Exploring DNA Damage Repair Therapeutics in Prostate Cancer beyond BRCAness

Prostate cancers harboring alterations of genes involved in DNA damage response and repair tend to be more aggressive and are associated with poorer survival outcomes. The application of poly (ADP-ribose) polymerase (PARP) enzyme inhibitors (PARPi) improves the survival of patients with prostate cancer carrying germline or somatic BRCA1 or BRCA2 gene mutations, whereas their role in tumors with alterations of DNA repair genes other than BRCA1/2 and proteins remains controversial, as inhibitors of such targets are currently in clinical development. In this study, we provide an overview of the most frequently observed genomic aberrations affecting DNA repair pathways in prostate cancer and discuss how patient selection needs improvement to identify the population that will eventually benefit from PARPi treatment beyond BRCA1/2 deficiency. Further, we explore emerging treatment approaches with novel DNA repair pathway inhibitors, highlighting the biological rationale and how they are believed to overcome current challenges posed by primary and secondary treatment resistance in this heterogeneous disease.