Prostate cancer remains a leading cause of cancer-related death in men worldwide. Recent research advances have emphasized the critical roles of mismatch repair (MMR) and double-strand break (DSB) in prostate cancer development and progression. Here, we provide a comprehensive review of the molecular mechanisms underlying DSB and MMR defects in prostate cancer, as well as their clinical implications. Furthermore, we discuss the promising therapeutic potential of immune checkpoint inhibitors and PARP inhibitors in targeting these defects, particularly in the context of personalized medicine and further perspectives. Recent clinical trials have demonstrated the efficacy of these novel treatments, including Food and Drugs Association (FDA) drug approvals, offering hope for improved patient outcomes. Overall, this review emphasizes the importance of understanding the interplay between MMR and DSB defects in prostate cancer to develop innovative and effective therapeutic strategies for patients.