Targeting poly(ADP-ribose) polymerase in metastatic prostate cancer: current landscape and future directions.

PARP inhibitors (PARPi) have rapidly reshaped the treatment landscape for metastatic prostate cancer, moving from biomarker-selected monotherapy in metastatic castration-resistant prostate cancer (mCRPC) to first-line combination strategies with androgen receptor pathway inhibitors (ARPIs) and more recently, into metastatic hormone-sensitive disease (mHSPC). This review summarizes the evidence-based use of PARPi in metastatic prostate cancer, integrating the mechanistic rationale and guideline perspectives. We also highlight the resistance mechanisms that inform patient selection and underpin emerging strategies. The most consistent and clinically meaningful benefit from PARPi is observed among patients with deleterious BRCA1/2 alterations, whereas outcomes among patients with non- BRCA defective homologous recombination repair (HRR) gene subsets are heterogeneous and often modest. Pairing PARPi with ARPI in mCRPC patients bearing HRR mutations, especially BRCA1/2 mutations, not only improves clinical outcomes but also increases toxicity. Furthermore, uncertainty remains regarding the overall impact of the incremental benefit of PARPi/ARPI combinations over sequential therapy. Expansion into mHSPC further underscores the field's shift toward earlier, genomically guided treatment intensification strategies. Clinical practice is converging on early comprehensive genomic testing and prioritization of PARPi-based therapy for HRR-altered, especially BRCA1/2 -mutated, prostate cancer. Key research priorities include functional biomarkers beyond gene panels, rational combinations to prevent/overcome resistance, and optimized sequencing across disease states.