In a UK phase II trial (NEPTUNES) reported in the Journal of Clinical Oncology, Leone et al evaluated the efficacy of nivolumab plus ipilimumab in previously treated patients with immunogenic signature–positive metastatic castration-resistant prostate cancer (mCRPC).
Study Details
The multicenter trial enrolled two cohorts of patients progressing on at least one previous line of treatment. Cohort 1 enrolled 35 evaluable patients between May 2018 and October 2020, with patients receiving four doses of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg followed by nivolumab at 480 mg every 4 weeks for up to 10 cycles. Cohort 2 enrolled 36 evaluable patients between November 2020 and June 2022, with patients receiving four doses of nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg followed by nivolumab at 480 mg every 4 weeks for up to 10 cycles. Immunogenic signature–positive status was defined by mismatch repair deficiency (MMRD), DNA damage repair gene loss, or high inflammatory infiltrate (HII). The primary outcome measure was composite response rate as assessed radiologically, biochemically, and by reduction of circulating tumor cells.
Key Findings
Composite response was observed in 14 of 35 patients (40%, 90% confidence interval [CI] = 26%–55%) in the nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg cohort and in 9 of 36 patients (25%, 90% CI = 14%–40%) in the nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg cohort. In both cohorts combined, composite response was observed in 23 of 71 patients (32%, 90% CI = 23%–43%).
Among all patients, response rates were highest in patients with MMRD (7/10 = 70%), BRCA2 loss (4/8 = 50%), and HII with or without other immune signature features (13/30 = 43%). Median durations of response included 2.6 months in patients with HII without other immune signature features, 6.5 months in those with HII with or without other immune signature features, 10 months in those with MMRD, and 17.3 months in those with DNA repair gene loss without MMRD.
Grade 3 or 4 treatment-related adverse events occurred in 63% of patients in the nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg cohort and 33% of patients in the nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg cohort. No treatment-related deaths were observed.
The investigators concluded: “Nivolumab [at] 1 mg/kg + ipilimumab [at] 3 mg/kg is an active treatment in [immune signature–positive] pretreated mCRPC. Nivolumab [at] 3 mg/kg + ipilimumab [at] 1 mg/kg has less toxicity but may have lower efficacy. HII is a promising prospectively tested predictive biomarker in prostate cancer that could be integrated into future trials.”
Mark D. Linch, MD, PhD, of the University College London Cancer Institute, London, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Bristol Myers Squibb, Rosetrees Trust and John Black Charitable Foundation, and Cancer Research UK. For full disclosures of all study authors, visit ascopubs.org.
