer, metastatic castration-sensitive 0323. The method of Embodiment 30, TAK-700 (orter prostate cancer, non-metastatic castration-sensitive prostate onel) is administered at a dose of about 300 mg twice per day cancer or high-risk localized prostate cancer in combination to about 600 mg twice per day. with a CYP17 inhibitor. Embodiment 32 Embodiment 22 0324. The method of Embodiment 30 or Embodiment 31, 0314. The method of Embodiment 21, further comprising where TAK-700 (orteronel) is administered at a dose of about administering a therapeutically effective amount of a gona 300 mg twice per day to about 600 mg twice per day, together dotropin-releasing hormone agonist orantagonist to the male with prednisone at about 5 mg twice per day human. Embodiment 33 Embodiment 23 0325 A method of treating prostate cancer in a male 0315. The method of Embodiment 21 or Embodiment 22, human comprising administering 4-7-(6-cyano-5-trifluo wherein the CYP17 inhibitor is abiraterone acetate (Zytiga), romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 TAK-700 (orteronel), TOK-001 (galeterone) or VT-464. oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti cally acceptable salt thereof, at a dose of about 30 mg per day Embodiment 24 to about 480 mg per day to a male human with metastatic 0316 The method of any one of Embodiments 21 to 23, castration-resistant prostate cancer, non-metastatic castra wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- tion-resistant prostate cancer, metastatic castration-sensitive oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth prostate cancer, non-metastatic castration-sensitive prostate ylbenzamide, or a pharmaceutically acceptable salt thereof, is cancer or high-risk localized prostate cancer in combination administered orally at a dose of about 120 mg per day to about with a gonadotropin-releasing hormone agonist or antago 240 mg per day. nist.

Embodiment 25 Embodiment 34 0317. The method of any one of Embodiments 21 to 24, 0326. The method of Embodiment 33, wherein the gona wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- dotropin-releasing hormone agonist or antagonist is Lupron, oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Zoladex (Goserelin), Degarelix, Ozarelix, ABT-620 ylbenzamide, or a pharmaceutically acceptable salt thereof, is (Elagolix), TAK-385 (Relugolix), EP-100 or KLH-2109. administered orally at a dose of about 240 mg per day. Embodiment 35 Embodiment 26 0327. The method of Embodiment 33 or Embodiment 34, 0318. The method of any one of Embodiments 21 to 25, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 120 mg per day to about administered orally in the form of a softgel capsule. 240 mg per day. US 2014/O 199236 A1 Jul. 17, 2014 27

Embodiment 36 Embodiment 45 0328. The method of any one of Embodiments 33 to 35, 0337 The method of Embodiment 44, further comprising wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- administering a therapeutically effective amount of a gona oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth dotropin-releasing hormone agonist orantagonist to the male ylbenzamide, or a pharmaceutically acceptable salt thereof, is human. administered orally at a dose of about 240 mg per day. Embodiment 46 Embodiment 37 0338. The method of Embodiment 44 or Embodiment 45, 0329. The method of any one of Embodiments 33 to 36, wherein the osteoprotective agent is Denosumab, AMG wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0007, CEP-37251, ALX-0141, Zoledronic acid, Alendronate oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Sodium (Fosamax), Pamidronate disodium (Aredia), ylbenzamide, or a pharmaceutically acceptable salt thereof, is Neridronic acid (Nerixia), Minodronic acid (Recalbon) or administered orally in the form of a softgel capsule. Risedronate sodium (Actonel). Embodiment 47 Embodiment 38 0339. The method of any one of Embodiments 44 to 46, 0330. The method of any one of Embodiments 33 to 37, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein the gonadotropin-releasing hormone agonist or oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth antagonist is Lupron. ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 120 mg per day to about Embodiment 39 240 mg per day. 0331. The method of Embodiment 38, wherein Lupron is administered as a depot injection at a dose of about 7.5 mg Embodiment 48 every 4 weeks, or 22.5 mg every 3 months, or about 30 mg 0340. The method of any one of Embodiments 44 to 47. every 4 months, or about 45 mg every 6 months. wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Embodiment 40 ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 240 mg per day. 0332 The method of any one of Embodiments 33 to 37, wherein the gonadotropin-releasing hormone agonist or Embodiment 49 antagonist is Zoladex (Goserelin). 0341 The method of any one of Embodiment 44 to 48, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- Embodiment 41 oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth 0333. The method of Embodiment 40, wherein Zoladex ylbenzamide, or a pharmaceutically acceptable salt thereof, is (Goserelin) is administered as a Subcutaneous implant at a administered orally in the form of a softgel capsule. dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 weeks. Embodiment 50 0342. The method of any one of Embodiment 44 to 49, Embodiment 42 wherein the osteoprotective agent is Denosumab. 0334) The method of any one of Embodiment 33 to 37, wherein the gonadotropin-releasing hormone agonist or Embodiment 51 antagonist is Degarelix. 0343. The method of Embodiment 50, wherein Denos umab is administered by Subcutaneous injection at a dose of Embodiment 43 about 60 mg to about 120 mg every 4 weeks to every 6 months. 0335. The method of Embodiment 42, wherein Degarelix is administered as a Subcutaneous injection at a dose of about Embodiment 52 240mg followed by about 80 mg administered every 4 weeks. 0344) The method of any one of Embodiment 44 to 49, Embodiment 44 wherein the osteoprotective agent is Zoledronic acid. 0336 A method of treating prostate cancer in a male Embodiment 53 human comprising administering 4-7-(6-cyano-5-trifluo romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 (0345. The method of Embodiment 52, wherein Zoledronic oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti acid is administered by intravenous infusionata dose of about cally acceptable salt thereof, at a dose of about 30 mg per day 4 mg every 4 weeks to every 12 weeks. to about 480 mg per day to a male human with metastatic castration-resistant prostate cancer, non-metastatic castra Embodiment 54 tion-resistant prostate cancer, metastatic castration-sensitive 0346 A method of treating prostate cancer in a male prostate cancer, non-metastatic castration-sensitive prostate human comprising administering 4-7-(6-cyano-5-trifluo cancer or high-risk localized prostate cancer in combination romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 with an osteoprotective agent. oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti US 2014/O 199236 A1 Jul. 17, 2014 28 cally acceptable salt thereof, at a dose of about 30 mg per day Embodiment 64 to about 480 mg per day to a male human with metastatic 0356. A method of treating prostate cancer in a male castration-resistant prostate cancer, non-metastatic castra human comprising administering 4-7-(6-cyano-5-trifluo tion-resistant prostate cancer, metastatic castration-sensitive romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 prostate cancer, non-metastatic castration-sensitive prostate oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti cancer or high-risk localized prostate cancer in combination cally acceptable salt thereof, at a dose of about 30 mg per day with a radiation therapy. to about 480 mg per day to a male human with post-abirater one acetate treated metastatic castration-resistant prostate Embodiment 55 cancer, metastatic castration-resistant prostate cancer, non 0347 The method of Embodiment 54, further comprising metastatic castration-resistant prostate cancer, metastatic cas administering a therapeutically effective amount of a gona tration-sensitive prostate cancer, non-metastatic castration dotropin-releasing hormone agonist orantagonist to the male sensitive prostate cancer or high-risk localized prostate human. cancer in combination with a kinase inhibitor.

Embodiment 56 Embodiment 65 0348. The method of Embodiment 54 or Embodiment 55, 0357 The method of Embodiment 64, further comprising wherein the radiation therapy is Alpharadin, ''Lu-J591, administering a therapeutically effective amount of a gona external beam radiation therapy (including Proton beam), or dotropin-releasing hormone agonist orantagonist to the male brachytherapy. human.

Embodiment 57 Embodiment 66 (0349 The method of any one of Embodiment 54 to 56, 0358. The method of any one of Embodiment 64 or wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- Embodiment 65, wherein 4-7-(6-cyano-5-trifluorometh oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5- ylbenzamide, or a pharmaceutically acceptable salt thereof, is yl)-2-fluoro-N-methylbenzamide, or a pharmaceutically administered orally at a dose of about 120 mg per day to about acceptable salt thereof, is administered orally at a dose of 240 mg per day. about 120 mg per day to about 240 mg per day. Embodiment 67 Embodiment 58 0359. The method of any one of Embodiments 64 to 66, 0350. The method of any one of Embodiment 54 to 57, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 240 mg per day. administered orally at a dose of about 240 mg per day. Embodiment 68 Embodiment 59 0360. The method of any one of Embodiments 64 to 67, 0351. The method of any one of Embodiment 54 to 58, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally in the form of a softgel capsule. administered orally in the form of a softgel capsule. Embodiment 69 Embodiment 60 0361. The method of any one of Embodiments 64 to 68, 0352. The method of any one of Embodiments 54 to 59, wherein the kinase inhibitor targets angiogenesis or bone wherein the radiation therapy is Alpharadin. metaStaSeS. Embodiment 61 Embodiment 70 0353. The method of claim 60, wherein Alpharadin is 0362. The method of any one of Embodiments 64 to 69, administered by intravenous infusion at a dose of about 25 to wherein the kinase inhibitor is a MET or VEGFR kinase about 50 kBq/kg every 4 weeks.\ inhibitor. Embodiment 62 Embodiment 71 0354) The method of any one of Embodiment 54 to 59, 0363. The method of Embodiment 70, wherein the kinase wherein the radiation therapy is ''Lu-J591. inhibitoris Cabozantinib (XL184), PF-2341066 (Crizotinib), ARQ-197 (Tivantinib), MK-2461, JNJ-38877605, Embodiment 63 MK-8033, INCB-28060, BMS-777607, AMG-208, LY-280.1653, EMD-1214063, EMD-1204831, AMG-337, 0355 The method of Embodiment 62, wherein '77Lu HMPL-504 (Volitinib), SAR-125844, LY2875358, J591 is administered by intravenous infusion at a dose of ABR-215050 (Tasquinimod), CHIR-258 (Dovitinib), EXEL about 30 mCi/m to about 70 mCi/m. 7647, OSI-930, BIBF-1120, BAY-73-4506 (Regorafenib), US 2014/O 199236 A1 Jul. 17, 2014 29

BMS-582664 (Brivanib), JNJ-26483327, AZD-2171 (Cedi Embodiment 83 ranib), Sorafenib, Aflibercept, Enzastaurin, AG-013736 0375. The method of Embodiment 82, wherein the kinase (Axitinib), OSI-632, or GSK-786.034 (Pazopanib). inhibitor is GDC0068, MK-2206, AT7867, GSK21 10183, GSK2141795, GSK690693, Vemurafenib (PLX4032/ Embodiment 72 RG7204), GSK21 18436, Dabrafenib (GSK208436), 0364 The method of any one of Embodiment 64 to 71, LGX818, RAF265, LY2780301, Dovitinib (TKI258), wherein the kinase inhibitor is Cabozantinib. BGJ398, AZD4547, PD-0332991 or LEE011.

Embodiment 73 Embodiment 84 0376. A method of treating prostate cancer in a male 0365. The method of Embodiment 72, wherein Cabozan human comprising administering 4-7-(6-cyano-5-trifluo tinib is administered orally at a dose of about 40 mg per day romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 to about 100 mg per day. oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti cally acceptable salt thereof, at a dose of about 30 mg per day Embodiment 74 to about 480 mg per day to a male human with metastatic 0366. The method of any one of Embodiment 64 to 69, castration-resistant prostate cancer, non-metastatic castra wherein the kinase inhibitor is an EGFR, MEK, or SRC tion-resistant prostate cancer, metastatic castration-sensitive kinase inhibitor. prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in combination Embodiment 75 with Provenge, Prostvac, Ipilimumab, or a PD-1 inhibitor. 0367 The method of Embodiment 74, wherein the kinase Embodiment 85 inhibitoris Erlotinib, Cetuximab, Gefitinib, Canertinib, Pani tumumab, Nimotuzumab, Lapatinib, Vandetanib, Afatinib, 0377 The method of Embodiment 84, further comprising MP-412, AEE-788, Neratinib, XL-647, AC-480, Dacomi administering a therapeutically effective amount of a gona tinib, AZD-8931, CUDC-101, AP-26113, CO-1686, Trame dotropin-releasing hormone agonist orantagonist to the male tinib, Selumetinib, MEK-162, Refametinib, TAK-733, human. RO-5 126766, BI-847325, AZD6244, GSK1 120212, PF-5208763 (Bosutinib), or AZD-0530 (Saracatinib). Embodiment 86 0378. The method of any one of Embodiment 84 or Embodiment 76 Embodiment 85, wherein 4-7-(6-cyano-5-trifluorometh ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5- 0368. The methodofany one of Embodiments 64 to 69,74 yl)-2-fluoro-N-methylbenzamide, or a pharmaceutically or 75, wherein the kinase inhibitor is Erlotinib. acceptable salt thereof, is administered orally at a dose of about 120 mg per day to about 240 mg per day. Embodiment 77 0369. The method of Embodiment 76, wherein Erlotinib is Embodiment 87 administered orally at a dose of about 100 mg to about 150 0379 The method of any one of Embodiment 84 to 86, ng. wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Embodiment 78 ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 240 mg per day. 0370. The methodofany one of Embodiments 64 to 69,74 or 75, wherein the kinase inhibitor is Gefitinib. Embodiment 88 Embodiment 79 (0380. The method of any one of Embodiment 84 to 87, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0371. The method of Embodiment 78, wherein Gefitinib is oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth administered orally at a dose of about 250 mg. ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally in the form of a softgel capsule. Embodiment 80 Embodiment 89 0372. The methodofany one of Embodiments 64 to 69,74 or 75, wherein the kinase inhibitor is Trametinib. (0381. The method of any one of Embodiment 84 to 88, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- Embodiment 81 oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is 0373 The method of Embodiment 80, wherein Trametinib administered in combination with Ipilimumab. is administered orally at a dose of about 1 mg to about 2 mg. Embodiment 90 Embodiment 82 (0382. The method of Embodiment 89, wherein Ipili 0374. The method of any one of Embodiment 64 to 69, mumab is administered by intravenous infusion at a dose of wherein the kinase inhibitor is an AKT, RAF, FGFR, or about 1.5 mg/Kg to about 3.0 mg/kg IV every 3 weeks for a CDK476 kinase inhibitor. total of 4 doses. US 2014/O 199236 A1 Jul. 17, 2014 30

Embodiment 91 Embodiment 100 0383. The method of any one of Embodiment 84 to 88, 0392 The method of any one of Embodiments 97 to 99, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered in combination with a PD-1 inhibitor. administered orally at a dose of about 240 mg per day. Embodiment 92 Embodiment 101 0384. The method of Embodiment 91, wherein the PD-1 0393. The method of any one of Embodiments 97 to 100, inhibitor is BMS-93.6558 and is administered by intravenous wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- infusion at a dose of about 1.0 mg/kg to about 10 mg/kg on oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth days 1, 15 and 29 of 6-week cycles. ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered orally in the form of a softgel capsule. Embodiment 93 Embodiment 102 0385. The method of any one of Embodiment 84 to 88, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0394. The method of any one of Embodiment 97 to 101, oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- ylbenzamide, or a pharmaceutically acceptable salt thereof, is oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth administered in combination with Provenge. ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered in combination with Docetaxel. Embodiment 94 Embodiment 103 0386 The method of Embodiment 93, wherein 3 doses of Provenge are administered doses at approximately 2 weeks 0395. The method of Embodiment 102, wherein Doc interval. etaxel is administered by intravenous infusion at a dose of about 35 mg/m to about 75 mg/m every 3 weeks. Embodiment 95 Embodiment 104 (0387. The method of any one of Embodiment 84 to 88, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0396 The method of any one of Embodiments 97 to 101, oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- ylbenzamide, or a pharmaceutically acceptable salt thereof, is oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth administered in combination with Prostvac. ylbenzamide, or a pharmaceutically acceptable salt thereof, is administered in combination with Cabazitaxel Embodiment 96 Embodiment 105 0388. The method of Embodiment 95, wherein Prostvac is administered by Subcutaneous injection. 0397. The method of claim 104, wherein Cabazitaxel is administered by intravenous infusion at a dose of about 13 Embodiment 97 mg/m to about 25 mg/m every 3 weeks. 0389. A method of treating prostate cancer in a male human comprising administering 4-7-(6-cyano-5-trifluo Embodiment 106 romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 0398. A method of treating prostate cancer in a male oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti human comprising administering 4-7-(6-cyano-5-trifluo cally acceptable salt thereof, at a dose of about 30 mg per day romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 to about 480 mg per day to a male human with metastatic oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti castration-resistant prostate cancer, or high-risk localized cally acceptable salt thereof, at a dose of about 30 mg per day prostate cancer in combination with a taxane or tubulin to about 480 mg per day to a male human with metastatic inhibitor. castration-resistant prostate cancer, non-metastatic castra tion-resistant prostate cancer, metastatic castration-sensitive Embodiment 98 prostate cancer, non-metastatic castration-sensitive prostate 0390 The method of Embodiment 97, further comprising cancer or high-risk localized prostate cancer in combination administering a therapeutically effective amount of a gona with an anti-STEAP-1 antibody drug conjugate. dotropin-releasing hormone agonist orantagonist to the male Embodiment 107 human. 0399. The method of Embodiment 106, further compris Embodiment 99 ing administering a therapeutically effective amount of a gonadotropin-releasing hormone agonist or antagonist to the 0391 The method of any one of Embodiment 97 or Embodiment 98, wherein 4-7-(6-cyano-5-trifluorometh male human. ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- yl)-2-fluoro-N-methylbenzamide, or a pharmaceutically Embodiment 108 acceptable salt thereof, is administered orally at a dose of 0400. The method of Embodiment 106 or Embodiment about 120 mg per day to about 240 mg per day. 107, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- US 2014/O 199236 A1 Jul. 17, 2014

8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- Embodiment 116 methylbenzamide, or a pharmaceutically acceptable salt (0408. The method of any one of Embodiment 113 to 115, thereof, is administered orally at a dose of about 120 mg per wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- day to about 240 mg per day. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is Embodiment 109 administered orally at a dose of about 240 mg per day. 04.01. The method of any one of Embodiments 106 to 108, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- Embodiment 117 oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth 04.09. The method of any one of Embodiments 113 to 116, ylbenzamide, or a pharmaceutically acceptable salt thereof, is wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- administered orally at a dose of about 240 mg per day. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is Embodiment 110 administered orally in the form of a softgel capsule. 0402. The method of any one of Embodiment 106 to 109, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- Embodiment 118 oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth 0410. The method of any one of Embodiment 113 to 117, ylbenzamide, or a pharmaceutically acceptable salt thereof, is wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- administered orally in the form of a softgel capsule. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is Embodiment 111 administered in combination with OGX-011 (Custirsen), 0403. The method of any one of Embodiments 106 to 110, OGX-427, AUY922, HSP990, PF-04928473, PF-04929113 wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- (SNX-5422), Retaspimycin or AT13387. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ylbenzamide, or a pharmaceutically acceptable salt thereof, is Embodiment 119 administered in combination with an anti-STEAP-1 antibody 0411. The method of any one of Embodiment 113 to 118, drug conjugate. wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Embodiment 112 ylbenzamide, or a pharmaceutically acceptable salt thereof, is 04.04 The method of any one of Embodiment 106 to 111, administered in combination with OGX-011 (Custirsen). wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Embodiment 120 ylbenzamide, or a pharmaceutically acceptable salt thereof, is 0412. The method of Embodiment 119, wherein OGX administered in combination with RG 7450 (DSTP3086S). 011 (Custirsen) is administered by intravenous infusion at a dose of about 320 mg to about 640 mg every week. Embodiment 113 Embodiment 121 0405. A method of treating prostate cancer in a male human comprising administering 4-7-(6-cyano-5-trifluo 0413. The method of any one of Embodiment 113 to 118, romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceuti oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth cally acceptable salt thereof, at a dose of about 30 mg per day ylbenzamide, or a pharmaceutically acceptable salt thereof, is to about 480 mg per day to a male human with metastatic administered in combination with OGX-427. castration-resistant prostate cancer, non-metastatic castra tion-resistant prostate cancer, metastatic castration-sensitive Embodiment 122 prostate cancer, non-metastatic castration-sensitive prostate 0414. The method of Embodiment 121, wherein OGX cancer or high-risk localized prostate cancer in combination 427 is administered by intravenous infusion at a loading dose with a HSP90 or HSP27 pathway modulator. of about 300 mg to about 600 mg followed by about 500 mg to about 1000 mg every week. Embodiment 114 0406. The method of Embodiment 113, further compris Embodiment 123 ing administering a therapeutically effective amount of a 0415. A pharmaceutical composition comprising a non gonadotropin-releasing hormone agonist or antagonist to the aqueous, lipid-based solution of 4-7-(6-cyano-5-trifluorom male human. ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- yl)-2-fluoro-N-methylbenzamide, or a pharmaceutically Embodiment 115 acceptable salt thereof, in a softgel capsule. 0407. The method of Embodiment 113 or Embodiment 114, wherein 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- Embodiment 124 8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- 0416) The pharmaceutical composition of Embodiment methylbenzamide, or a pharmaceutically acceptable salt 123, wherein the nonaqueous, lipid-based solution of 4-7- thereof, is administered orally at a dose of about 120 mg per (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, day to about 240 mg per day. 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide, or US 2014/O 199236 A1 Jul. 17, 2014 32 a pharmaceutically acceptable salt thereof, comprises: 4-7- 0422. In some embodiments, the lipid-based solution is (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, placed into oral hard gelatin capsules. 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide, or a pharmaceutically acceptable salt thereof. Vitamin E d-C.- Example 2 tocopheryl polyethylene glycol 1000 succinate NF (Vitamin ETPGS), polyethylene glycol 400 NF/EP (PEG 400), glyc Softgel Capsule Formulation erol monocaprylocaprate EP and caprylocaproyl macroglyc erides EP/NF. 0423 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth Embodiment 125 ylbenzamide is formulated as a nonaqueous, lipid-based solu tion that is filled into size 18 oblong softgel capsules for oral 0417. The pharmaceutical composition of Embodiment administration. The fill solution is composed of 4-7-(6-cy 123 or Embodiment 124, wherein the nonaqueous, lipid ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia based solution of 4-7-(6-cyano-5-trifluoromethylpyridin-3- Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide in vita yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- min Ed-C.-tocopheryl polyethylene glycol 1000 succinate NF methylbenzamide, or a pharmaceutically acceptable salt (Vitamin E TPGS), polyethylene glycol 400 NF/EP (PEG thereof, comprises about 3% of 4-7-(6-cyano-5-trifluorom 400), glycerol monocaprylocaprate EP (Capmul MCM), and ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- caprylocaproyl macroglycerides EP/NF (Acconon MCs). yl)-2-fluoro-N-methylbenzamide, or a pharmaceutically The softgel capsule shell, contains gelatin NF/EP, a 50:50 acceptable salt thereof. sorbitol/glycerin blend USP/EP, and purified water USP/EP. The softgel capsules (where each capsule includes 30 mg of Embodiment 126 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- 0418. The pharmaceutical composition of any one of thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben Embodiment 123 to 125, wherein the softgel capsule shell Zamide) are packaged in 30-ct, 100 cc HDPE bottles with comprises gelatin NF/EP, a 50:50 sorbitol/glycerin blend child-resistant closures and tamper proof heat induction USP/EP, and purified water USP/EP. seals. Embodiment 127 TABLE 2 0419. The pharmaceutical composition of any one of Softgel Capsule Formulation Embodiment 123 to 126, wherein a single unit dosage com Amount per Unit wiw prises about 30 mg of 4-7-(6-cyano-5-trifluoromethylpyri Component (mg Capsule) (%) din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- 4-7-(6-cyano-5-trifluoromethylpyridin- 30.00 3.00 fluoro-N-methylbenzamide, or a pharmaceutically 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct acceptable salt thereof. 5-yl)-2-fluoro-N-methylbenzamide PEG 400 291.OO 29.10 Capmul MCM 436.50 43.65 EXAMPLES Acconon MC8-2 97.00 9.70 Vitamin ETPGS 144.50 14.SS 0420. These examples are provided for illustrative pur Softgel Capsule Shell Size 18 Oblong NA poses only and not to limit the scope of the claims provided Softgel Capsules herein. Total Fill Formulation Weight 1OOO.OO 1OOOO Example 1 Anhydrous Lipid-Based Formulation Manufacturing Process for Softgel Capsule: 0421. In one embodiment, an anhydrous lipid-based for 0424 Fill Formulation Manufacturing mulation of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- 0425 Polyethylene glycol 400 NF/EP (PEG 400) and oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth caprylocaproyl macroglycerides EP/NF (Acconon MCs) ylbenzamide is prepared with the following list of are transferred under vacuum to a preheated (30°C.) 30 L ingredients: Becomix mixer and homogenizer. The mixture is warmed to 35° C. under vacuum with agitation and homogenization. TABLE 1. Vitamin E d-C-tocopheryl polyethylene glycol 1000 succi nate NF (vitamin E TPGS) is warmed to 35-45° C. in a Anhydrous Lipid-Based Formulation stainless steel vessel then transferred under vacuum to the L Final Becomix. The mixture is agitated and homogenized under Ingredient Concentration vacuum at 35° C. for NLT 15 minutes. 4-7-(6-Cyano-5- 4-7-(6-cyano-5-trifluoromethylpyridin- 3-30 mg/mL trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and one third of 5-yl)-2-fluoro-N-methylbenzamide the total quantity of glycerol monocaprylocaprate EP (Cap Capmul MCM 45% Wiw mul MCM) are transferred to a nitrogen purged glove bag. PEG-400 30% wiw Vit E-TPGS 15% Wiw 4-7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- Acconon MC8-2 10% Wiw thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben Zamide is transferred to a stainless steel beaker and wetted with Capmul MCM (aliquot 1) to afford a suspension. The US 2014/O 199236 A1 Jul. 17, 2014

mixture is homogenized for no less than 15 minutes to afford Example 3 a fine Suspension with no aggregates. The Suspension is removed from the glove bag then transferred under vacuum to MDA MB 453: Breast Cancer Xenograft Assay the 30 L. Becomix. The 4-7-(6-cyano-5-trifluoromethylpyri 0430 Time release pellets (12.5 mg 5C.-Dihydrotestoster din-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro3.4 oct-5-yl)-2- one/60 days) were subcutaneously implanted into female fluoro-N-methylbenzamide and Capmul MCM stainless ves SCID Hairless Outbred (SHO) mice. MDA MB 453 cells sel is rinsed with the second one third portion of Capmul were grown in RPMI containing 10% FBS, 10 g/ml insulin, MCM (aliquot 2) then transferred under vacuum to the 30 L 10 mM Sodium Pyruvate, 10 mM Non-Essential Amino Becomix. This process is repeated with the final one third Acids at 5% CO., 37° C. Cells were spun down and re portion of Capmul MCM (aliquot3). The mixture is agitated suspended in 50% RPMI (serum free) and 50% Matrigel (BD, and homogenized under vacuum at 35°C. for no less than 60 high concentration containing phenol red) at 1x107 cells/ml. minutes. Once a clear Solution is obtained, the homogenizer is MDA MB 453 cells were subcutaneously injected (100 turned off and the solution is deaerated under vacuum with ul/animal) on the right flank 2-3 days postpellet implantation. agitation at 35° C. for NLT 60 minutes. The solution is then Tumor volume (lengthxwidth/2) was monitored bi-weekly. filtered through a 75 mm stainless steel in-line filter and When tumors reached an average volume of ~350 mm, ani transferred to a suitable in-process storage container. The mals were randomized and treatment was started. Animals final 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- were treated with vehicle or 4-7-(6-cyano-5-trifluorometh thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5- Zamide fill solution is weighed and reconciled. yl)-2-fluoro-N-methylbenzamide daily for 28 days. Tumor volume and body weight were monitored bi-weekly through 0426 Softgel Capsule Encapsulation out the study. At the conclusion of the treatment period; 0427. The 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- plasma and tumor samples were taken for pharmacokinetic 8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- and pharmacodynamic analyses, respectively. methylbenzamide fill solution and softgel mass (Gelatin) are transferred to the softgel encapsulation machine. The softgel TABLE 3 mass is cast into two ribbons while lubricating. The lubricated Breast Cancer Xenograft Assay Results softgel ribbons are passed between the rotating dies and the 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- Number of Tumor thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben Compound Regressions Zamide fill solution is fed by gravity to the encapsulation Vehicle (+5C-Dihydrotestosterone (DHT)) 1.8 Vehicle (-DHT) 3.8 pump under nitrogen gas NF. The pump operates by positive 4-7-(6-cyano-5-trifluoromethylpyridin- 5/10 displacement and delivers the target fill weight through a 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct heated (30°C.) filling wedge between rotating dies resulting 5-yl)-2-fluoro-N-methylbenzamide 30 mg/kg/day (-DHT) in the expansion of the gel ribbons to form the size 18, oblong 4-7-(6-cyano-5-trifluoromethylpyridin- 9.9 softgel capsules. The dies form seals and cut capsules out 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct from the ribbons in a continuous, hermetically sealed process. 5-yl)-2-fluoro-N-methylbenzamide 30 mg/kg/day Following the encapsulation, the 4-7-(6-cyano-5-trifluo (+DHT) romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide softgel capsules are air-dried in a tumble drier then transferred to shallow drying Example 4 trays. The softgel capsules are spread into single layers in the drying trays and dried in environmentally controlled drying Hirsutism Model tunnels. After drying, the softgel capsules are transferred to deep holding trays. The softgel capsules are processed 0431) Approximately 11 weeks old female Syrian Golden through a finishing process to remove the Surface lubricant Hamsters Lak: LVG (SYR) (Outbred) are purchased. On used in the encapsulation and to help reduce size variability in each of 5 successive days, the dorsal hair on and around the the finished product prior to manually packing into a bulk flank organs often animals is clipped with electric clippers, storage carton containing two polyethylene liners. The Soft and the stubble is removed with Surgex Hair Remover Cream. gel capsules are weighed, reconciled and stored under refrig The hamsters are under ether anesthesia during this proce erated conditions (2-8 C.) until clinical packaging is per dure, as well as during Subsequent treatments. Each group of formed. ten hamsters receive one of the following doses of testoster one propionate (TP) per animal in 0.05 ml of peanut oil 0428 Softgel Capsule Packaging injected Subcutaneously in the dorsal neck or Scapular region: 0429. The 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)- 400 ug. 135ug, 45ug. 15ug, Oug. Injections are given daily, 8-oxo-6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N- except weekends, for 3 weeks. The hamsters are terminated methylbenzamide softgel capsules are packaged in 30-count, on the 22" day after the initial treatment day by carbon 100 cc HDPE bottles with a child-resistance closure (CRC). dioxide inhalation. All of the pelage hair within 1 cm of the An appropriate torque is applied to seal each bottle, the induc regrown flank organ hair is cut as close to the skin as possible tion seal is activated and the closure retorqued to achieve an with fine scissors. The TP-stimulated flank organ hair, distin immediate removal range of 10-16 inch-pounds. The bottle guished by its coarseness and pigmentation from the pelage label is applied to the filled, sealed bottles. The bottles are hair, is then plucked with wax. The hair is recovered by reconciled, inspected and stored under refrigerated condi dissolving the wax in Xylene and trapping the hair on humid tions 2°C.-8°C. (36° F-46°F). ity-equilibrated, tarred, glass fibre filters. After the hairs have US 2014/O 199236 A1 Jul. 17, 2014 34 been washed free of wax and the residual xylene has been 0434 Purpose: The purposes of this study is to assess the evaporated, the hairs and filters are again humidity-equili efficacy of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- brated and weighed. Hamsters used to determine the effect of oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth topical 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo ylbenzamide as single agent or in combination, as first- or 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl second-line treatment of breast cancer in which AR could be benzamide on flank organ hair growth in TP-Stimulated ani the driver of tumor growth, collect information on any side mals are 12 weeks old at the start of the experiment. These effects the compound may cause as single agent or in combi hamsters are stimulated with a subcutaneous injection of 200 nation, and evaluate the pharmacokinetic properties of the ug of TP daily, for approximately 3 weeks, a dose estimated compound as single agent or in combination. by probit analysis to produce at least a doubling of the flank 0435 Intervention: Patients are administered up to 480 mg organ hair mass in the test animals. Immediately following of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- injection, each hamster receives a topical treatment of 4-7- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben (6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5, Zamide per day as single agent or in combination. 7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide in a 0436 Outcome Measures: Primary Outcome Measures: carrier Such as acetone on one flank organ and control (i.e. tumor response and/or disease control. acetone only) on the contralateral flank organ. The control 0437. Secondary Outcome Measures: (a) side-effects; (b) group received no TP and the acetone vehicle only. The hair pharmacokinetic properties; (c) time to progression and over from the treatment and control groups is recovered as all survival; and (d) biomarkers predictive of clinical described above and weighed. response. 0438. Detailed Description: Patients will be given 4-7-(6- Example 5 cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide, Uterine Leiomyoma Studies orally once a day as single agent or in combination. Prior to each dosing cycle, a physical exam, blood work and assess 0432 Healthy female Eker rats at 12 months of age are ment of any side effects will be performed. Every 8-12 weeks randomized into study article and vehicle groups to study the the patients cancer will be re-evaluated with either a CT scan effect of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- or MRI to determine whether the treatment is working Par oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth ticipation in this study will last until disease progression or ylbenzamide on uterine leiomyoma. In the 4-7-(6-cyano-5- unacceptable toxicity. trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 0439 Eligibility: Female subjects that are 18 years and 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide treatment older. group, 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo 0440 Inclusion Criteria: Histologically or cytologically 6-thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methyl confirmed diagnosis of invasive breast cancer, stage 1 V dis benzamide is dosed daily in twelve-month-old and 10 four ease; at least one measurable target lesion as defined by teen-month-old ratS. 4-7-(6-Cyano-5- RECIST that has not been previously treated with local trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro therapy; post-menopausal status; AR positive breast cancer, 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide treated animals HER2-negative breast cancer or HER2-positive breast cancer are individually tracked using nonsurgically inserted Subcu (following treatment with HER-2 targeting agent(s)); up to taneous transponders. Statistical analysis of tumor incidence one prior hormonal therapy for advanced or metastatic dis data is performed using chi-square analysis and the compari ease, ECOG performance status 0-1; life expectancy >12 Son of tumor size between groups is performed by a contin weeks; adequate liver and bone marrow function: AST<2.5x gency table analysis using Fisher exact method. Two hours ULN; Bilirubin <1.5xULN; ANC >1.500/u1; platelet count before sacrifice, rats from each group are injected with >100,000/ul; normal PT and PTT; at least 2 weeks since prior 5'-bromo-2'-deoxyuridine (BrdU) at 100 mg/kg. Animals are radiation and recovered from treatment-related toxicity. euthanized by CO (g) and examined for grossly observable 0441. Exclusion Criteria: Prior chemotherapy regimen for tumors of the reproductive tract. Vaginas, ovaries, and uteri metastatic disease; history of, or presence of brain are fixed in 10%, neutral-buffered formalin (NBF). Measure metastases; concurrent investigational drug treatment; his ments of grossly observable uterine tumors are taken and tory of other malignancy within the last 5 years, not including sections of tumors fixed in 10%, NBF. Portions from tumors curatively-treated carcinoma in situ of the cervix or non of Sufficient size are quick-frozen in liquid nitrogen. Tissues melanoma skin cancer, uncontrolled infection; active bleed remain in 10%, NBF for 48 hours and are paraffin embedded ing, or history of bleeding requiring transfusion; active car by routine methods. All samples are sectioned and stained with hematoxylin and eosin. Microscopic lesions of the uteri diac disease; serious medical or psychiatric illness. are recorded and all tumors are classified based on their Example 7 morphology Histologic slides are coded and read by two independent pathologists. Endometrial Carcinoma Clinical Trial Example 6 0442. A non-limiting example of an endometrial carci noma clinical trial in humans involving the use of 4-7-(6- cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- Breast Cancer Clinical Trial diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is 0433) A non-limiting example of a breast cancer clinical described below. trial in humans involving the use of 4-7-(6-cyano-5-trifluo 0443) Purpose: The purposes of this study is to assess the romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 efficacy of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- oct-5-yl)-2-fluoro-N-methylbenzamide is described below. oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth US 2014/O 199236 A1 Jul. 17, 2014 ylbenzamide as single agent or in combination in the treat thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben ment of advanced or metastatic endometrial carcinoma, Zamide per day as single agent or in combination. collect information on any side effects the compound as 0453. Outcome Measures: The outcome measures of this single agent or in combination may cause, and evaluate the study are symptoms improvement and/or pain relief, amount pharmacokinetic properties of the compound as single agent of menstrual blood loss, and shrinkage of endometrial tissue. or in combination. 0454. Detailed Description: Patients will be given 4-7-(6- 0444 Intervention: Patients are administered up to 480 mg cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben orally once or twice a day as single agent or in combination. Zamide per day as single agent or in combination. Prior to each dosing cycle, a physical exam, blood work and 0445 Outcome Measures: Primary Outcome Measures: assessment of any side effects will be performed. tumor response and/or disease control Secondary Outcome 0455 Eligibility: Female subjects that are 18 years and Measures: (a) side-effects; (b) pharmacokinetic properties; older. (c) time to progression and overall Survival; and (d) biomar 0456 Inclusion Criteria: Diagnosis of symptomatic kers predictive of clinical response. endometriosis; pre- or peri-menopausal status; ECOG perfor 0446 Detailed Description: Patients will be given 4-7-(6- mance status 0-1; adequate liver and bone marrow function: cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- AST-2.5xULN; Bilirubin < 1.5xULN; ANCD1,500/u1; diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide platelet count >100,000/u1; normal PT and PTT at least 2 orally once a day as single agent or in combination. Prior to weeks since prior Surgery or treatment-related toxicity. each dosing cycle, a physical exam, blood work and assess 0457. Exclusion Criteria: Pregnancy or lactating; history ment of any side effects will be performed. Every 8-12 weeks of other malignancy within the last 5 years, not including the patients cancer will be re-evaluated with either a CT scan curatively-treated carcinoma in situ of the cervix or non or MRI to determine whether the treatment is working Par melanoma skin cancer, concurrent investigational drug treat ticipation in this study will last until disease progression or ment; uncontrolled infection; active cardiac disease; aerious unacceptable toxicity. medical or psychiatric illness. 0447 Eligibility: Female subjects that are 18 years and older. Example 9 0448. Inclusion Criteria: Histologically or cytologically confirmed diagnosis of advanced or metastatic endometrial Uterine Leiomyoma Clinical Trial carcinoma; at least one measurable target lesion as defined by 0458. A non-limiting example of an uterine leiomyoma RECIST that has not been previously treated with local clinical trial in humans involving the use of 4-7-(6-cyano-5- therapy; hormone receptor positive endometrial carcinoma; trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro ECOG performance status 0-1; life expectancy >12 weeks: 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide is described adequate liver and bone marrow function: AST<2.5xULN; below. Bilirubin <1.5xULN: ANC>1,500/u1; platelet count >100, 0459 Purpose: The purposes of this study is to assess the 000/u1; normal PT and PTT; at least 2 weeks since prior efficacy of 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8- radiation and recovered from prior Surgery or treatment-re oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5-yl)-2-fluoro-N-meth lated toxicity. ylbenzamide as single agent or in combination in the treat 0449 Exclusion Criteria: History of, or presence of brain ment of patients with symptomatic uterine leiomyoma, metastases; concurrent investigational drug treatment; his collect information on any side effects the compound may tory of other malignancy within the last 5 years, not including cause as single agent or in combination, and evaluate the curatively-treated carcinoma in situ of the cervix or non pharmacokinetic properties of the compound as single agent melanoma skin cancer, uncontrolled infection; active bleed or in combination. ing, or history of bleeding requiring transfusion; active car 0460 Intervention: Patients are administered 480 mg of diac disease; serious medical or psychiatric illness. 4-7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylben Example 8 Zamide per day as single agent or in combination. 0461 Outcome Measures: The outcome measures of this Endometriosis Clinical Trial study are symptoms improvement and/or pain relief and 0450 A non-limiting example of an endometriosis clinical shrinkage of leiomyomas. trial in humans involving the use of 4-7-(6-cyano-5-trifluo 0462 Detailed Description: Patients will be given 4-7-(6- romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- oct-5-yl)-2-fluoro-N-methylbenzamide is described below. diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide 0451 Purpose: The purposes of this study is to assess the orally once or twice a day as single agent or in combination. efficacy of a compound of 4-7-(6-cyano-5-trifluorometh Prior to each dosing cycle, a physical exam, blood work and ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- assessment of any side effects will be performed. yl)-2-fluoro-N-methylbenzamide as single agent or in com 0463 Eligibility: Female subjects that are 18 years and bination in the treatment of patients with symptomatic/severe older. endometriosis, collect information on any side effects the 0464) Inclusion Criteria: Diagnosis of symptomatic uter compound may cause as single agent or in combination, and ine leiomyoma; pre- or peri-menopausal status, ECOG per evaluate the pharmacokinetic properties of the compound as formance status 0-1; adequate liver and bone marrow func single agent or in combination. tion: AST-2.5xULN; Bilirubin < 1.5xULN; ANCD1,500/u1; 0452 Intervention: Patients are administered up to 480 mg platelet count >100,000/u1; normal PT and PTT at least 2 of 4-7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- weeks since prior Surgery or treatment-related toxicity. US 2014/O 199236 A1 Jul. 17, 2014 36

0465 Exclusion Criteria: Pregnancy or lactating; history TABLE 5 of other malignancy within the last 5 years, not including curatively-treated carcinoma in situ of the cervix or non Combination with a TORC inhibitor melanoma skin cancer, concurrent investigational drug treat Number ment; uncontrolled infection; active cardiac disease; serious Compound of regres medical or psychiatric illness. Compound 1 2 Sions >50% 4-7-(6-cyano-5-trifluoromethylpyridin- 1,10 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct Example 10 5-yl)-2-fluoro-N-methylbenzamide 3 mg/kg/day Everolimus 5 mg/kg/day Of8 LNCaP/AR Model for Castrate Resistant Prostate Everolimus 10 mg/kg/day 2.10 Cancer Xenograft Studies in Combination Therapy 4-7-(6-cyano-5-trifluoromethylpyridin- Everolimus 49 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct- 5 mg/kg 5-yl)-2-fluoro-N-methylbenzamide day 0466 Six to Seven week old male SCID Hairless Outbred 3 mg/kg/day mice (SHO, Charles Rivers Laboratories) underwent bilateral 4-7-(6-cyano-5-trifluoromethylpyridin- Everolimus 6.10 orchiectomy under isoflurane anesthesia. LNCaP/AR cells 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct- 10 mg/kg/ were grown in RPMI at 5% CO,37° C. Cells were spun down 5-yl)-2-fluoro-N-methylbenzamide day and re-suspended in 50% serum-free RPMI and 50% Matri 3 mg/kg/day gel at 1x10" cells/ml. LNCaP/AR cells were subcutaneously injected (100 ul/animal) on the right flank 3-5 days post castration. Tumor volume (lengthxwidth/2) was monitored Example 11 weekly. When tumors reached an average volume of ~200 mm animals were randomized into treatment groups. During PTEN KO Model of Prostate Cancer the treatment period tumor volume was monitored bi-weekly. 0469 Ptenlox/lox; PB-Cre mice (age 6-8 months) are At the termination of the study, tumors were collected and imaged by Small animal MRI imaging core prior to and at the stored for further analyses. All compounds were administered completion of treatment. All mice are castrated. Surgical daily by oral gavage. Statistical analyses were performed castration is performed under anesthesia with isoflurane. using Graphpad Prism. Mice are monitored postoperatively for recovery. 0467 By way of example, in one embodiment, 4-7-(6- 0470 Mice are administered control vehicle or test article cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- by oral gavage daily Monday through Friday schedule for a diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide total of 35 days. MRI tumor volumes are reported for each (ARN-509) was administered in combination with BKM120 mouse at time point Zero (TO) at initiation of study and time (a PI3K inhibitor that is also known as 5-(2,6-dimorpholi point 35 days (T35) at completion of study. Changes in tumor nopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine) in Volumes between T0 and T35 are calculated for individual this LNCaPI AR Model of CRPC. mice and reported in waterfall plots. At study end, mice were euthanized by CO asphyxiation, and tissue was collected for TABLE 4 histology, mRNA analysis, protein analysis and other analy SCS. Combination with a PI3K inhibitor Example 12 Number Compound of regres Clinical Trial for the Combination of an Compound 1 2 Sions >50% Anti-Androgen with a PI3K Inhibitor, TORC 4-7-(6-cyano-5-trifluoromethylpyridin- 2,10 Inhibitor, or Dual PI3K/TORC Inhibitor 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct 5-yl)-2-fluoro-N-methylbenzamide 0471. A non-limiting example of a prostate cancer clinical 3 mg/kg/day trial in humans involving the combination of 4-7-(6-cyano BKM120 20 mg/kg 1,10 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza BKM120 40 mg/kg O.9 spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and a PI3K 4-7-(6-cyano-5-trifluoromethylpyridin- BKM120 O.9 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct- 20 mg/kg inhibitor, TORC inhibitor, or dual PI3K/TORC inhibitor is 5-yl)-2-fluoro-N-methylbenzamide described below. 3 mg/kg/day 0472. Purpose: The purposes of this study is to assess the 4-7-(6-cyano-5-trifluoromethylpyridin BKM120 5.10 safety and efficacy of a combination of 4-7-(6-cyano-5-trif 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct 40 mg/kg luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 5-yl)-2-fluoro-N-methylbenzamide 4 oct-5-yl)-2-fluoro-N-methylbenzamide and a PI3K inhibi 3 mg/kg/day tor, TORC inhibitor, or dual PI3K/TORC inhibitor in humans with prostate cancer (e.g. post-abiraterone acetate treated metastatic castration-resistant prostate cancer, metastatic cas 0468. In another embodiment, 4-7-(6-cyano-5-trifluo tration-resistant prostate cancer, non-metastatic castration romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 resistant prostate cancer, metastatic castration-sensitive pros oct-5-yl)-2-fluoro-N-methylbenzamide (ARN-509) was tate cancer, non-metastatic castration-sensitive prostate administered in combination with Everolimus in this LNCaP/ cancer or high-risk localized prostate cancer), collect infor ARModel of CRPC. mation on any side effects the combination therapy may US 2014/O 199236 A1 Jul. 17, 2014 37 cause, and evaluate the pharmacokinetic properties of the 0479. Purpose: The purposes of this study is to assess the compounds in the context of combination therapy. safety and efficacy of a combination of 4-7-(6-cyano-5-trif 0473 Intervention: Patients are administered 4-7-(6-cy luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia 4 oct-5-yl)-2-fluoro-N-methylbenzamide and a CYP17 Zaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose inhibitor in humans with prostate cancer (e.g. metastatic cas of 240 mg per day. However, dose adjustment of 4-7-(6- tration-resistant prostate cancer, non-metastatic castration cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- resistant prostate cancer, metastatic castration-sensitive pros diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 tate cancer, non-metastatic castration-sensitive prostate mg to 480 mg per day) will be considered during the trial if cancer or high-risk localized prostate cancer), collect infor deemed necessary. The TORC inhibitor everolimus will be mation on any side effects the combination therapy may administered at a dose of 5 mg per day. However, dose adjust cause, and evaluate the pharmacokinetic properties of the ment of everolimus (5 mg to 20 mg per day) will be consid compounds in the context of combination therapy. ered during the trial if deemed necessary. 0480 Intervention: Patients are administered 4-7-(6-cy 0474. Outcome Measures: Overall and 12-week PSA ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia response (decrease of PSA by >50% from basesline); Time to Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose PSA Progression; overall survival (OS); PFS (Progression of 240 mg per day. However, dose adjustment of 4-7-(6- free survival by CT/MRI/radio-tracer); quality of life (QOL); cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- side-effects; pharmacokinetics (PK); tumor response and/or diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 disease control; proportion of patients that have complete or mg to 480 mg per day) will be considered during the trial if partial response or stable disease at defined time points; deemed necessary. The CYP17 inhibitor abiraterone acetate biomarkers predictive of clinical response. will be administered at a dose of 1000 mg once per day. 0475 Eligibility: Male subjects that are 18 years and older. However, dose adjustment of abiraterone acetate (500 mg to 0476 Inclusion Criteria: Histologically or cytologically 1000 mg per day) will be considered during the trial if deemed confirmed adenocarcinoma of the prostate (e.g. post-abirater necessary. Patients that are administered abiraterone acetate one acetate treated metastatic castration-resistant prostate will also be administered prednisone (5 mg) twice per day. cancer, metastatic castration-resistant prostate cancer, non 0481. Outcome Measures: Overall and 12-week PSA metastatic castration-resistant prostate cancer, metastatic cas response (decrease of PSA by >50% from basesline); Time to tration-sensitive prostate cancer, non-metastatic castration PSA Progression; overall survival (OS); PFS (Progression sensitive prostate cancer or high-risk localized prostate free survival by CT/MRI/radio-tracer); quality of life (QOL); cancer); castration-resistant prostate cancer demonstrated side-effects; pharmacokinetics (PK); tumor response and/or during continuousandrogen deprivation therapy (ADT)/post disease control; proportion of patients that have complete or orchiectomy, defined as 3 consecutive rises of PSA, 1 week partial response or stable disease at defined time points; apart, resulting in two 50% increases over the nadir, with the biomarkers predictive of clinical response. last PSA>2 ng/mL, maintain castrate levels of testosterone 0482 Eligibility: Male subjects that are 18 years and older. (<50 ng/dL (1.72 nmol/L) within 4 weeks of randomization 0483 Inclusion Criteria: Histologically or cytologically and throughout the study; patients currently receiving bone confirmed adenocarcinoma of the prostate (e.g. metastatic loss prevention treatment with bone-sparing agents (e.g., bis castration-resistant prostate cancer, non-metastatic castra phosphonates, denosumab ProliaRI) must be on stable doses tion-resistant prostate cancer, metastatic castration-sensitive for at least 4 weeks prior to randomization; patients who prostate cancer, non-metastatic castration-sensitive prostate received a first generation anti-androgen (e.g., bicalutamide, cancer or high-risk localized prostate cancer); castration-re flutamide, nilutamide) as part of an initial combined androgen sistant prostate cancer demonstrated during continuous blockade therapy or as second-line hormonal therapy must androgen deprivation therapy (ADT)/post orchiectomy, show continuing disease (PSA) progression off the anti-an defined as 3 consecutive rises of PSA, 1 week apart, resulting drogen for at least 4 weeks prior to randomization; at least 4 in two 50% increases over the nadir, with the last PSA>2 weeks must have elapsed from the use of 5-O. reductase ng/mL, maintain castrate levels of testosterone (<50 ng/dL inhibitors (e.g., dutasteride, finasteride, aminoglutethamide), 1.72 nmol/L) within 4 weeks of randomization and through estrogens, and any otheranti-cancer therapy prior to random out the study; patients currently receiving bone loss preven ization, including chemotherapy given in the adjuvant/neo tion treatment with bone-sparing agents (e.g., bisphospho adjuvant setting (e.g., clinical trial); at least 4 weeks must nates, denosumab ProliaR) must be on stable doses for at have elapsed from major Surgery or radiation therapy prior to least 4 weeks prior to randomization; patients who received a randomization. first generation anti-androgen (e.g., bicalutamide, flutamide, 0477 Exclusion Criteria: History of seizure, CNS nilutamide) as part of an initial combined androgen blockade metastasis. therapy or as second-line hormonal therapy must show con tinuing disease (PSA) progression off the anti-androgen for at Example 13 least 4 weeks prior to randomization; at least 4 weeks must have elapsed from the use of 5-O. reductase inhibitors (e.g., dutasteride, finasteride, aminoglutethamide), estrogens, and Clinical Trial for the Combination of an any other anti-cancer therapy prior to randomization, includ Anti-Androgen with a CYP17 Inhibitor ing chemotherapy given in the adjuvant/neoadjuvant setting 0478 A non-limiting example of a prostate cancer clinical (e.g., clinical trial); at least 4 weeks must have elapsed from trial in humans involving the combination of 4-7-(6-cyano major Surgery or radiation therapy prior to randomization. 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza 0484 Exclusion Criteria: Prior chemotherapy, prior spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and a CYP17 or second-generation antiandrogen therapy, CNS CYP17 inhibitor is described below. metastasis, prior history of seizure. US 2014/O 199236 A1 Jul. 17, 2014 38

Example 14 to randomization, including chemotherapy given in the adju vant/neoadjuvant setting (e.g., clinical trial) must have recov Clinical Trial for the Combination of an ered from the acute toxicities of the treatment; at least 4 weeks Anti-Androgen with a GnRH/LHRH must have elapsed from major Surgery or radiation therapy Agonist/Antagonist prior to randomization. 0485. A non-limiting example of a prostate cancer clinical 0491 Exclusion Criteria: Prior CYP17 or second-genera trial in humans involving the combination of 4-7-(6-cyano tion antiandrogen therapy, CNS metastasis, prior history of 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza seizure. spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and a GnRH/LHRH agonist/antagonist is described below. Example 15 0486 Purpose: The purposes of this study is to assess the efficacy of a combination of 4-7-(6-cyano-5-trifluorometh Clinical Trial for the Combination of an ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- Anti-Androgen with an Osteoprotective Agent yl)-2-fluoro-N-methylbenzamide and a GnRH/LHRH ago 0492. A non-limiting example of a prostate cancer clinical nist/antagonist in humans with prostate cancer (e.g. trial in humans involving the combination of 4-7-(6-cyano metastatic castration-resistant prostate cancer, non-meta 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza static castration-resistant prostate cancer, metastatic castra spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and an tion-sensitive prostate cancer, non-metastatic castration-sen osteoprotective agent is described below. sitive prostate cancer or high-risk localized prostate cancer), 0493 Purpose: The purposes of this study is to assess the collect information on any side effects the combination safety and efficacy of a combination of 4-7-(6-cyano-5-trif therapy may cause, and evaluate the pharmacokinetic prop luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. erties of the compounds in the context of combination 4 oct-5-yl)-2-fluoro-N-methylbenzamide and an osteopro therapy. tective agent in humans with prostate cancer (e.g. metastatic 0487 Intervention: Patients are administered 4-7-(6-cy castration-resistant prostate cancer, non-metastatic castra ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia tion-resistant prostate cancer, metastatic castration-sensitive Zaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose prostate cancer, non-metastatic castration-sensitive prostate of 240 mg per day. However, dose adjustment of 4-7-(6- cancer or high-risk localized prostate cancer), collect infor cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- mation on any side effects the combination therapy may diazaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 cause, and evaluate the pharmacokinetic properties of the mg to 480 mg per day) will be considered during the trial if compounds in the context of combination therapy. deemed necessary. The patients will also be administered a 0494 Intervention: Patients are administered 4-7-(6-cy GnRH/LHRH agonist/antagonist in addition to 4-7-(6-cy ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose Zaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. In some of 240 mg per day. However, dose adjustment of 4-7-(6- embodiments, the GnRH/LHRH agonist/antagonist is cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- Lupron which is administered as a depot injectionata dose of diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 about 7.5 mg every 4 weeks, or 22.5 mg every 3 months, or mg to 480 mg per day) will be considered during the trial if about 30 mg every 4 months, or about 45 mg every 6 months. deemed necessary. The patients will also be administered an In other embodiments, the GnRH/LHRH agonist/antagonist osteoprotective agent in addition to 4-7-(6-cyano-5-trifluo is Zoladex (Goserelin) which is administered as a Subcutane romethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3.4 ous implant at a dose of about 3.6 mg every 4 weeks or about oct-5-yl)-2-fluoro-N-methylbenzamide. In some embodi 10.8 mg every 12 weeks. In some other embodiments, the ments, the osteoprotective agent is denosumab which is GnRH/LHRH agonist/antagonist is Degarelix which is administered by subcutaneous injection at a dose of about 60 administered as a Subcutaneous injection at a dose of about mg to about 120 mg every 4 weeks to every 6 months. In other 240mg followed by about 80 mg administered every 4 weeks. embodiments, the osteoprotective agent is Zoledronic acid 0488 Outcome Measures: Overall and 12-week PSA which is administered by intravenous infusion at a dose of response (decrease of PSA by >50% from basesline); Time to about 4 mg every 4 weeks to every 12 weeks. PSA Progression; overall survival (OS); PFS (Progression 0495 Outcome Measures: Overall and 12-week PSA free survival by CT/MRI/radio-tracer); quality of life (QOL); response (decrease of PSA by >50% from basesline); Time to side-effects; pharmacokinetics (PK); tumor response and/or PSA Progression; overall survival (OS); PFS (Progression disease control; proportion of patients that have complete or free survival by CT/MRI/radio-tracer); quality of life (QOL); partial response or stable disease at defined time points; side-effects; pharmacokinetics (PK); tumor response and/or biomarkers predictive of clinical response. disease control; proportion of patients that have complete or 0489 Eligibility: Male subjects that are 18 years and older. partial response or stable disease at defined time points; 0490 Inclusion Criteria: Histologically or cytologically biomarkers predictive of clinical response. confirmed adenocarcinoma of the prostate (e.g. metastatic 0496 Eligibility: Male subjects that are 18 years and older. castration-resistant prostate cancer, non-metastatic castra 0497 Inclusion Criteria: Histologically or cytologically tion-resistant prostate cancer, metastatic castration-sensitive confirmed adenocarcinoma of the prostate (e.g. metastatic prostate cancer, non-metastatic castration-sensitive prostate castration-resistant prostate cancer, non-metastatic castra cancer or high-risk localized prostate cancer); patients cur tion-resistant prostate cancer, metastatic castration-sensitive rently receiving bone loss prevention treatment with bone prostate cancer, non-metastatic castration-sensitive prostate sparing agents (e.g., bisphosphonates, denosumab Prolia RI) cancer or high-risk localized prostate cancer); metastatic cas must be on stable doses for at least 4 weeks prior to random tration-resistant prostate cancer demonstrated during con ization; patients who received prior anti-cancer therapy prior tinuous androgen deprivation therapy (ADT)/post orchiec US 2014/O 199236 A1 Jul. 17, 2014 39 tomy, defined as 3 consecutive rises of PSA, 1 week apart, partial response or stable disease at defined time points; resulting in two 50% increases over the nadir, with the last biomarkers predictive of clinical response. PSA>2 ng/mL. maintain castrate levels of testosterone (<50 0503 Eligibility: Male subjects that are 18 years and older. ng/dL (1.72 nmol/L) within 4 weeks of randomization and 0504 Inclusion Criteria: Histologically or cytologically throughout the study; patients who received a first generation confirmed adenocarcinoma of the prostate (e.g. metastatic anti-androgen (e.g., bicalutamide, flutamide, nilutamide) as castration-resistant prostate cancer, non-metastatic castra part of an initial combined androgen blockade therapy or as tion-resistant prostate cancer, metastatic castration-sensitive second-line hormonal therapy must show continuing disease prostate cancer, non-metastatic castration-sensitive prostate (PSA) progression off the anti-androgen for at least 4 weeks cancer or high-risk localized prostate cancer); castration-re prior to randomization; at least 4 weeks must have elapsed sistant prostate cancer demonstrated during continuous from the use of 5-C. reductase inhibitors (e.g., dutasteride, androgen deprivation therapy (ADT)/post orchiectomy, finasteride, aminoglutethamide), estrogens, and any other defined as 3 consecutive rises of PSA, 1 week apart, resulting anti-cancer therapy prior to randomization, including chemo in two 50% increases over the nadir, with the last PSA>2 therapy given in the adjuvant/neoadjuvant setting (e.g., clini ng/mL, maintain castrate levels of testosterone (<50 ng/dL cal trial); at least 4 weeks must have elapsed from major 1.72 nmol/L) within 4 weeks of randomization and through Surgery or radiation therapy prior to randomization. out the study; patients currently receiving bone loss preven 0498 Exclusion Criteria: Prior second-generation antian tion treatment with bone-sparing agents (e.g., bisphospho drogen therapy, CNS metastasis, prior history of seizure. nates, denosumab ProliaR) must be on stable doses for at least 4 weeks prior to randomization; patients who received a Example 16 first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) as part of an initial combined androgen blockade Clinical Trial for the Combination of an therapy or as second-line hormonal therapy must show con Anti-Androgen with Radiation Therapy tinuing disease (PSA) progression off the anti-androgen for at least 4 weeks prior to randomization; at least 4 weeks must 0499. A non-limiting example of a prostate cancer clinical have elapsed from the use of 5-O. reductase inhibitors (e.g., trial in humans involving the combination of 4-7-(6-cyano dutasteride, finasteride, aminoglutethamide), estrogens, and 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza any other anti-cancer therapy prior to randomization, includ spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and radia ing chemotherapy given in the adjuvant/neoadjuvant setting tion therapy is described below. (e.g., clinical trial); at least 4 weeks must have elapsed from 0500 Purpose: The purposes of this study is to assess the major Surgery or radiation therapy prior to randomization. safety and efficacy of a combination of 4-7-(6-cyano-5-trif 0505 Exclusion Criteria: Prior second-generation antian luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. drogen therapy, CNS metastasis, prior history of seizure. 4 oct-5-yl)-2-fluoro-N-methylbenzamide and radiation therapy in humans with prostate cancer (e.g. metastatic cas Example 17 tration-resistant prostate cancer, non-metastatic castration resistant prostate cancer, metastatic castration-sensitive pros Clinical Trial for the Combination of an tate cancer, non-metastatic castration-sensitive prostate Anti-Androgen with a Kinase Inhibitor cancer or high-risk localized prostate cancer), collect infor 0506 A non-limiting example of a prostate cancer clinical mation on any side effects the combination therapy may trial in humans involving the combination of 4-7-(6-cyano cause, and evaluate the pharmacokinetic properties of the 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza compounds in the context of combination therapy. spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and a 0501 Intervention: Patients are administered 4-7-(6-cy kinase inhibitor is described below. ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia 0507 Purpose: The purposes of this study is to assess the Zaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose safety and efficacy of a combination of 4-7-(6-cyano-5-trif of 240 mg per day. However, dose adjustment of 4-7-(6- luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- 4 oct-5-yl)-2-fluoro-N-methylbenzamide and a kinase diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 inhibitor in humans with prostate cancer (e.g. post-abirater mg to 480 mg per day) will be considered during the trial if one acetate treated metastatic castration-resistant prostate deemed necessary. The patients will also be administered a cancer, metastatic castration-resistant prostate cancer, non second thereapuletic agent in addition to 4-7-(6-cyano-5- metastatic castration-resistant prostate cancer, metastatic cas trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro tration-sensitive prostate cancer, non-metastatic castration 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide. In some sensitive prostate cancer or high-risk localized prostate embodiments, the second therapeutic agent is Alpharadin cancer), collect information on any side effects the combina which is administered by intravenous infusion at a dose of tion therapy may cause, and evaluate the pharmacokinetic about 25 to about 50 kBq/kg every 4 weeks. In other embodi properties of the compounds in the context of combination ments, the second therapeutic agent is ''Lu-J591 which is therapy. administered by intravenous infusion at a dose of about 30 0508 Intervention: Patients are administered 4-7-(6-cy mCi/m to about 70 mCi/m. ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia 0502. Outcome Measures: Overall and 12-week PSA Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose response (decrease of PSA by >50% from basesline); Time to of 240 mg perday. However, dose adjustment of 4-7-(6- PSA Progression; overall survival (OS); PFS (Progression cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- free survival by CT/MRI/radio-tracer); quality of life (QOL); diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 side-effects; pharmacokinetics (PK); tumor response and/or mg to 480 mg per day) will be considered during the trial if disease control; proportion of patients that have complete or deemed necessary. The patients will be also be administered US 2014/O 199236 A1 Jul. 17, 2014 40 a kiase inhibitor in addition to 4-7-(6-cyano-5-trifluorom luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- 4 oct-5-yl)-2-fluoro-N-methylbenzamide and Provenge, yl)-2-fluoro-N-methylbenzamide. In some embodiments, the Prostvac, Ipilimumab, or a PD-1 inhibitor in humans with kinase inhibitor is cabozantinib which is administered orally prostate cancer (e.g. metastatic castration-resistant prostate at a dose of about 40 mg per day to about 100 mg per day. In cancer, non-metastatic castration-resistant prostate cancer, other embodiments, the kinase inhibitor is erlotinib which is metastatic castration-sensitive prostate cancer, non-meta administered orally at a dose of about 100 mg to about 150 static castration-sensitive prostate cancer or high-risk local mg. In some other embodiments, the kinase inhibitor is gefi ized prostate cancer), collect information on any side effects tinib which is administered orally at a dose of about 250 mg the combination therapy may cause, and evaluate the phar per day. In yet some other embodiments, the kinase inhibitor macokinetic properties of the compounds in the context of is trametinib which is administered orally at a dose of about 1 combination therapy. mg to about 2 mg. 0515 Intervention: Patients are administered 4-7-(6-cy 0509. Outcome Measures: Overall and 12-week PSA ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia response (decrease of PSA by >50% from basesline); Time to Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose PSA Progression; overall survival (OS); PFS (Progression of 240 mg per day. However, dose adjustment of 4-7-(6- free survival by CT/MRI/radio-tracer); quality of life (QOL); cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- side-effects; pharmacokinetics (PK); tumor response and/or diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 disease control; proportion of patients that have complete or mg to 480 mg per day) will be considered during the trial if partial response or stable disease at defined time points; deemed necessary. The patients will also be administered a biomarkers predictive of clinical response. second therapeutic agent in addition to 4-7-(6-cyano-5-trif 0510 Eligibility: Male subjects that are 18 years and older. luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. 0511 Inclusion Criteria: Histologically or cytologically 4 oct-5-yl)-2-fluoro-N-methylbenzamide. In some embodi confirmed adenocarcinoma of the prostate (e.g. post-abirater ments, the additional therapeutic agent is pilimumab which one acetate treated metastatic castration-resistant prostate is administered by intravenous infusion at a dose of about 1.5 cancer, metastatic castration-resistant prostate cancer, non mg/kg to about 3.0 mg/kg IV every 3 weeks for a total of 4 metastatic castration-resistant prostate cancer, metastatic cas doses. In other embodiments, the additional therapeutic agent tration-sensitive prostate cancer, non-metastatic castration is the PD-1 inhibitor BMS-936558 which is administered by sensitive prostate cancer or high-risk localized prostate intravenous infusion at a dose of about 1.0 mg/kg to about 10 cancer); castration-resistant prostate cancer demonstrated mg/kg on days 1, and 29 of 6-week cycles. In some other during continuousandrogen deprivation therapy (ADT)/post embodiments, the additional therapeutic agent is Provenge R. orchiectomy, defined as 3 consecutive rises of PSA, 1 week (sipuleucel-T) which is administered as 3 doses, given at apart, resulting in two 50% increases over the nadir, with the approximately 2 week intervals. In yet some other embodi last PSA>2 ng/mL, maintain castrate levels of testosterone ments, the additional therapeutic agent is Prostvac which is (<50 ng/dL (1.72 nmol/L) within 4 weeks of randomization administered by Subcutaneous injection on days 1, 14, 28, 56. and throughout the study; patients currently receiving bone 84, 112, and 140. Priming immunization with rV-PSA-TRI loss prevention treatment with bone-sparing agents (e.g., bis COM (2x10 pfu) with subsequent boosts using rF-PSA phosphonates, denosumab ProliaRI) must be on stable doses TRICOM (1x10 pfu) with or without GM-CSF at 100 ug for at least 4 weeks prior to randomization; patients who Subcutaneously on the day of each vaccination. received a first generation anti-androgen (e.g., bicalutamide, 0516 Outcome Measures: Overall and 12-week PSA flutamide, nilutamide) as part of an initial combined androgen response (decrease of PSA by >50% from basesline); Time to blockade therapy or as second-line hormonal therapy must PSA Progression; overall survival (OS); PFS (Progression show continuing disease (PSA) progression off the anti-an free survival by CT/MRI/radio-tracer); quality of life (QOL); drogen for at least 4 weeks prior to randomization; at least 4 side-effects; pharmacokinetics (PK); tumor response and/or weeks must have elapsed from the use of 5-O. reductase disease control; proportion of patients that have complete or inhibitors (e.g., dutasteride, finasteride, aminoglutethamide), partial response or stable disease at defined time points; estrogens, and any otheranti-cancer therapy prior to random biomarkers predictive of clinical response. ization, including chemotherapy given in the adjuvant/neo adjuvant setting (e.g., clinical trial); at least 4 weeks must 0517 Eligibility: Male subjects that are 18 years and older. have elapsed from major Surgery or radiation therapy prior to 0518. Inclusion Criteria: Histologically or cytologically randomization. confirmed adenocarcinoma of the prostate (e.g. metastatic castration-resistant prostate cancer, non-metastatic castra 0512 Exclusion Criteria: Prior second-generation antian tion-resistant prostate cancer, metastatic castration-sensitive drogen therapy, CNS metastasis, prior history of seizure. prostate cancer, non-metastatic castration-sensitive prostate Example 18 cancer or high-risk localized prostate cancer); castration-re sistant prostate cancer demonstrated during continuous Clinical Trial for the Combination of an androgen deprivation therapy (ADT)/post orchiectomy, Anti-Androgen with Immunotherapy defined as 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with the last PSA>2 0513. A non-limiting example of a prostate cancer clinical ng/mL, maintain castrate levels of testosterone (<50 ng/dL trial in humans involving the combination of 4-7-(6-cyano 1.72 nmol/L) within 4 weeks of randomization and through 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza out the study; patients currently receiving bone loss preven spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and immu tion treatment with bone-sparing agents (e.g., bisphospho notherapy is described below. nates, denosumab ProliaR) must be on stable doses for at 0514 Purpose: The purposes of this study is to assess the least 4 weeks prior to randomization; patients who received a safety and efficacy of a combination of 4-7-(6-cyano-5-trif first generation anti-androgen (e.g., bicalutamide, flutamide, US 2014/O 199236 A1 Jul. 17, 2014

nilutamide) as part of an initial combined androgen blockade nadir, with the last PSA>2 ng/mL. maintain castrate levels of therapy or as second-line hormonal therapy must show con testosterone (<50 ng/dL (1.72 nmol/L) within 4 weeks of tinuing disease (PSA) progression off the anti-androgen for at randomization and throughout the study; patients currently least 4 weeks prior to randomization; at least 4 weeks must receiving bone loss prevention treatment with bone-sparing have elapsed from the use of 5-O. reductase inhibitors (e.g., agents (e.g., bisphosphonates, denosumab Prolia R) must be dutasteride, finasteride, aminoglutethamide), estrogens, and on stable doses for at least 4 weeks prior to randomization; any other anti-cancer therapy prior to randomization, includ patients who received a first generation anti-androgen (e.g., ing chemotherapy given in the adjuvant/neoadjuvant setting bicalutamide, flutamide, nilutamide) as part of an initial com (e.g., clinical trial); at least 4 weeks must have elapsed from bined androgen blockade therapy or as second-line hormonal major Surgery or radiation therapy prior to randomization. therapy must show continuing disease (PSA) progression off 0519 Exclusion Criteria: Prior second-generation antian the anti-androgen for at least 4 weeks prior to randomization; drogen therapy, CNS metastasis, prior history of seizure. at least 4 weeks must have elapsed from the use of 5-C. reductase inhibitors (e.g., dutasteride, finasteride, aminoglu Example 19 tethamide), estrogens, and any otheranti-cancertherapy prior to randomization, including chemotherapy given in the adju Clinical Trial for the Combination of an vant/neoadjuvant setting (e.g., clinical trial); at least 4 weeks Anti-Androgen with Chemotherapy must have elapsed from major Surgery or radiation therapy 0520. A non-limiting example of a prostate cancer clinical prior to randomization. trial in humans involving the combination of 4-7-(6-cyano 0526 Exclusion Criteria: Prior second-generation antian 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza drogen therapy, CNS metastasis, prior history of seizure. spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and che motherapy is described below. Example 20 0521 Purpose: The purposes of this study is to assess the Clinical Trial for the Combination of an safety and efficacy of a combination of 4-7-(6-cyano-5-trif Anti-Androgen with an Anti-STEAP-1 Antibody luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. Drug Conjugate 4 oct-5-yl)-2-fluoro-N-methylbenzamide and a taxane or tubulin inhibitor in males with metastatic castration-resistant 0527. A non-limiting example of a prostate cancer clinical prostate cancer or high-risk localized prostate cancer, collect trial in humans involving the combination of 4-7-(6-cyano information on any side effects the combination therapy may 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza cause, and evaluate the pharmacokinetic properties of the spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and an compounds in the context of combination therapy. anti-STEAP-1 antibody drug conjugate is described below. 0522 Intervention: Patients are administered 4-7-(6-cy 0528 Purpose: The purposes of this study is to assess the ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia safety and efficacy of a combination of 4-7-(6-cyano-5-trif Zaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. of 240 mg per day. However, dose adjustment of 4-7-(6- 4 oct-5-yl)-2-fluoro-N-methylbenzamide and an anti cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- STEAP-1 antibody drug conjugate in males with prostate diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 cancer (e.g. metastatic castration-resistant prostate cancer, mg to 480 mg per day) will be considered during the trial if non-metastatic castration-resistant prostate cancer, meta deemed necessary. The patients will be administered a second static castration-sensitive prostate cancer, non-metastatic therapeutic agent in addition to 4-7-(6-cyano-5-trifluorom castration-sensitive prostate cancer or high-risk localized ethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- prostate cancer), collect information on any side effects the yl)-2-fluoro-N-methylbenzamide. In some embodiments, the combination therapy may cause, and evaluate the pharmaco second therapeutic agent is docetaxel which is administered kinetic properties of the compounds in the context of combi by intravenous infusion at a dose of about 35 mg/m to about nation therapy. 75 mg/m every 3 weeks. In other embodiments, the second 0529 Intervention: Patients are administered 4-7-(6-cy therapeutic agent is cabazitaxel which is administered by ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia intravenous infusion at a dose of about 13 mg/m to about 25 Zaspiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose mg/m every 3 weeks. of 240 mg per day. However, dose adjustment of 4-7-(6- 0523 Outcome Measures: Overall and 12-week PSA cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- response (decrease of PSA by >50% from basesline); Time to diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 PSA Progression; overall survival (OS); PFS (Progression mg to 480 mg per day) will be considered during the trial if free survival by CT/MRI/radio-tracer); quality of life (QOL); deemed necessary. Patients also will be administered an anti side-effects; pharmacokinetics (PK); tumor response and/or STEAP-1 antibody drug conjugate. disease control; proportion of patients that have complete or 0530 Outcome Measures: Overall and 12-week PSA partial response or stable disease at defined time points; response (decrease of PSA by >50% from basesline); Time to biomarkers predictive of clinical response. PSA Progression; overall survival (OS); PFS (Progression 0524 Eligibility: Male subjects that are 18 years and older. free survival by CT/MRI/radio-tracer); quality of life (QOL); 0525 Inclusion Criteria: Histologically or cytologically side-effects; pharmacokinetics (PK); tumor response and/or confirmed adenocarcinoma of the prostate (e.g. metastatic disease control; proportion of patients that have complete or castration-resistant prostate cancer or high-risk localized partial response or stable disease at defined time points; prostate cancer); castration-resistant prostate cancer demon biomarkers predictive of clinical response. strated during continuous androgen deprivation therapy 0531 Eligibility: Male subjects that are 18 years and older. (ADT)/post orchiectomy, defined as 3 consecutive rises of 0532. Inclusion Criteria: Histologically or cytologically PSA, 1 week apart, resulting in two 50% increases over the confirmed adenocarcinoma of the prostate (e.g. metastatic US 2014/O 199236 A1 Jul. 17, 2014 42 castration-resistant prostate cancer, non-metastatic castra by intravenous infusion at a dose of about 320 mg to about tion-resistant prostate cancer, metastatic castration-sensitive 640 mg every week. In other embodiments, the HSP inhibitor prostate cancer, non-metastatic castration-sensitive prostate is OGX-427 which is administered by intravenous infusion at cancer or high-risk localized prostate cancer); castration-re a loading dose of about 300 mg to about 600 mg followed by sistant prostate cancer demonstrated during continuous androgen deprivation therapy (ADT)/post orchiectomy, about 500 mg to about 1000 mg every week. defined as 3 consecutive rises of PSA, 1 week apart, resulting 0537 Outcome Measures: Overall and 12-week PSA in two 50% increases over the nadir, with the last PSA>2 response (decrease of PSA by >50% from basesline); Time to ng/mL, maintain castrate levels of testosterone (<50 ng/dL PSA Progression; overall survival (OS); PFS (Progression 1.72 nmol/L) within 4 weeks of randomization and through free survival by CT/MRI/radio-tracer); quality of life (QOL); out the study; patients currently receiving bone loss preven side-effects; pharmacokinetics (PK); tumor response and/or tion treatment with bone-sparing agents (e.g., bisphospho disease control; proportion of patients that have complete or nates, denosumab ProliaR) must be on stable doses for at least 4 weeks prior to randomization; patients who received a partial response or stable disease at defined time points; first generation anti-androgen (e.g., bicalutamide, flutamide, biomarkers predictive of clinical response. nilutamide) as part of an initial combined androgen blockade 0538 Eligibility: Male subjects that are 18 years and older. therapy or as second-line hormonal therapy must show con tinuing disease (PSA) progression off the anti-androgen for at 0539 Inclusion Criteria: Histologically or cytologically least 4 weeks prior to randomization; at least 4 weeks must confirmed adenocarcinoma of the prostate (e.g. metastatic have elapsed from the use of 5-O. reductase inhibitors (e.g., castration-resistant prostate cancer, non-metastatic castra dutasteride, finasteride, aminoglutethamide), estrogens, and tion-resistant prostate cancer, metastatic castration-sensitive any other anti-cancer therapy prior to randomization, includ prostate cancer, non-metastatic castration-sensitive prostate ing chemotherapy given in the adjuvant/neoadjuvant setting cancer or high-risk localized prostate cancer); castration-re (e.g., clinical trial); at least 4 weeks must have elapsed from sistant prostate cancer demonstrated during continuous major Surgery or radiation therapy prior to randomization. androgen deprivation therapy (ADT)/post orchiectomy, 0533 Exclusion Criteria: Prior second-generation antian drogen therapy, CNS metastasis, prior history of seizure. defined as 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with the last PSA>2 Example 21 ng/mL, maintain castrate levels of testosterone (<50 ng/dL 1.72 nmol/L) within 4 weeks of randomization and through Clinical Trial for the Combination of an out the study; patients currently receiving bone loss preven Anti-Androgen with a Heat Shock Protein (HSP) tion treatment with bone-sparing agents (e.g., bisphospho Inhibitor nates, denosumab ProliaR) must be on stable doses for at 0534. A non-limiting example of a prostate cancer clinical least 4 weeks prior to randomization; patients who received a trial in humans involving the combination of 4-7-(6-cyano first generation anti-androgen (e.g., bicalutamide, flutamide, 5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diaza nilutamide) as part of an initial combined androgen blockade spiro3.4 oct-5-yl)-2-fluoro-N-methylbenzamide and a HSP therapy or as second-line hormonal therapy must show con inhibitor is described below. tinuing disease (PSA) progression off the anti-androgen for at 0535 Purpose: The purposes of this study is to assess the safety and efficacy of a combination of 4-7-(6-cyano-5-trif least 4 weeks prior to randomization; at least 4 weeks must luoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro 3. have elapsed from the use of 5-O. reductase inhibitors (e.g., 4 oct-5-yl)-2-fluoro-N-methylbenzamide and a HSP inhibi dutasteride, finasteride, aminoglutethamide), estrogens, and tor (e.g. HSP90 or HSP27) in males with prostate cancer (e.g. any other anti-cancer therapy prior to randomization, includ metastatic castration-resistant prostate cancer, non-meta ing chemotherapy given in the adjuvant/neoadjuvant setting static castration-resistant prostate cancer, metastatic castra (e.g., clinical trial); at least 4 weeks must have elapsed from tion-sensitive prostate cancer, non-metastatic castration-sen major Surgery or radiation therapy prior to randomization. sitive prostate cancer or high-risk localized prostate cancer), collect information on any side effects the combination 0540 Exclusion Criteria: Prior second-generation antian therapy may cause, and evaluate the pharmacokinetic prop drogen therapy, CNS metastasis, prior history of seizure. erties of the compounds in the context of combination 0541. The examples and embodiments described herein therapy. are for illustrative purposes only and various modifications or 0536 Intervention: Patients are administered 4-7-(6-cy changes Suggested to persons skilled in the art are to be ano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-dia included within the spirit and purview of this application and Zaspiro 3.4 oct-5-yl)-2-fluoro-N-methylbenzamide at a dose Scope of the appended claims. of 240 mg per day. However, dose adjustment of 4-7-(6- cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- What is claimed is: diazaspiro[3.4 oct-5-yl)-2-fluoro-N-methylbenzamide (120 1. A method of treating a male human patient having mg to 480 mg per day) will be considered during the trial if advanced castration-sensitive prostate cancer, castration-re deemed necessary. The patients will also be administered a sistant prostate cancer, or high-risk localized prostate cancer HSP inhibitor in addition to 4-7-(6-cyano-5-trifluorometh comprising administering the compound of Formula (I), or a ylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 oct-5- pharmaceutically acceptable salt thereof, at a dose in a range yl)-2-fluoro-N-methylbenzamide. In some embodiments, the offrom about 30 mg per day to about 480 mg per day to a male HSP inhibitor is OGX-011 (Custirsen) which is administered human patient in need of such treatment. US 2014/O 199236 A1 Jul. 17, 2014 43

GDC0068, GDC-0980, GDC0941, GDC0032,

(I) MK-2206, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF0469 1502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal 101, PWT33597, LY-317615 (enzastaurin hydro chloride), CU-906, or CUDC-907, and if the TORC inhibitor is everolimus, it is administered at a dose of CH about 5 mg per day to about 20 mg per day; or NH (b) a kinase inhibitor, preferably where the kinase inhibitor is: (i) a MET or VEGFR kinase inhibitor, more preferably 2. The method of claim 1, wherein the treating results in a Cabozantinib (XL184), PF-2341066 (Crizotinib), decrease in the patient’s prostate-specific antigen levels of at ARQ-197 (Tivantinib), MK-2461, JNJ-38877605, least 50% from baseline after 3 months of the compound of MK-8033, INCB-28060, BMS-777607, AMG-208, Formula (I), or a pharmaceutically acceptable salt thereof, on LY-280.1653, EMD-1214063, EMD-1204831, AMG a continuous daily dosing schedule. 337, HMPL-504 (Volitinib), SAR-125844, LY2875358, ABR-215050 (Tasquinimod), CHIR 258 (Dovitinib), EXEL-7647, OSI-930, BIBF-1120,

(I) BAY-73-4506 (Regorafenib), BMS-582664 (Bri vanib), JNJ-26483327, AZD-2171 (Cediranib), Sor afenib, Aflibercept, Enzastaurin, AG-013736 (Axi tinib), OSI-632, or GSK-78.6034 (Pazopanib), and if Cabozantinib, it is administered orally at a dose of about 40 mg per day to about 100 mg per day; or CH3 (ii) an EGFR, MEK, or SRC kinase inhibitor, more preferably Erlotinib, Cetuximab, Gefitinib, Caner NH tinib, Panitumumab, Nimotuzumab, Lapatinib, Van detanib, Afatinib, MP-412, AEE-788, Neratinib, XL-647, AC-480, Dacomitinib, AZD-8931, CUDC 101, AP-26113, CO-1686, Trametinib, Selumetinib, 3. A method of treating post-abiraterone acetate treated MEK-162, Refametinib, TAK-733, RO-5126766, metastatic castration-resistant prostate cancer, metastatic cas BI-847325, AZD6244, GSK1120212, PF-5208763 tration-resistant prostate cancer, non-metastatic castration (Bosutinib), or AZD-0530 (Saracatinib), and if Erlo resistant prostate cancer, metastatic castration-sensitive pros tinib, it is administered orally at a dose in a range of tate cancer, non-metastatic castration-sensitive prostate from about 100 mg to about 150 mg; and if Gefitinib, cancer or high-risk localized prostate cancer in a male human it is administered orally at a dose of about 250 mg; and patient comprising orally administering the compound of if Trametinib, it is administered orally at a dose of Formula (I), or a pharmaceutically acceptable salt thereof: about 1 mg to about 2 mg; or (iii) an AKT, RAF, FGFR, or CDK4/6 kinase inhibitor,

(I) more preferably GDC0068, MK-2206, AT7867, GSK2110183, GSK2141795, GSK690693, Vemu rafenib (PLX4032/RG7204), GSK21 18436, Dab rafenib (GSK208436), LGX818, RAF265, LY2780301, Dovitinib (TKI258), BGJ398, AZD4547, PD-0332991 or LEE011. CH3 4. The method of claim 3, further comprising administer ing a therapeutically effective amount of a gonadotropin NH releasing hormone agonist or antagonist to the male human 5. A method of treating metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non in the form of a softgel capsule to a human male patient in metastatic castration-sensitive prostate cancer or high-risk need of such treatment at a dose of about 30 mg per day to localized prostate cancer in a male human patient comprising about 480 mg per day, preferably at a dose of about 240 mg orally administering the compound of Formula (I), or a phar per day in combination with: maceutically acceptable salt thereof, in the form of a softgel (a) a phosphoinositide 3-kinase (PI3K) inhibitor, TORC capsule to a human male patient in need of Such treatment at inhibitor, or dual PI3K/TORC inhibitor, preferably a dose of about 30 mg per day to about 480 mg per day, everolimus, BEZ-235, BKM120, BGT226, BYL-719, preferably at a dose of about 240 mg per day, US 2014/O 199236 A1 Jul. 17, 2014 44

Alendronate Sodium (Fosamax), Pamidronate disodium (I) (Aredia), Neridronic acid (Nerixia), Minodronic acid (Recalbon) or Risedronate sodium (Actonel), and if Denosumab, it is administered by Subcutaneous injec tion at a dose of about 60 mg to about 120 mg every 4 weeks to every 6 months, and if Zoledronic acid, it is administered by intravenous infusion at a dose of about 4 mg every 4 weeks to every 12 weeks; or CH (c) a radiation therapy, preferably Alpharadin, '77Lu-J591, NH external beam radiation therapy (including Proton beam), or brachytherapy, and if Alpharadin, it is admin istered by intravenous infusion at a dose of about 25 to about 50 kBq/kg every 4 weeks, and if '77Lu-J591, it is administered by intravenous infusion at a dose of about in combination with a gonadotropin-releasing hormone ago 30 mCi/m to about 70 mCi/m; or nist or antagonist, preferably Lupron, Zoladex (Goserelin), (d) Provenge, Prostvac, Ipilimumab, or a PD-1 inhibitor, Degarelix, Ozarelix, ABT-620 (Elagolix), TAK-385 (Rel preferably where Ipilimumab administered by intrave ugolix), EP-100 or KLH-2109, and if Lupron, it is adminis nous infusion at a dose of about 1.5 mg/Kg to about 3.0 tered as a depot injection at a dose of about 7.5 mg every 4 mg/kg IV every 3 weeks for a total of 4 doses, or where weeks, or 22.5 mg every 3 months, or about 30 mg every 4 the PD-1 inhibitor is BMS-93.6558 is administered by months, or about 45 mg every 6 months, and if Zoladex intravenous infusion at a dose of about 1.0 mg/kg to (Goserelin), it is administered as a Subcutaneous implant at a about 10 mg/kg on days 1, 15 and 29 of 6-week cycles, dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 or where the Provenge is administered in 3 doses at weeks, and if Degarelix, it is administered as a Subcutaneous approximately 2 weeks interval, or where the Prostvac is injection at a dose of about 240 mg followed by about 80 mg administered by Subcutaneous injection; or administered every 4 weeks. (e) an anti-STEAP-1 antibody drug conjugate, preferably 6. A method of treating metastatic castration-resistant RG7450 (DSTP3086S); or prostate cancer, non-metastatic castration-resistant prostate (f) a HSP90 or HSP27 pathway modulator, preferably cancer, metastatic castration-sensitive prostate cancer, non OGX-011 (Custirsen), OGX-427, AUY922, HSP990, metastatic castration-sensitive prostate cancer or high-risk PF-04928473, PF-04929113 (SNX-5422), Retaspimy localized prostate cancer in a male human patient comprising cin or AT13387, and if OGX-011 (Custirsen), it is orally administering the compound of Formula (I), or a phar administered by intravenous infusion at a dose of about maceutically acceptable salt thereof, 320 mg to about 640 mg every week, and if OGX-427, it is administered by intravenous infusionataloading dose of about 300 mg to about 600 mg followed by about 500 (I) mg to about 1000 mg every week. 7. The method of claim 6, further comprising administer ing a therapeutically effective amount of a gonadotropin releasing hormone agonist or antagonist to the male human. 8. A method of treating breast cancer, androgen dependent hirsutism, androgenic alopecia, uterine fibroids, leiomyoma, endometrial carcinoma or endometriosis in a human patient, CH said method comprising orally administering the compound NH of Formula (I), or a pharmaceutically acceptable salt thereof, in the form of soft-gel capsules to a human patient in need of Such treatment at a dose in a range of from about 30 mg per day to about 480 mg per day, preferably at a dose of about 240 in the form of a softgel capsule to a human male patient in mg per day, on a continuous daily dosing schedule. need of such treatment at a dose of about 30 mg per day to about 480 mg per day, preferably at a dose of about 240 mg per day, in combination with: (I) (a) a CYP17 inhibitor, preferably wherein the CYP17 inhibitor is abiraterone acetate (Zytiga), TAK-700 (ort eronel), TOK-001 (galeterone) or VT-464, and if abi raterone acetate (Zytiga), it is administered at a dose in a range of from about 500 mg per day to about 1000 mg per day together with prednisone at a dose of about 5 mg CH twice per day, and if the CYP17 inhibitor is TAK-700 (orteronel), it is administered at a dose in a range of from NH about 300 mg twice per day to about 600 mg twice per day together with prednisone at about 5 mg twice per O day; or (b) an osteoprotective agent, preferably Denosumab, 9. A method of treating metastatic castration-resistant AMG-0007, CEP-37251, ALX-0141, Zoledronic acid, prostate cancer, or high-risk localized prostate cancer in a US 2014/O 199236 A1 Jul. 17, 2014 45 male human patient comprising orally administering the

compound of Formula (I), or a pharmaceutically acceptable (I) salt thereof,

(I)

CH NH

CH NH 13. The pharmaceutical composition of claim 11, wherein O the nonaqueous, lipid-based solution the compound of For mula (I), or a pharmaceutically acceptable salt thereof, com in the form of a softgel capsule to a human male patient in prises about 3% of the compound of Formula (I), or a phar need of such treatment at a dose of about 30 mg per day to maceutically acceptable salt thereof, about 480 mg per day, preferably at a dose of about 120 mg per day to about 240 mg per day or about 240 mg per day, in combination with a taxane or tubulin inhibitor, preferably (I) Docetaxel administered by intravenous infusion at a dose of about 35 mg/m to about 75 mg/m every 3 weeks or Caba Zitaxel administered by intravenous infusion at a dose of about 13 mg/m to about 25 mg/m every 3 weeks. 10. The method of claim 9, further comprising administer ing a therapeutically effective amount of a gonadotropin releasing hormone agonist or antagonist to the male human. CH3. 11. A pharmaceutical composition comprising a nonaque NH ous, lipid-based solution of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a softgel cap Sule 14. The pharmaceutical composition of 11, wherein the (I) softgel capsule shell comprises gelatin NF/EP, a 50:50 sorbi

tol/glycerin blend USP/EP, and purified water USP/EP. 15. The pharmaceutical composition of claim 11, wherein a single unit dosage comprises about 30 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof,

CH3.

(I) NH

12. The pharmaceutical composition of claim 11, wherein the nonaqueous, lipid-based solution of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, CH3. comprises: the compound of Formula (I), or a pharmaceuti NH cally acceptable salt thereof, vitamin Ed-C.-tocopheryl poly ethylene glycol 1000 succinate NF (Vitamin ETPGS), poly ethylene glycol 400 NF/EP (PEG 400), glycerol monocaprylocaprate EP and caprylocaproyl macro glycer ides EP/NF.