Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer

SIMPLE SUMMARY: Stage IV (metastatic) prostate cancer remains an incurable disease despite many treatment advances in recent years. Approximately a quarter of men with advanced prostate cancer have alterations in DNA repair pathways, namely, homologous recombination repair (HRR). Poly(ADP-ribose) polymerase (PARP) is a protein directly involved in repair of damaged DNA within the cell. Therefore, inhibition of PARP leads to accumulation of DNA damage during DNA replication. Patients with underlying HRR abnormalities within cancer cells can be treated with PARP inhibitors (oral targeted therapy) to prevent cancer cell repair and progression. Our understanding of the role of PARP inhibitors as single agent and as combination therapy in prostate cancer, as well as predicting which patients will benefit most from PARP inhibitors, is evolving. In this review, we summarise the clinical trial data, as well as biomarker data, for patient selection and provide perspective as treating clinicians. ABSTRACT: Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.