Abstract. Purpose: Despite the success of immune checkpoint inhibitors (ICIs) 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. Methods: We conducted a phase II, multi-center, single-arm trial evaluating nivolumab in post-docetaxel mCRPC patients. DRD was assessed using circulating tumor DNA (ctDNA). The primary endpoint was PSA50 response. Secondary endpoints included objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS). Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing (WES) of tumor samples and matched normal tissue, alongside PD-L1 expression evaluation. Results: