Nivolumab and ipilimumab for metastatic prostate cancer with an immunogenic signature: The NEPTUNES multi-centre two-cohort, biomarker-selected phase 2 trial.

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 .