Nivolumab in Patients with Metastatic Castration-Resistant Prostate Cancer with and without DNA Repair Defects

Abstract Purpose: Despite the success of immune checkpoint inhibitors (ICI) across various cancers, their efficacy in metastatic castration-resistant prostate cancer (mCRPC) is modest, except for a subset of patients who experience significant, yet unpredictable, benefits. DNA repair defects (DRD) are associated with higher neoantigen load, which may predict response. Our study explored the potential of DRD for enhanced responsiveness to the ICI nivolumab. Patients and Methods: We conducted a phase II, multicenter, single-arm trial evaluating nivolumab in patients with mCRPC with prior docetaxel therapy. The DRD were assessed using ctDNA. The primary endpoint was PSA50 response. Secondary endpoints included the objective response rate, radiographic progression-free survival (rPFS), and overall survival. Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing of tumor samples and matched normal tissues, alongside PD-L1 expression evaluation. Results: Among the 38 enrolled patients, DRD was identifiable in 30.5% (11/36) through ctDNA and/or whole-exome sequencing analyses. The overall PSA50 response rate was 10.5% (4/38). The PSA50 and objective response rates did not significantly differ between patients with and without DRD (18.2% vs. 8%; P = 0.57 and 50% vs. 17.6%; P = 0.27, respectively). The median PSA-PFS (1.9 vs. 2.8 months; P = 0.52) and rPFS (3.4 vs. 5.5 months; P = 0.7) were not statistically different between patients with and without DRD. Grade ≥ 3 adverse events were reported in 47.3% of participants. Conclusions: Nivolumab has clinical activity in a subset of patients with mCRPC; however, DRD does not predict response. These results highlight the necessity of identifying new biomarkers to more accurately determine patients with mCRPC who might respond to ICIs.