Phase 1b/2 study of pembrolizumab plus belzutifan and belzutifan alone in patients with docetaxel-treated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort J.
Authors: Yu Evan Y. , Joshua Anthony M. , Shore Neal D. , Kramer Gero , Hu Haixia , Poehlein Christian Heinrich , Schloss Charles , De Bono Johann S. 
Published: January 2024

TPS250 Background: Treatment options are needed for patients (pts) with mCRPC whose disease progresses after docetaxel. Hypoxia-inducible factor–2α (HIF-2α) is a transcription factor established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC). Expression of HIF-2α in prostatectomy specimens has been associated with tumor volume and large tumors more often exhibited higher levels of HIF-2α expression. The selective HIF-2α inhibitor, belzutifan, blocks the heterodimerization of HIF-2α with HIF-1β and has demonstrated antitumor activity and manageable safety in pts with ccRCC. The anti–PD-1 antibody pembrolizumab has been shown to have activity as monotherapy and combination therapy in pts with mCRPC. Therefore, the combination of pembrolizumab and belzutifan may provide additional benefit for mCRPC. Cohort J of the multicohort, open-label, phase 1b/2 KEYNOTE-365 (NCT02861573) study will evaluate the safety and efficacy of pembrolizumab in combination with belzutifan in pts with mCRPC who previously received docetaxel. Methods: Eligible pts must be aged ≥18 years, have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology, have an ECOG PS of 0 or 1, and have received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy and ≤2 second-generation hormonal manipulations are allowed. Approximately 20 pts will receive belzutifan monotherapy 120 mg orally daily. If an efficacy signal is detected in the monotherapy arm, up to 180 pts will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV every 3 weeks (Q3W) + belzutifan 120 mg orally daily or belzutifan alone in an expansion phase. Randomization for the expansion phase will be stratified by ECOG PS (0 vs 1). Imaging assessments (computed tomography/magnetic resonance imaging, and bone scans) will be performed every 9 weeks through week 54 and every 12 weeks thereafter, at treatment discontinuation, and during follow-up. Prostate-specific antigen (PSA) will be measured Q3W until progression. Adverse events (AEs) will be monitored and assessed by investigators using NCI Common Terminology Criteria for Adverse Events version v4.0 throughout the study and for 30 days (90 days for serious AEs, or 30 days if new anticancer therapy is initiated, whichever occurs first) after the last dose of study treatment. Primary end points are safety and tolerability, PSA response rate (PSA decline ≥50%), and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression, ORR and rPFS per PCWG3-modified RECIST v1.1, DOR and DCR per RECIST v1.1 by BICR, and OS. Efficacy and safety will be analyzed in all allocated pts who received ≥1 dose of study treatment. No formal hypothesis testing will be performed. Enrollment for this study is currently ongoing. Clinical trial information: NCT02861573 .