PURPOSE: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer (mCRPC). Novel combinations may enhance immunotherapy efficacy. PATIENTS AND METHODS: We conducted an open-label, non-comparative platform trial (NCT03835533) in mCRPC to assess nivolumab-based combinations. The cohorts were: A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg intravenously Q3W, B) stereotactic body radiation therapy 30-50 Gray, CDX-301 75 μg/kg subcutaneously for 5 days, poly-ICLC 1 mg intramuscularly twice weekly for 3 weeks, and nivolumab 480 mg Q4W, and C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on Lead-in Day 8, Day 1 of Cycles 1-3, then Q12W, and nivolumab 480 mg Q4W. The primary endpoint was safety
secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control. RESULTS: 43 patients enrolled (N = 14, 15, 14 in Cohorts A, B, C). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one Grade 5 TRAE in Cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with pre-existing memory/regulatory T cells, TNFα, and other inflammatory pathways. CONCLUSIONS: Cohort B, which combined radiation therapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Pre-existing rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.