PARP Inhibition in Prostate Cancer: Current Status, Resistance Mechanisms, and Clinical Challenges.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) rewiring (e.g., homologous recombination repair (HRR) restoration, fork protection, checkpoint tolerance, and altered drug handling) converges with treatment-induced dormancy and quiescent therapy-tolerant residual states that sustain minimal residual disease (MRD) under androgen receptor pathway inhibition (ARPI) and PARP blockade. We synthesize clinical and translational evidence for PARPi monotherapy and PARPi-based combinations across disease states. In first-line metastatic castration-resistant prostate cancer (mCRPC), PARPi plus ARPI consistently prolongs radiographic progression-free survival, with the greatest benefit in HRR-altered tumors, and emerging overall-survival signals in selected subgroups. In later-line settings, monotherapy activity is most robust in BRCA2-mutated disease, whereas non-BRCA HRR alterations show heterogeneous and often modest responses, underscoring the need for biomarkers beyond gene panels. We also discuss combination strategies with DDR-targeting agents, radioligand therapies, and immunotherapy, and summarize ongoing phase III programs in metastatic castration-sensitive prostate cancer (mCSPC). Finally, we outline practical considerations for biomarker-informed patient selection, monitoring, sequencing, and toxicity management, with particular emphasis on intercepting MRD and resistance evolution.