NEPTUNES: Nivolumab, Ipilimumab for Metastatic Prostate Cancer With an Immunogenic Signature

Dr. Mark David Linch, of University College London, presented the results of NEPTUNES—a multicenter, 2-cohot, biomarker-selected, phase 2 trial—at the 2024 American Society of Clinical Oncology Annual Meeting.

Patient responses to immune checkpoint inhibitor monotherapy for metastatic castration-resistant prostate cancer (mCRPC) have been limited to date, likely due to the “cold” tumor immune microenvironment.

Dr. Linch and colleagues believed that patients with mCRPC would be more likely to respond to immunotherapy if they have a positive immunogenic signature. They designed the NEPTUNES trial with 2 different dose schedules for nivolumab plus ipilimumab (nivolumab [1 mg/kg] plus ipilimumab [3 mg/kg; C1] then nivolumab [3 mg/kg] plus ipilimumab [1 mg/kg; C2] Q3W for 4 doses; both followed by nivolumab [480 mg] every 4 weeks for up to 1 year) in patients with positive immunogenic signature mismatch repair deficiency (MMRD) by immunohistochemistry, DNA damage repair deficiency detected by the UW-OncoPlex targeted exome sequencing assay, or high tumor-infiltrating lymphocytes on multiplexed immunohistochemistry.

The primary end point of NEPTUNES was composite response rate (CRR) defined by confirmed radiological response, confirmed prostate-specific antigen response of at least 50%, or conversion of circulating tumor cells at week 9. CRR of at least 40% was deemed clinically favorable. Secondary end points included toxicity, duration of response (DOR), and overall survival (OS).

Between May 2018 and June 2022, 35 patients (C1) and 36 patients (C2) who had progressed following at least 1 line of therapy were enrolled in the trial. Dr. Linch reported that the CRR in C1 was 40% (90% CI, 26%-55%) and in C2 was 25% (90% CI, 14%-40%). The combined CRR was 32% (90% CI, 23%-43%).

Additionally, researchers found that grade 3/4 treatment-related adverse events occurred in 63% and 31% of patients, respectively.

The median DOR was 10.4 months and 6.4 months, respectively. After a median follow-up of 47.0 and 21.0 months, the median OS was 16.2 months (95% CI, 9.2-22.8 months) and 15.2 months (95% CI, 8.9 months-not available), respectively.

Interestingly, researchers found that positive immunogenic signature determinants in patients who responded were MMRD, BRCA1/2, high tumor-infiltrating lymphocytes, CDK12, ATM, and CHD1. In the C1 patients, 44% with high tumor-infiltrating lymphocytes responded to treatment.

“Inflammatory infiltrate is a promising prospectively tested predictive biomarker in pretreated mCRPC,” study authors concluded, adding that the nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) schedule and this inflammatory infiltrate biomarker need further validation in a phase 3 trial.