PARP inhibitors for HRR-deficient metastatic castration-resistant prostate cancer: mechanisms and clinical strategies.

As an advanced malignancy, metastatic castration-resistant prostate cancer (CRPC) resists conventional approaches such as androgen deprivation therapy (ADT). Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized therapeutic strategies for metastatic CRPC cases with homologous recombination repair (HRR) deficiencies. Despite progress, the mechanisms responsible for the efficacy of PARP inhibitors, along with the mechanisms of resistance and ways to address them, are not fully comprehended. This review examines the molecular basis of HRR deficiency in metastatic CRPC, illustrating how PARP inhibitors capitalize on synthetic lethality to eradicate tumor cells. Moreover, the review elucidates the interplay between androgen receptor (AR) signaling and the HRR pathway, highlighting opportunities for combined therapeutic approaches. It discusses biomarker-driven strategies, such as HRR mutation detection and advancements in circulating tumor DNA (ctDNA) research, while also assessing the role of the tumor microenvironment (TME) in modulating PARP inhibitor efficacy. Resistance mechanisms such as drug target effects, HRR restoration, and replication fork stabilization are critically evaluated in this review. Furthermore, the integration of PARP inhibitors with AR pathway inhibitors, immune checkpoint inhibitors (ICIs), radiopharmaceuticals, and chemotherapy is highlighted as a promising approach to optimizing therapeutic efficacy. This review aims to elucidate the functional mechanisms of PARP inhibitors, the molecular basis of their resistance, and potential strategies to overcome such resistance. The review accentuates the central role of PARP inhibitors in advancing precision oncology for metastatic CRPC, identifying prospects for research and clinical implementation.