Background: The combination of pembro, an anti–PD-1 antibody, added to enza, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC) in the KEYNOTE-365 trial (NCT02861573) and in pts with mCRPC for whom enza was ineffective in the KEYNOTE-199 trial (NCT02787005). The efficacy of enza may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembro. These data indicate that pembro + enza with ADT warrants phase 3 evaluation. Methods: KEYNOTE-991 (NCT04191096) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial evaluating the efficacy and safety of enza + ADT (luteinizing hormone-releasing hormone agonist/antagonist during study treatment or bilateral orchiectomy) + pembro or placebo in pts with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Pts must provide tissue for biomarker analysis. Approximately 1232 pts will be randomized in a 1:1 ratio to receive enza 160 mg orally once daily + ADT + pembro 200 mg intravenously (IV) every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembro up to 35 cycles and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Computed tomography or magnetic resonance imaging and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 12 weeks (Q12W) from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The dual-primary endpoints are BICR-assessed radiographic progression-free survival (rPFS; according to PCWG3-modified RECIST v1.1) and overall survival (OS). Key secondary endpoints are time to first subsequent anticancer therapy (TFST) and time to symptomatic skeletal-related event (TTSSRE). Safety and tolerability will be evaluated using a tiered approach. The dual-primary (rPFS and OS) and key secondary (TFST and TTSSRE) endpoints will be evaluated using a stratified log-rank test. Event rates will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Germany, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States. Clinical trial information: NCT04191096