1771MO - Pembrolizumab (pembro) plus enzalutamide (enza) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Randomized double-blind phase III KEYNOTE-641 study

Background

Pts with mCRPC with progressive disease (PD) during 2^nd generation hormonal agent therapy typically receive chemo next. Additional therapies are needed in this setting. Pembro + enza had antitumor activity in pretreated mCRPC in early phase studies. KEYNOTE-641 (NCT03834493) evaluated pembro + enza vs placebo (pbo) + enza in pts with chemo-naïve mCRPC with/without prior abiraterone (abi).

Methods

Eligible pts were male, aged ≥18 years, had ECOG PS ≤1, had confirmed mCRPC with no prior chemo except docetaxel in the hormone-sensitive setting, and had intolerance to or PD during prior abi or no prior abi. Pts were randomized 1:1 to pembro 200 mg or pbo IV Q3W for ≤35 cycles + enza 160 mg orally daily. Dual primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 by blinded independent central review. Time to initiation of first subsequent anticancer therapy (TFST) was a key secondary endpoint. Safety/tolerability was a secondary endpoint.

Results

1244 pts were enrolled between Aug 21, 2019, and Jun 10, 2022 (n=621 to pembro + enza; n=623 to pbo + enza). As of Dec 12, 2022, the median (range) follow-up time at first prespecified interim analysis was 27.6 mo (6.1–39.8). 60.9% of all pts had prior abi and 29.1% had prior docetaxel, balanced between arms. The dual primary endpoints of rPFS (median 10.4 mo with pembro + enza vs 9.0 mo with pbo + enza; HR 0.98, 95% CI 0.84−1.14; P=0.41) and OS (median 24.7 mo vs 27.3 mo; HR 1.04, 95% CI 0.88−1.22; P=0.66) were not met. The prespecified boundary for futility for OS was crossed and the study was stopped. Median TFST was 13.2 mo vs 12.6 mo, respectively (HR 0.95, 95% CI 0.83−1.09). Any-grade and grade ≥3 treatment-related AEs occurred in 77.9% and 31.2% of 615 pts with ≥1 dose pembro + enza and 61.6% and 10.8% of 620 pts with ≥1 dose pbo + enza. 3 treatment-related deaths occurred with pembro + enza and none with pbo + enza.

Conclusions

Pembro + enza did not significantly improve efficacy outcomes vs pbo + enza in pts with mCRPC with/without prior abi. Pembro + enza was associated with more treatment-related AEs vs pbo + enza; no new safety signals were observed.

Clinical trial identification

NCT03834493.

Editorial acknowledgement

Writing assistance was provided by Ina Nikolaeva of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Astellas provided the enzalutamide for this study.

Legal entity responsible for the study

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

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

J.N. Graff: Financial Interests, Personal, Invited Speaker, CME vendor: P3; Financial Interests, Personal, Invited Speaker, CME: Binaytara Foundation; Financial Interests, Personal, Other, Testicular cancer chair- make around $7,000 USD per year: Elsevier; Financial Interests, Personal, Other, Testicular cancer chair: Elsevier; Financial Interests, Institutional, Coordinating PI, Two Investigator initiated, lead in a phase 3 trial (KN 641), local PI for several studies: Merck Sharpe Dohme; Financial Interests, Institutional, Steering Committee Member: Janssen, Curium; Financial Interests, Institutional, Coordinating PI: Sanofi; Non-Financial Interests, Leadership Role: Veterans Affairs Hospital. M. Burotto: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS; Financial Interests, Personal, Advisory Board: Merck & Co., Inc., Roche. 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. D. Pook: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: BMS, MSD, Ipsen, Pfizer, Eisai, Astellas; Financial Interests, Institutional, Invited Speaker: BMS, Astellas, Pfizer, Roche, Ipsen, MSD, Amgen. R. Manneh Kopp: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, BMS, Janssen, Astellas, Pfizer, Bayer, Eli Lilly, Roche, Tecnofarma, Procaps; Financial Interests, Personal, Advisory Board: MSD, Bayer, Tecnofarma; Financial Interests, Personal and Institutional, Invited Speaker: MSD, Bayer, BMS, Roche, Pfizer, Novartis, AstraZeneca; Non-Financial Interests, Leadership Role: Asociación Colombiana de Hematología y Oncología. G. Kramer: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bayer, Janssen, Pfizer, Sandoz; Financial Interests, Personal, Advisory Role: Ferring, MSD, Novartis; Financial Interests, Personal, Other, Travel Expenses: Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis. R. Ratta: Financial Interests, Personal, Invited Speaker: Ipsen, Astellas; Financial Interests, Personal, Advisory Board: Pfizer, Merck, BMS, AstraZeneca. M. Kwiatkowski: Financial Interests, Personal, Invited Speaker: Janssen Cilag, Novartis, Roche; Non-Financial Interests, Principal Investigator, Clinical Trials: MSD, BMS; Non-Financial Interests, Principal Investigator, Clinical trials: AstraZeneca, Roche, Hengrui, Janssen Cilag, BeiGene, Shanghai Jinshu, Bayer. M. Retz: Financial Interests, Personal, Research Grant: BMS. J.A. Arranz Arija: Financial Interests, Personal, Advisory Board: Astellas, BMS, Merck, Pfizer, Bayer, MSD, Eisai; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker, SOGUG: BMS. H.P. Gurney: Financial Interests, Personal, Advisory Board: Merck, Pfizer, AstraZeneca, BMS, MSD, Ipsen, Astellas. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Invited Speaker: Janssen, AstraZeneca, Bayer, Roche, MSD, Taiho, Astellas, Amgen, Eisai, Eli Lilly, Pfizer, Chugai, AbbVie. L.W. Liang, J. Todoric, K. Imai: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. A. Stenzl: Financial Interests, Personal, Advisory Board: Astellas, Pfizer, Bayer, Ipsen Pharma, Roche Pharma, AstraZeneca, Cystotech, GSK, MSD; Non-Financial Interests, Other, Preparation of an official project related to connection between Hospitals/doctors and Industry in general, Z.I.M.T: BioRegioSTERN; Non-Financial Interests, Leadership Role, Secretary General: European Assoc. of Urology (EAU); Non-Financial Interests, Leadership Role, Member Board of Directors: European Cancer Organisation. All other authors have declared no conflicts of interest.