Deoxyribonucleic Acid Damage Response Defects: Clinical Implications and the Role of Poly-ADP Ribose Polymerase Inhibitors in Genitourinary Cancers and Beyond

Abstract

The intact deoxyribonucleic acid (DNA) damage response (DDR) is critical to guard against DNA damage and maintain genomic integrity/stability. DDR defects have been involved in cancer initiation, progression, and have been associated with anticancer treatment response and outcomes. A better understanding of the role of DDR alterations in cancer development has led to the utilization of DDR defects as relevant therapeutic targets and putative biomarkers, which is the focus of our review, focusing on genitourinary (GU) cancers. Poly-ADP ribose polymerase inhibitors (PARPi) have become a crucial tool for targeting this pathway in the treatment of certain cancers, including prostate cancer. Unfortunately, resistance to PARPi is common and this primarily drives the investigation of multiple combination strategies with other agents. Novel agents targeting the DDR pathway, in addition to PARPi constitute a promising therapeutic approach, while translational research aiming to refine patient selection and prove the clinical utility of putative biomarkers across various cancer types remains crucial.