Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial

Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7–expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1–NR) in cohort 1 and 2.7 (95% CI: 2.1–5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8–7.5) in cohort 1 and 2.9 (95% CI: 1.3–5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%–45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%–52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5–10.4) in cohort 1 and 14.2 (95% CI: 8.5–NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11–0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06–0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03–0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47–13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, −7, and −17) may be prognostic for outcomes to immunotherapy.