Leone, Gianmarco, Wong, Yien Ning Sophia, Jones, Robert J., Sankey, Peter, Josephs, Debra H., Crabb, Simon J., Harris, Louise, Zarkar, Anjali, Protheroe, Andrew, Vasudev, Naveen, Rashid, Memuna, Lopes, Andre, Tasnim, Aniqa, Ensell, Leah, Hartley, John, Jayaram, Anuradha, Kularatne, Bihani, Kayani, Mahaz, Pritchard, Colin C., Konnick, Eric Q., Freeman, Alex, Haider, Aiman, Linares, Josep, Attard, Gerhardt, Quezada, Sergio A., Swanton, Charles, Marafioti, Teresa and Linch, Mark D. (2025) Nivolumab and ipilimumab for metastatic castration-resistant prostate cancer with an immunogenic signature: the multicenter, two-cohort, phase II NEPTUNES study. Journal of Clinical Oncology, JCO2402637, [JCO-24-02637]. (doi:10.1200/JCO-24-02637).
Abstract
Purpose: efficacy of immune checkpoint inhibitors in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) is limited. The NEPTUNES study evaluated combination nivolumab and ipilimumab in patients with immunogenic signature-positive (ImS+) mCRPC.
Materials and methods: this open-label, 2-cohort, phase II trial enrolled patients with ImS+ mCRPC progressing on ≥1 previous line of treatment. ImS+ was defined by (1) mismatch repair deficiency (MMRD); (2) DNA damage repair gene loss; and/or (3) high inflammatory infiltrate (HII). Patients received four doses of nivolumab 1 mg/kg + ipilimumab 3 mg/kg (C1) or nivolumab 3 mg/kg + ipilimumab 1 mg/kg (C2) followed by nivolumab 480 mg once every 4 weeks up to 10 cycles. The primary end point was composite response rate (CRR) assessed radiologically, biochemically, and by reduction of circulating tumor cells. Secondary end points included toxicity, progression-free survival, overall survival, and duration of response.
Results: between May 2018 and June 2022, 35 (C1) and 36 (C2) patients commenced treatment. The CRR in C1 was 14/35 (40%, 90% CI, 26% to 55%) and in C2 was 9/36 (25%, 90% CI, 14% to 40%). The overall CRR was 23/71 (32%, 90% CI, 23% to 43%). Response rates were higher in patients with MMRD (7/10), BRCA2 loss (4/8), and HII ± other ImS+ features (13/30). Duration of response for patients with HII without other ImS+ features, DNA repair gene loss without MMRD, and MMRD was 2.6, 17.3, and 10 months, respectively. Grade 3 to 4 treatment-related adverse events occurred in 22/35 (63%) in C1 and 12/36 (33%) patients in C2. There were no treatment-related deaths.
Conclusion: nivolumab 1 mg/kg + ipilimumab 3 mg/kg is an active treatment in ImS+ pretreated mCRPC. Nivolumab 3 mg/kg + ipilimumab 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.
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