Genomic signature–based risk score for PARP inhibitor response in <i>BRCA</i> -mutated ovarian cancer: A whole-exome sequencing analysis.

Abstract

5547 Background: To identify whole-exome sequencing (WES)–based genomic signatures associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors and develop a prediction model for PARP inhibitor effectiveness in BRCA -mutated advanced ovarian cancer, given the heterogeneous real-world treatment outcomes. Methods: This retrospective cohort study included patients with advanced ovarian cancer harboring BRCA 1/2 mutations who received olaparib or niraparib as first-line maintenance therapy between 2020 and 2022 at the National Cancer Center, South Korea. Among them, patients with at least one year of follow-up from the reference date (August 1, 2024) and sufficient additional tumor samples for WES were identified. Baseline characteristics were collected, and progression-free survival (PFS) and overall survival (OS) from the initiation date of PARP inhibitors were extracted from electronic medical records. Formalin-fixed, paraffin-embedded tumor samples of eligible patients underwent DNA extraction and WES. Prognostic modeling incorporated clinical and genetic variables using Cox proportional hazards regression with the least absolute shrinkage and selection operator (Lasso) method with leave-one-out cross-validation. Model performance was assessed using time-dependent area under the curve (AUC(t)). Results: Fifty-five patients were included. The median patient age was 57 years (range, 39–72). High-grade serous carcinoma comprised 96.4%. Neoadjuvant chemotherapy (NACT) was performed in 40.0%. Complete remission after adjuvant chemotherapy occurred in 87.3%. Olaparib was administered in 76.4% and niraparib in 23.6%. NACT-exposed samples had lower Mutant-Allele Tumor Heterogeneity (MATH) scores than non-NACT-exposed samples, indicating reduced intratumor heterogeneity (P &lt; 0.001). Recurrence during PARPi maintenance occurred in 11 patients (20.0%) (olaparib: 5/42 [11.9%]; niraparib: 6/13 [46.2%]). No deaths were observed. The median PFS was 37.9 months (range, 4.2–54.5), and the median OS was 43.3 months (range, 20.2–60.1). Mutations significantly associated with progression-free survival included POLN (HR, 2.02; 95% CI, 1.12–3.67), ABCC10 (HR, 4.57; 95% CI, 1.13–18.5), GTPBP6 (HR, 2.07; 95% CI, 1.04–4.12), and TCTEX1D1 (HR, 0.19; 95% CI, 0.05–0.82). A genomic risk score model incorporating these mutations stratified patients ino low- and high-risk groups with strong prognostic discrimination for progression-free survival (HR, 4.44; 95% CI, 2.26–8.68; log-rank P &lt; 0.001; AUC(t), 0.87). Conclusions: The genomic signature-based risk score model independently predicted PARP inhibitor effectiveness. External validation is warranted.