Mutational Signature-Based Biomarker for Phase II Trial of Olaparib Maintenance in Advanced High-Grade Ovarian Cancer

We aimed to develop the mutational signature-based BioMarker (MSBM) to define homologous recombination deficiency (HRD) in newly diagnosed, advanced ovarian cancer and overcome limitations of genomic scar-based assays. We conducted a phase 2 trial (MSBM-OL) to evaluate the efficacy of olaparib maintenance monotherapy and to validate MSBM as a novel HRD biomarker. The MSBM was designed to integrate three whole-exome sequencing-derived features without using genomic scars: tumor-BRCA mutation status, Mutational Signature 3 similarity score > 0.5, or score > 0.25 without CCNE1 amplification. Among 170 patients with stage IIIC/IV high-grade ovarian carcinoma, 58 HRD-positive patients responding to platinum-doublet chemotherapy (without bevacizumab) were enrolled. Thirty-two were randomized 2:1 to olaparib or placebo, and 26 enrolled after switching to a single-arm study. The primary endpoint was progression-free survival (PFS), evaluated against a predefined median of 9 months. Of 170 patients, 169 were evaluable for HRD (99.5%) and 123 (72.4%) were HRD-positive by MSBM, including 21.1% with tumor-BRCA mutations. The olaparib arm (n = 45) showed a median PFS of 22.3 months, significantly exceeding the 9-month threshold (p < 0.001), meeting the primary endpoint. The placebo arm (n = 11) with a median PFS of 16.7 months was not powered for comparison. Grade ≥ 3 adverse events included anemia (25.5%) and neutropenia (12.8%). In a subset (n = 16), MSBM showed 81% concordance with myChoice CDx and correlated with genomic instability scores (R = 0.63). MSBM enables robust HRD evaluation from a whole-exome sequencing assay. Olaparib monotherapy demonstrated clinical benefit for first-line maintenance in HRD-positive ovarian cancer without bevacizumab.