Belzutifan in docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): Phase 1b/2 KEYNOTE-365 cohort J.

5058 Background: Hypoxia-inducible factor 2α (HIF-2α) is an established oncogenic driver, and HIF-2α expression in prostate cancer is positively correlated with aggressive disease. Belzutifan is a selective HIF-2α inhibitor approved for use in clear cell renal cell carcinoma. Cohort J of the multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573) evaluated the safety and efficacy of belzutifan in participants (pts) with mCRPC. Methods: Eligible adults had histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology, had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had received prior docetaxel for mCRPC. Prior treatment with 1 other chemotherapy and ≤2 second-generation hormonal agents were allowed. Pts received oral belzutifan 120 mg daily. Primary end points were safety and tolerability, prostate-specific antigen (PSA) response rate (PSA decline ≥50%), and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included time to PSA progression, ORR, and radiographic progression-free survival (rPFS) per PCWG3-modified RECIST v1.1, duration of response and disease control rate (DCR; complete response + partial response + stable disease ≥6 mo) per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR, and overall survival (OS). Results: A total of 21 pts were allocated to receive belzutifan. Median age was 69.0 y (range, 56-84). Median study follow-up was 17.6 mo (range, 15.9-21.8). All pts discontinued treatment as of the data cutoff (August 25, 2025), most commonly due to progressive disease (n = 12; 57%). Median duration of belzutifan therapy was 2.8 mo (range, 0.7-8.7). Treatment-related adverse events (AEs) occurred in 20 pts (95%); grade 3 or 4 treatment-related AEs occurred in 11 pts (52%), most commonly anemia (n = 8; 38%). A total of 2 pts (10%) discontinued treatment, and no pts died due to treatment-related AEs. Among pts with a baseline PSA measurement (n = 20), PSA response rate was 0% (95% CI, 0-17) and median time to PSA progression was 3.0 mo (95% CI, 2.8-not reached [NR]). Among 12 pts with RECIST-measurable disease, ORR and DCR per RECIST v1.1 were both 0%; ORR and DCR per PCWG3-modified RECIST v1.1 were 0% and 8%, respectively. In all pts, median rPFS was 3.7 mo (95% CI, 1.9-NR) and median OS was 16.9 mo (95% CI, 10.8-NR). Conclusions: In cohort J of the KEYNOTE-365 trial, belzutifan monotherapy had a manageable safety profile but did not show meaningful antitumor activity in mCRPC. Future research is needed to determine effective treatments for pts with mCRPC. Clinical trial information: NCT02861573 .