Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature (NEPTUNES).

Abstract

TPS5090 Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is in part attributed to low tumour mutational burden (TMB) and low tumour infiltrating lymphocytes (TILs). Previously ~20% patients with prostate cancer have demonstrated high TILs or TMB1. We hypothesize that patients with higher TMB due to mismatch repair deficiency (dMMR) or defective DNA damage response (dDDR) and patients with high TILs are more likely to respond to combination CPI with anti PD-1 and anti CTLA-4 therapy. Methods: NEPTUNES is a single arm phase II trial designed to assess the efficacy of nivolumab and ipilimumab in biomarker selected patients with mCRPC that have progressed following ≥1 line of therapy. The immunogenic signature (ImS) biomarker is defined by ≥1 of the following: 1) dMMR by immunohistochemistry (IHC); 2) dDDR detected by the UW-OncoPlex sequencing assay and; 3) high TILs on multiplexed IHC. The UW-OncoPlex assay detects mutations in >260 genes and provides an estimation of TMB. Assuming an ImS+ rate of 20%, we aim to pre-screen 175 patients in order to enrol 35 patients into the main study. The primary endpoint is composite response rate (CRR), achieved if ≥1 of the following criteria are satisfied: 1) radiological response by RECIST 1.1; 2) PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) count from ≥5 cells at baseline to <5 cells at week 9. The treatment will be deemed ineffective if the CRR is <20%. Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) is dosed every three weeks for up to 4 times, followed by a 480mg flat dose of nivolumab every 4 weeks for up to one year. Baseline biopsies are mandated and paired biopsy at week 12 is encouraged. The secondary endpoints include safety, overall survival, and radiological and PSA progression free survival. Exploratory biological markers including TMB, mutational profiles, change in TILs and liquid biomarkers will be correlated with the primary clinical endpoint. Since opening in February 2018, 126 patients have been pre-screened with 25 ImS+. To date, 9/25 ImS+ patients have been enrolled into the main study. The trial is ongoing, with patient accrual expected to complete by late 2019.