Editor's Note: The efficacy of endocrine therapy in advanced prostate cancer patients is poor, with most ultimately progressing to castration-resistant prostate cancer (CRPC). Although previous single-agent immunotherapies have shown limited success in prostate cancer, recent studies indicate that combination immunotherapies exhibit higher antitumor activity in patients with metastatic CRPC (mCRPC). At the recent ASCO Annual Meeting, a study analyzed the efficacy of different immunotherapy combinations for mCRPC patients and examined potential biomarkers.

Abstract Number (Report Type): 5013 (Rapid Oral Abstract Session)

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

Background:

For patients with metastatic castration-resistant prostate cancer (mCRPC), single checkpoint inhibitor (CPI) therapy may be limited in efficacy, likely due to the “cold” tumor immune microenvironment. This study hypothesized that mCRPC patients with a positive immunogenic signature (ImS+) are more likely to respond to treatment. Researchers conducted a phase 2 trial in ImS+ mCRPC patients, using two different dosing regimens of nivolumab combined with ipilimumab.

Methods:

Patients with mCRPC who had progressed after ≥1 line of therapy and were ImS+ were enrolled. ImS+ was defined by at least one of the following criteria:

1. Mismatch repair deficiency (MMRD) detected by immunohistochemistry (IHC);
2. DNA damage repair deficiency (DDRD) detected by UW-OncoPlex targeted exome sequencing;
3. High tumor-infiltrating lymphocytes (TILs) identified by multiplex IHC (nuclear cells ≥20%).

Patients were divided into two cohorts: nivolumab 1 mg/kg + ipilimumab 3 mg/kg (C1) and nivolumab 3 mg/kg + ipilimumab 1 mg/kg (C2) administered every three weeks for four doses, followed by nivolumab 480 mg every four weeks for up to one year. The primary endpoint was the composite response rate (CRR), defined as at least one of the following:

1. Radiographic response confirmed by RECIST 1.1;
2. Confirmed PSA response ≥50%;
3. Circulating tumor cell (CTC) conversion at week 9.

A CRR ≥40% was considered clinically favorable (minimum 20%). Secondary endpoints included toxicity, duration of response (DOR), and overall survival (OS). Tissue samples were required for biomarker analysis.

Results:

From May 2018 to June 2022, 380 screened patients were identified, with 119 (31%) being ImS+. Among these, 35 (C1) and 36 (C2) participated in the trial.

In C1, the CRR was 14/35 (40%, 90% CI: 26-55%), while in C2, it was 9/36 (25%, 90% CI: 14-40%). The overall CRR for all patients was 23/71 (32%, 90% CI: 23-43%).

Grade 3/4 treatment-related adverse events occurred in 22/35 (63%) patients in C1 and 11/36 (31%) in C2, with diarrhea being the most common event (15 cases in C1 and 3 in C2). The median DOR was 10.4 months for C1 and 6.4 months for C2.

After a median follow-up of 47 months (C1) and 21 months (C2), the median OS was 16.2 months (95% CI: 9.2-22.8 months) for C1 and 15.2 months (95% CI: 8.9 months-NA) for C2.

In responders, ImS+ determinants included MMRD (8/10), BRCA1/2 (4/8), high TILs (8/21), CDK12 (2/8), ATM (1/13), and CHD1 (1/9). Among high TILs patients in C1, 4/9 (44%) responded. Exploratory biomarker analysis is ongoing.

Conclusion:

Inflammatory infiltration can serve as a potential prospective predictive biomarker for previously treated mCRPC. Despite higher toxicity, nivolumab 1 mg/kg + ipilimumab 3 mg/kg demonstrated better efficacy than nivolumab 3 mg/kg + ipilimumab 1 mg/kg. A phase 3 trial is currently analyzing this dosing regimen and associated biomarkers.