pcij-2751-1787435755 20260822215555 PCIJ bmpublisher@bmpublisher.net Pathophysiology of Cell Injury Journal Pathophysiology of Cell Injury Journal 2378-5225 15 2026 6 22 Nasser Ghaly Yousif FRCP Karen Grigoryan PhD Background: Poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors have emerged as an important therapeutic option for metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors harboring homologous recombination repair (HRR) alterations. However, the magnitude of benefit across molecular subgroups and the balance between efficacy and toxicity remain incompletely defined. Objective: To evaluate the efficacy and safety of PARP inhibitors administered as monotherapy or in combination with androgen-receptor pathway inhibitors in patients with mCRPC. Methods: MEDLINE/PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from inception through August 2026. Randomized trials comparing a PARP inhibitor–based regimen with placebo or active systemic therapy were included. The primary efficacy outcomes were radiographic progression-free survival (rPFS) and overall survival (OS). Secondary outcomes included objective response, prostate-specific antigen response, and treatment-related toxicity. Hazard ratios (HRs) were pooled using a random-effects model. Risk of bias was assessed using the revised Cochrane Risk of Bias tool, and certainty of evidence was evaluated using the GRADE approach. Results: Eight randomized trials involving approximately 3,400 patients were included. Six trials provided directly extractable comparative rPFS estimates. PARP inhibitor–based therapy significantly reduced the risk of radiographic progression or death by 38% (pooled HR, 0.62; 95% CI, 0.56–0.69; I² = 4%). The exploratory pooled OS analysis also favored PARP inhibition (HR, 0.81; 95% CI, 0.73–0.91; I² = 0%), although survival effects varied according to molecular eligibility, treatment setting, crossover, and follow-up maturity. Patients with BRCA1/2 alterations—particularly BRCA2—derived the greatest and most consistent benefits in rPFS, OS, objective response, and prostate-specific antigen response. Evidence for benefit in isolated ATM, CDK12, or CHEK2 alterations was inconsistent, while findings in HRR-negative disease differed across trials. PARP inhibitor–based treatment increased grade 3 or higher hematologic toxicity, particularly anemia, thrombocytopenia, and neutropenia. Dose interruption, dose reduction, transfusion, and treatment discontinuation were more frequent with combination therapy. Conclusion: PARP inhibitor–based therapy significantly improves rPFS in mCRPC, with the most favorable benefit–risk profile observed in patients with BRCA1/2-altered tumors. Overall-survival benefit is emerging but remains less uniform across molecular subgroups. Comprehensive genomic testing and biomarker-directed treatment selection are essential, while the uncertain benefit in HRR-proficient and selected non-BRCA tumors should be weighed against increased hematologic toxicity. Keywords: PARP inhibitors; metastatic castration-resistant prostate cancer; homologous recombination repair; BRCA1; BRCA2 2026 6 22 10.18081/2378-5225/15.76 https://pcij.net/archives/2751