HRR gene promoter methylation-guided nomogram predicts PARP inhibitor efficacy and progression-free survival in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) remains a lethal gynecologic malignancy with limited tools for accurately predicting PARP inhibitor (PARPi) efficacy. While promoter methylation of homologous recombination repair (HRR) genes is a potential biomarker, its clinical utility remains underexplored. This study aimed to systematically evaluate HRR gene promoter methylation profiles to predict PARPi sensitivity in HGSOC patients. We conducted a retrospective analysis of 96 HGSOC patients receiving PARPi maintenance therapy (olaparib or niraparib). The promoter methylation status of 12 HRR genes was quantitatively assessed via pyrosequencing. Patients were stratified into PARPi-sensitive and -insensitive groups based on OReO/ENGOT-ov38 criteria. Differential methylation sites were identified, lasso and multivariate logistic regression identified key methylation sites to construct a nomogram and a PARPi Resistance Score (PRS). PFS was analyzed by Kaplan‑Meier and Cox regression. The PARPi-insensitive group exhibited significantly higher median methylation levels across HRR gene promoters compared to the sensitive group. Through rigorous screening, 12 CpG sites were consistently associated with PARPi response across subgroups. Through screening and LASSO regression, five CpG sites-ATM_Pos1, BRCA1(2S)_Pos2, BRCA2(1S)_Pos1, BRCA2(1S)_Pos7, and RAD51D_Pos6-were identified as independent predictors of PARPi sensitivity. The logistic model based on these five sites showed good discrimination, with area under the ROC curve (AUC) of 0.847 in the training set and 0.903 in the validation set; calibration and decision curve analysis supported clinical utility. Using the optimal PRS cutoff of - 1.023, High-PRS patients had significantly shorter median PFS (14 months vs. not reached; log‑rank P < 0.0001) and lower 12‑month PFS rate (52% vs. 97.2%). Multivariate Cox analysis confirmed PRS as the only independent prognostic factor for PFS (HR 4.85, 95% CI 2.31-10.20, P < 0.001). HRR gene promoter methylation, particularly at specific BRCA1, BRCA2 and RAD51D CpG sites, robustly predicts PARPi sensitivity and independently stratifies PFS in HGSOC patients. The nomogram and PRS provide clinically actionable tools for individualized PARPi therapy.