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WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT

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WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT (51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, C07K 16/28 (2006.01) A61K 31/4166 (2006.01) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 59/595 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (21) International Application Number: PCT/US20 17/065841 Declarations under Rule 4.17: (22) International Filing Date: — as to applicant's entitlement to apply for and be granted a 12 December 2017 (12.12.2017) patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the (25) Filing Language: English earlier application (Rule 4.17(Hi)) (26) Publication Langi English — of inventorship (Rule 4.1 7(iv)) (30) Priority Data: Published: 62/433,158 12 December 2016 (12.12.2016) US — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) (71) Applicant (for all designated States except AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, P T RO, RS, SE, SI, SK, SM, TR): GENENTECH, INC. [US/US]; 1 DNA Way, South San Francisco, CA 94080-4990 (US). (71) Applicant (for AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR only): F. HOFFMANN-LA-ROCHE AG [CH/CH]; Gren- zacherstrasse 124, 4070 Basel (CH). (72) Inventors: MARIATHASAN, Sanjeev; 1 DNA Way, South San Francisco, CA 94080-4990 (US). SCHIFF, Christina; 1 DNA Way, South San Francisco, CA 94080-4990 (US). NARAYANAN, Sujata; 1 DNA Way, South San Francisco, CA 94080-4990 (US). (74) Agent: ELBING, Karen, L.; Clark & Elbing LLP, 101 Federral Street, 15th Ploor, Boston, MA 021 10 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (54) Title: METHODS OF TREATING CANCER USING ANTI-PD-L1 ANTIBODIES AND ANTIANDROGENS (57) Abstract: The present invention relates to the treatment of cancers, such as a prostate cancer (e.g., castration-resistant prostate cancer (CRPC)). More specifically, the invention concerns the treatment of human patients having a prostate cancer (e.g., CRPC, e.g., metastatic CRPC) with a combination therapy including an PD- 1 axis binding antagonist and an antiandrogen. 1ETHODS OF TREATING CANCER USING ANT!-PD-L1 ANTIBODIES AND A T A NDROGE S The instant application contains a Sequence Listing which has been submitted electronically in ASCI I format and is hereby incorporated by reference in its entirety. Said ASCI I copy, created on December 4 , 20 , is named 50474-1 53W02_Sequence_Listing_1 2.4. 17_ST25 and is 9,553 bytes in size. F!!ELD OF THE INVENTION The present invention relates to the treatment of cancers, such as prostate cancer (e.g., castration-resistant prostate cancer (CRPC)). More specifically, the invention concerns the treatment of human patients having a prostate cancer, such as metastatic CRPC (mCRPC) or locally confined, inoperable CRPC, by administering a combination of a PD-1 axis binding antagonist (e.g. , an anti-PD-L1 antibody, e.g. , atezolizumab) and an antiandrogen (e.g., enzalutamide). BACKGROUND Cancers are characterized by the uncontrolled growth of ceil subpopulations. Cancers are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 4 million new cancer cases diagnosed and over eight million cancer deaths occurring each year. The National Cancer Institute has estimated that greater than half a million Americans will die of cancer in 2Q1 6 , accounting for nearly one out of every four deaths in the country. As the elderly population has grown, the incidence of cancer has concurrently risen, as the probability of developing cancer is more than two-fold higher after the age of seventy. Cancer care thus represents a significant and ever-increasing societal burden. With approximately 1.1 million newly diagnosed cases and more than 3 ,00 deaths each year worldwide, prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of death in men in the Western world. The incidence rates are highest in developed regions, including North America and Australia. Whereas most men with localized prostate cancer are cured with treatment, men with recurrent or newly diagnosed metastatic prostate cancer suffer significant morbidity and mortality. For patients who have recurrent prostate cancer following localized treatment and for those patients identified with de novo metastatic prostate cancer, the primary treatment is androgen deprivation therapy (ADT); however, up to one-third of prostate cancer patients will progress despite reduction in testosterone levels to castrate levels (< 50 ng/dL) through surgical or medical castration. The majority of these men with castration- resistant prostate cancer (CRPC), and in particular metastatic CRPC (mCRPC), will experience deterioration in quality of life, disability, and ultimately die of their disease. The median life expectancy in patients diagnosed with mCRPC is less than three years, and less than one year in patients who have failed two prior lines of therapy. Given the limitations of current treatments available for patients with prostate cancer (e.g., mCRPC), and particularly for prostate cancer (e.g. , mCRPC) patients who have previously failed treatment with an androgen synthesis inhibitor and have faiied , are ineiigibie for, or refused a taxane regimen, there remains an unmet need in the field for improved and tolerable treatment options for prostate cancer (e.g. , mCRPC). SUMMARY OF THE INVENTION The present invention relates to methods of treating a subject having cancer (e.g. , prostate cancer, e.g. , castration-resistant prostate cancer (CRPC), e.g., metastatic CRPC (mCRPC) or locally confined, inoperable CRPC) by administering a combination of a PD-1 axis binding antagonist (e.g ., an anti-PD-L1 antibody, e.g. , atezolizumab) and an antiandrogen (e.g., enzalutamide). In one aspect, the invention features a method of treating a subject having a prostate cancer (e.g. , CRPC) comprising administering to the subject an effective amount of an anti-PD-L1 antibody and an antiandrogen in one or more dosing cycles. in some embodiments of the above aspect, the antiandrogen is an androgen receptor (AR) antagonist. In some embodiments, the AR antagonist is a non-steroidal AR antagonist. In some embodiments, the non-steroidal AR antagonist is enzalutamide. In some embodiments, the method comprises administering enzalutamide at a dose of between about 80mg to about 240 g. In some embodiments, the method comprises administering enzalutamide at a dose of about 1 Q mg. In some embodiments, the method comprises administering enzalutamide at a dose of about 160 mg on each day of the one or more dosing cycles. n some embodiments of the above aspect, the anti-PD-L1 antibody inhibits the binding of PD-L1 to PD- , the binding of PD-L1 to B7-1 , or the binding of PD-L1 to both PD-1 and B7-1 . In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab (MPDL3280A), YW243.55.S70, SB001071 8C, MDX-1 105, and MEDI4736. in some embodiments, the anti-PD-L1 antibody comprises the following hypervariable regions (HVRs): (a) an HVR-H1 sequence of GFTFSDSWIH (SEQ D NO: 1) , (b) an HVR-H2 sequence of AW!SPYGGSTYYADSVKG (SEQ ID NO: 2) , (c) an HVR-H3 sequence of RHWPGGFDY (SEQ D NO: 3) , (d) an HVR-L1 sequence of RASQDVSTAVA (SEQ D NO: 4), (e) an HVR-L2 sequence of SASFLYS (SEQ D NO: 5) , and (f) an HVR-L3 sequence of QQYLYHPAT (SEQ D NO: 6). n some embodiments, the anti-PD-L1 antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ D NO: 7 , (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ D NO: 8 , or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the anti-PD-L1 antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ D NO: 7 , (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8 , or (c) a VH domain as in (a) and a VL domain as in (b).
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