1362MO - Pembrolizumab + olaparib vs abiraterone (abi) or enzalutamide (enza) for patients (pts) with previously treated metastatic castration-resistant prostate cancer (mCRPC): Randomized open-label phase III KEYLYNK-010 study

Background

There is unmet need for effective therapies for pts with heavily pretreated mCRPC. KEYLYNK-010 (NCT03834519) evaluated efficacy and safety of pembrolizumab (P) + olaparib (O) vs abi or enza for molecularly unselected pts with mCRPC after a next-generation hormonal agent (NHA) and docetaxel.

Methods

Eligible pts were ≥18 yrs; had mCRPC that progressed on or after abi or enza (but not both) as well as docetaxel; had ECOG PS ≤1. Pts were randomized 2:1 to 200 mg P IV Q3W for ≤35 cycles + 300 mg O orally BID, or to NHA: 1000 mg abi orally QD (if prior enza) or 160 mg enza orally QD (if prior abi). Dual primary endpoints were radiographic PFS (rPFS) by blinded independent central review (BICR) per PCWG-modified RECIST 1.1 (final testing at first interim analysis [IA1]), and OS (final testing at IA2). Secondary endpoints included ORR by BICR per PCWG-modified RECIST 1.1 and safety/AEs.

Results

793 pts were randomized to P + O (n=529) or NHA (n=264) between May 30, 2019 and July 16, 2021. The KEYLYNK-010 study was stopped for futility. As of Jan 18, 2022, median (range) follow-up for IA2 was 11.9 mo (0.9–31.0). Baseline characteristics were balanced between arms. The primary endpoints of rPFS (median 4.4 mo with P + O vs 4.2 mo with NHA; HR 1.02, 95% CI 0.82−1.25; P=0.55) and OS (15.8 mo vs 14.6 mo; HR 0.94, 95% CI 0.77−1.14; P=0.26) were not met. ORR was 17% with P + O vs 6% with NHA (nominal P=0.002). Exploratory analysis of subgroups by tissue-based homologous recombination repair gene alteration (HRRm) at IA2 suggested a potential difference in rPFS (HRRm [P + O n=81, NHA n=37]: HR 0.53, 95% CI 0.33–0.86; non-HRRm [P + O n=246, NHA n=118]: HR 1.19, 95% CI 0.90–1.58) but not in OS (HRRm: HR 0.91, 95% CI 0.53–1.56; non-HRRm: HR 1.03, 95% CI 0.77–1.38). Gr ≥3 TRAEs occurred in 35% of pts with P + O and 9% of pts with NHA; 5% and 1% of pts, respectively, had gr ≥3 immune-mediated AEs.

Conclusions

Pembrolizumab + olaparib did not improve rPFS or OS in the unselected population despite a higher ORR. While pembrolizumab + olaparib resulted in more gr ≥3 TRAEs vs NHA in pts with previously treated mCRPC, no new safety signals occurred.

Clinical trial identification

KEYLYNK-010, NCT03834519.

Editorial acknowledgement

Writing assistance was provide by Ina Nikolaeva of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

E.Y. Yu: Financial Interests, Personal, Advisory Board: AbbVie, Advanced Accelerator Applications, Bayer, Clovis, Exelixis, Janssen, Merck, Genzyme; Financial Interests, Institutional, Research Grant: Bayer, Blue Earth, Daiichi Sankyo, Dendreon, Lantheus, Merck, Seagen, Taiho. J.C.H. Goh: Financial Interests, Personal, Advisory Board, Prior member of the BMS RCC Advisory Board: BMS; Financial Interests, Personal, Advisory Board, Uterine Cancer Advisory Board: GSK; Financial Interests, Personal, Other, Chairing RCC meeting: Ipsen; Financial Interests, Personal, Invited Speaker, Speaking at MSD sponsored event on Gynaecological cancer: MSD; Financial Interests, Personal, Advisory Board, Met RCC Advisory Board: MSD/ Eisai; Financial Interests, Personal, Other, Asia-Pacific Advisory Board member for prostate cancer: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Private Cancer Centres in Australia: ICON Cancer Centres; Financial Interests, Institutional, Funding, Funding for phase 2 metastatic cervical cancer trial: BeiGene; Non-Financial Interests, Principal Investigator, local PI for CHECKMATE-914, CHECKMATE-9KD trial, CHECKMATE-7DX & CHECKMATE-9ER trials: BMS. N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Invited Speaker: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Principal Investigator, Co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Leadership Role: Castration-resistant Prostate Cancer Registry. R. McDermott: Financial Interests, Personal, Advisory Board: Amgen, Bayer, BMS, Clovis, Janssen, Pfizer; Financial Interests, Personal, Invited Speaker: Astellas, Ipsen, MSD; Financial Interests, Institutional, Principal Investigator: Astellas, Bayer, BMS, Clovis, MSD, Regeneron. M.A. Sala Gonzalez: Non-Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Advisory Board: AstraZeneca. P.C. Fong: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Oncology meeting attendance/Accommodation: Pfizer; Non-Financial Interests, Advisory Role: New Zealand Prostate Cancer Foundation. R. Greil: Financial Interests, Personal, Other: Celgene, Roche, Merck, Takeda, AstraZeneca Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Personal, Advisory Board: Celgene, Novartis, Roche , BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Institutional, Research Grant: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie Gilead, Daiichi Sankyo; Financial Interests, Personal, Funding: Roche, Amgen, Janssen, AstraZeneca Novartis, MSD, Celgene, Gilead, BMS, AbbVie, Daiichi Sankyo. Y. Huang: Financial Interests, Personal, Invited Speaker: Astellas, BMS, Ipsen, Janssen, Pfizer, AstraZeneca; Financial Interests, Personal, Advisory Board: Astellas, Bayer. S. Begbie: Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Principal Investigator: Merck; Financial Interests, Institutional, Research Grant: MSD, Merck; Financial Interests, Institutional, Principal Investigator: MSD, Merck. F. Rey: Financial Interests, Institutional, Funding: MSD. G. Kramer: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Novartis, Sanofi Genzyme, Takeda, Ferring. H. Suzuki: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca, MSD, Takeda, Sanofi, Bayer; Financial Interests, Personal, Advisory Board: Janssen, Astellas, AstraZeneca, MSD, Takeda, Sanofi, Bayer, Chugai-Roche, Eli Lilly; Financial Interests, Institutional, Research Grant: Takeda, Astellas, Bayer, AstraZeneca, MSD, Chuga-Roche, Nippon Shinyaku, Nihon Kayaku. J. Zhang: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. J. Kim: Financial Interests, Institutional, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Institutional, Stocks/Shares: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. E.S. Antonarakis: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Sanofi, Dendreon, Bayer, BMS, Amgen, ESSA, Constellation, Blue Earth, Exact Sciences, Invitae, Curium, Pfizer, AstraZeneca, Clovis, Eli Lilly; Financial Interests, Personal, Research Grant: Janssen, J&J, Sanofi, BMS, Pfizer, Novartis, Curium, Constellation, ESSA, Celgene, Merck, Bayer, Clovis. All other authors have declared no conflicts of interest.