1772MO - Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Randomized double-blind phase III KEYNOTE-991 study

Background

New therapeutic options are needed to delay disease progression for pts with mHSPC. The combination of pembro + enza has shown antitumor activity in pts with metastatic prostate cancer. The phase 3 KEYNOTE-991 study (NCT04191096) investigated pembro or placebo (pbo) + enza + ADT in pts with next-generation hormonal agent (NHA)-naïve mHSPC.

Methods

Eligible pts (aged ≥18 yrs, ECOG PS ≤1) had confirmed mHSPC (≥2 bone lesions and/or visceral disease, verified centrally), no prior NHA, and had completed any prior docetaxel (≤6 cycles) ≤2 mo from randomization. Pts were randomized 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + enza 160 mg orally daily + continuous ADT (if no history of bilateral orchiectomy). Dual primary endpoints were radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS). Key secondary endpoints included time to initiation of first subsequent anticancer therapy (TFST) and time to first symptomatic skeletal-related event (TTSSRE). Safety was a secondary endpoint.

Results

Between Mar 2, 2020, and Aug 9, 2021, 626 pts were randomized to pembro + enza and 625 to pbo + enza. As of Oct 31, 2022, the median (range) follow-up time at first prespecified interim analysis was 21.1 mo (14.8−32.0). Baseline characteristics were generally balanced between arms; ∼10% of pts received prior docetaxel in each arm. The primary endpoint of rPFS for pembro + enza vs pbo + enza was not met (median not reached [NR] vs NR, HR 1.20, 95% CI 0.96−1.49, P=0.95). Median OS was NR vs NR (HR 1.16, 95% CI 0.88−1.53). Median TFST was NR in both arms (HR 1.24, 95% CI 1.01−1.54). Median TTSSRE was NR in both arms (HR 0.89, 95% CI 0.61−1.30). Serious AEs occurred in 40.3% vs 23.2% of pts with pembro + enza vs pbo + enza. Any-grade and grade ≥3 treatment-related AEs occurred in 88.0% vs 67.0% and 41.8% vs 13.9% of pts, respectively.

Conclusions

The study was stopped for futility. The addition of pembro to enza plus ADT did not improve rPFS or OS in pts with NHA-naïve mHSPC and was associated with more serious and treatment-related AEs vs enza plus ADT.

Clinical trial identification

NCT04191096.

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

C.J. Gratzke: Financial Interests, Personal, Advisory Board: Astellas Pharma, Bayer, GSK, MSD, AstraZeneca, Janssen, Steba Biotech; Financial Interests, Personal, Invited Speaker: Astellas Pharma, Bayer, MSD, MSD, Bayer, Recordati, Amgen, AstraZeneca, AstraZeneca, Ipsen, Janssen, Janssen, Novartis, Pfizer; Financial Interests, Personal and Institutional, Invited Speaker: MSD, MSD; Financial Interests, Personal and Institutional, Funding: MSD; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Invited Speaker: Bayer, Janssen, Lilly, AstraZeneca; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Project Lead: Janssen, Bayer; Non-Financial Interests, Advisory Role: STEBA. M. Ozguroglu: Financial Interests, Personal, Advisory Board, prostate cancer: Astellas; Financial Interests, Personal, Invited Speaker, travel and accommodation: Regeneron; Financial Interests, Personal, Advisory Board, lung cancer meeting: Sanofi. A. Peer: Financial Interests, Personal, Advisory Board, and Invited speaker: MSD; Financial Interests, Personal, Advisory Board, And invited speaker: BMS; Financial Interests, Personal, Expert Testimony, and invited speaker: Roche; Financial Interests, Personal, Advisory Board, and invited speaker: Astellas; Financial Interests, Personal, Advisory Board: Janssen, Bayer, Teva, Takeda, Medison pharma; Financial Interests, Personal, Invited Speaker: Exelixis; Financial Interests, Institutional, Research Grant: Sanofi aventis. M.A.N. Sendur: Financial Interests, Personal, Advisory Board: BMS, Pfizer, Takeda, Roche, Astellas; Financial Interests, Personal, Invited Speaker: Astellas, Pfizer, BMS, MSD, Roche. M. Retz: Financial Interests, Personal, Research Grant: BMS. 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 @ MSD sponsored event on Gynaecological cancerSpeaking at MSD sponsored event on RCC: MSD; Financial Interests, Personal, Advisory Board, Met RCC Advisory Board: MSD/ Eisai; Financial Interests, Personal, Other, 1. Asia-Pacific Advisory Board member for prostate cancer2. Invited Speaker at AZ sponsored molecular/genomic testing meeting: 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. G. Jayram: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca; Financial Interests, Personal, Invited Speaker: Photocure, BMS; Financial Interests, Institutional, Invited Speaker: Janssen, Merck. S. Byun: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Clinical trial investigator: Astellas, MSD; Financial Interests, Personal, Other, Clinical trial investigator: Pfizer; Financial Interests, Personal, Invited Speaker, Clinical trial investigator: Janssen; Financial Interests, Personal, Officer, CEO: Inivites Biocore; Financial Interests, Personal, Stocks/Shares: PROCAGEN; Non-Financial Interests, Leadership Role, President: Korean Urological Research Society. 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. 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. J.C. Vazquez Limon: Financial Interests, Institutional, Full or part-time Employment, Attending physician and chief of oncology service: Hospital Civil de Guadalajara; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Novartis, Janssen, AstraZeneca, Roche, Regeneron, AbbVie, GSK; Non-Financial Interests, Advisory Role: Janssen; Non-Financial Interests, Institutional, Product Samples: GSK. J.F. Escobar Penagos: Financial Interests, Personal, Invited Speaker, Participate like principal investigator in clinical trials: AstraZeneca; Financial Interests, Personal, Invited Speaker, principal investigator in clinical trial: BMS; Financial Interests, Personal, Invited Speaker, principal investigator in clinical trials: MSD. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. K.M.D. Trindade: Financial Interests, Personal, Invited Speaker: Janssen, Merck, Astellas, AstraZeneca, Adium; Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Merck; Financial Interests, Institutional, Invited Speaker: MSD, Janssen, BMS, Roche. C. Niu: Financial Interests, Personal, Full or part-time Employment: MSD China; Financial Interests, Personal, Stocks/Shares: MSD China. Y. Liu, C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati. All other authors have declared no conflicts of interest.