Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

SIMPLE SUMMARY: In recent years, the development of sequencing techniques to reveal the genomic information of prostate cancer tumors has allowed for the emergence of targeted therapies. Genomic aberrations in tumor cells have become popular due to the successful development of PARP inhibitors, which are particularly active in those tumors harboring DNA repair genomic defects. This review focuses on PARP inhibitors, two of which were approved for use by the US Food and Drug Administration in 2020 in metastatic castration-resistant prostate cancer. The article highlights the development of PARP inhibitors in the preclinical setting, summarizes the impactful clinical trials in the field, and discusses the need for continued research for further success in treating men with advanced prostate cancer. ABSTRACT: Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based on the concept of synthetic lethality. Several PARP inhibitors (PARPis) have been successful in various malignancies with HRR gene mutations including BRCA1/2, especially in breast cancer and ovarian cancer. More recently, olaparib and rucaparib were approved for mCRPC refractory to novel hormonal therapies, and other PARPis will likely follow. This article highlights the mechanism of action of PARPis at the cellular level, the preclinical data regarding a proposed mechanism of action and the effectiveness of PARPis in cancer cell lines and animal models. The article expands on the clinical development of PARPis in mCRPC, discusses potential biomarkers that may predict successful tumor control, and summarizes present and future clinical research on PARPis in the metastatic disease landscape.