Expanding PARP Inhibitor Use in Prostate Cancer Beyond DNA Repair Defects

Prostate cancer (PCa) is the most common malignancy among men in the Western world and a leading cause of cancer-related mortality. Despite advances in molecularly targeted therapies for other cancers, their application in PCa remains limited, underscoring the need for more effective personalised treatments, particularly after progression following taxane-based chemotherapy. Targeted therapies are also less toxic, offering a crucial advantage for the older and frailer PCa population.

Poly(ADP-ribose)polymerase inhibitors (PARPi) are currently approved for PCa with DNA repair defects, which represent less than 25% of cases. Recent clinical studies suggest that combining PARPi with androgen receptor signalling inhibitors (ARSI) may extend benefits to a broader cohort, beyond those with established DNA repair deficiencies. This review aims to summarise current evidence to inform research and clinical practice.

Relevant publications were reviewed using PubMed, EMBASE, and Medline, focusing on the genetic landscape of PCa, PARPi mechanism of action, and pre-clinical and clinical data on PARPi use in PCa.

PARPi/ARSI combinations elicit variable responses. BRCA-mutated PCa demonstrates consistently better outcomes, while PCa with other homologous repair defects (HRD) shows lower benefits. The benefit for non-HRD cohorts remains controversial, and may be confined to specific subsets.

The therapeutic potential must be weighed against the increased toxicity of combination therapies. Future efforts should focus on developing more tolerable PARPi, optimising combination strategies, refining diagnostic approaches for evaluating DNA repair deficiencies, and identifying molecular pathways driving PARPi response in PCa.