Nivolumab and ipilimumab for metastatic prostate cancer with an immunogenic signature: The NEPTUNES multi-centre two-cohort, biomarker-selected phase 2 trial.
Authors: Mark David Linch, Gianmarco Leone, Yien Ning Sophia Wong, Robert J. Jones, Peter Sankey, Debra Hannah Josephs, Simon J. Crabb, Louise Harris, Aniqa Tasnim, Memuna Rashid, Sergio A. Quezada, Leah Ensell, Anuradha Jayaram, Mahaz Kayani, Colin C. Pritchard, Alex Freeman, Aiman Haider, Gerhardt Attard, Charles Swanton, Teresa Marafioti
Journal: Journal of Clinical Oncology (2024)

5013 Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is likely due to a “cold” tumour immune microenvironment. We hypothesised that patients with mCRPC would be more likely to respond if they had a positive immunogenic signature (ImS+). We report a phase 2 trial of two different dose schedules for nivolumab (NIVO) + ipilimumab (IPI) in patients with ImS+ mCRPC. Methods: Patients with mCRPC who progressed following ≥1 line of therapy and ImS+ were eligible. ImS+ was defined by ≥1 of the following: 1) mismatch repair deficient (MMRD) by immunohistochemistry (IHC); 2) DNA damage repair deficient (DDRD) detected by the UW-OncoPlex targeted exome sequencing assay and; 3) High Tumour infiltrating lymphocytes (TILs) on multiplexed IHC (≥20% of nucleated cells). There were two patient cohorts conducted sequentially: NIVO 1 mg/kg + IPI 3 mg/kg (C1) then NIVO 3 mg/kg + IPI 1 mg/kg (C2) Q3W for 4 doses; both followed by NIVO 480 mg every 4 weeks up to 1 year. Primary endpoint was composite response rate (CRR) defined by ≥1 of the following: 1) confirmed radiological response by RECIST 1.1; 2) confirmed PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) at week 9. CRR ≥40% would be clinically favourable (minimum of 20%). Secondary endpoints included toxicity, duration of response (DOR), and overall survival (OS). Tissue collection for biomarker analyses was mandated. Results: Between May 2018 and June 2022 119/380 (31%) screened patients were ImS+, of whom 35 (C1) and 36 (C2) enrolled in the trial. The CRR in C1 was 14/35 (40%, 90%CI: 26-55%) and in C2 was 9/36 (25%, 90%CI: 14-40%). The combined CRR was 23/71 (32%, 90%CI: 23-43%). Grade 3-4 treatment-related adverse events occurred in 22/35 (63%) in C1 and 11/36 (31%) in C2. The most common G3-4 event was diarrhoea present in 15 (42%) and 3 (8%) patients for C1 and C2. The median DOR was 10.4 (C1) and 6.4 (C2) months. After a median follow-up of 47 (C1) and 21 (C2) months, median OS was 16.2 months (95%CI 9.2-22.8m) and 15.2 months (95%CI 8.9-NA) respectively. The ImS+ determinants in responding patients were MMRD (8/10), BRCA1/2 (4/8), high TILs (8/21), CDK12 (2/8), ATM (1/13) and CHD1 (1/9). In C1 4/9 (44%) of patients with exclusively high TILs responded. Exploratory biomarker analyses are ongoing. Conclusions: Inflammatory infiltrate is a promising prospectively tested predictive biomarker in pre-treated mCRPC. Although NIVO 1 mg/kg + IPI 3 mg/kg had more toxicities than NIVO 3 mg/kg + IPI 1 mg/kg, the efficacy results were consistently better. This dose schedule and biomarker should now be tested in a phase 3 clinical trial. Clinical trial information: NCT03061539 .