Expanding indications for PARP inhibitors in prostate cancer

Recent advances in metastatic prostate cancer (mCaP) have increasingly focused on molecularly targeted therapies, particularly those addressing alterations in DNA damage repair (DDR) pathways. Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated substantial and clinically meaningful efficacy in patients harboring homologous recombination repair (HRR) gene alterations, most notably BRCA1/2, as well as selected additional DDR genes. To expand the population that may benefit from PARPi therapy, multiple combination strategies are currently being explored. This narrative review provides an overview of the current evidence on the role of PARPi in mCaP, summarizes their clinical implementation, and discusses future perspectives, including rational combination approaches and potential applications in earlier disease stages. PARPi demonstrate the most pronounced and consistent efficacy in BRCA-mutated CaP. Patients with non-BRCA HRR alterations may derive heterogeneous but potentially meaningful benefit from PARPi, particularly when PARPi are combined with androgen-receptor pathway inhibitors (ARPI). While activity of PARPi monotherapy is limited in patients without detectable HRR alterations, emerging data indicate clinically relevant benefit in selected subgroups treated with PARPi-based combinations, potentially mediated by functional DNA repair deficiencies, androgen-receptor (AR)-PARP pathway crosstalk, or treatment-induced "BRCAness." Refinement of biomarker strategies and improved molecular stratification are, therefore, critical to extend PARPi benefit beyond classical HRR alterations. Nevertheless, a standardized framework defining the optimal timing of HRR testing and the clinical relevance of individual gene alterations remains to be established. PARPi are now firmly established as an important targeted treatment option in metastatic castration-resistant CaP (mCRCaP), with therapeutic efficacy closely linked to tumor genomic features. However, the identification of robust predictive biomarkers beyond BRCA1/2 and the optimal integration of combination therapies remain key challenges. Emerging evidence supports further evaluation of PARPi-based combinations, as well as their earlier use in disease stages such as metastatic hormone-sensitive CaP (mHSCaP), which may ultimately broaden their clinical impact.