KEYNOTE-991: Pembrolizumab Plus Enzalutamide, ADT for mHSPC

Research presented at the European Society for Medical Oncology Congress 2023 shed light on the safety and efficacy of pembrolizumab plus enzalutamide and androgen deprivation therapy (ADT) in patients with next-generation hormonal agent (NHA)-naïve metastatic hormone-sensitive prostate cancer (mHSPC).

Novel therapeutic approaches are needed to delay disease progression for patients with mHSPC. Previous research has shown that pembrolizumab plus enzalutamide has antitumor activity in patients with metastatic prostate cancer.

Christian J. Gratzke, MD, of Albert-Ludwigs-University of Freiburg, and colleagues designed the randomized, double-blind, phase 3 KEYNOTE-991 study to investigate pembrolizumab or placebo plus enzalutamide and ADT in patients with NHA-naïve mHSPC. Eligible patients—those aged at least 18 years and with an Eastern Cooperative Oncology Group performance status of ≤1—had confirmed mHSPC (≥2 bone lesions and/or visceral disease), no prior NHA, and had completed any prior docetaxel ≤2 months from randomization. Patients were randomized (1:1) to receive pembrolizumab (200 mg; n=626) or placebo (n=625) plus enzalutamide (160 mg orally, daily) plus continuous ADT (if no history of bilateral orchiectomy).

The dual primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Secondary end points included time to initiation of first subsequent anticancer therapy (TFST), time to first symptomatic skeletal-related event (TTSSRE), and safety. As of October 31, 2022, the median follow-up time at first prespecified interim analysis was 21.1 months (range, 14.8-32.0 months).

Dr. Gratzke and colleagues reported that the primary end point of rPFS was not met (median not reached [NR] versus NR, respectively; hazard ratio [HR], 1.20; 95% CI, 0.96-1.49; P=.95). Additionally, median OS was NR versus 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), and median TTSSRE was NR in both arms (HR, 0.89; 95% CI, 0.61-1.30).

Serious adverse events (AEs) occurred in 40.3% and 23.2% of patients, respectively. Any-grade and grade ≥3 treatment-related AEs occurred in 88.0% versus 67.0% and 41.8% versus 13.9% of patients, respectively.

Researchers noted that the study was stopped for futility and concluded that “the addition of pembrolizumab to enzalutamide plus ADT does not improve rPFS or OS in patients with NHA-naïve mHSPC and was associated with more serious and treatment-related adverse events versus enzalutamide plus ADT.”