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

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. 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. 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. 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.