Abstract A044: Application of HRDefine: a biomarker for identifying root causes of homologous recombination deficiency to a phase 3, randomized, placebo-controlled trial of veliparib in front-line treatment of advanced ovarian cancer (VELIA/GOG-3005)

Abstract Purpose: Our goal was to determine if the HRDefine biomarker combining methylation and mutation assessment of key homologous recombination repair genes identifies BRCA wildtype (BRCAwt) ovarian cancer (OC) with outcomes similar to BRCA mutated (BRCAm) OC within the context of a frontline PARP inhibitor trial for advanced ovarian cancer. Methods: We performed an exploratory biomarker analysis of blood and neoplastic samples from the VELIA trial, a phase 3 study evaluating the PARP inhibitor veliparib as frontline maintenance therapy in OC. We developed a highly sensitive droplet digital PCR assay for quantitative BRCA1 and RAD51C promoter methylation and assessed germline/somatic mutations using the BROCA next generation sequencing platform. Cases were grouped into: BRCAm, HRDefine positive (BRCAwt HRDefine+), and HRDefine negative (BRCAwt HRDefine-). Carcinomas were considered HRDefine+ if quantitative BRCA1 or RAD51C promoter methylation was >/= 60% or if a germline or somatic pathogenic variant (PV) was identified in the following non-BRCA HRR repair genes: RAD51C, RAD51D, PALB2, BARD1. For this analysis, the control group included the two study arms with placebo maintenance compared to the investigational arm of veliparib with chemotherapy and continued as maintenance (veliparib throughout group). HRDefine was compared to the Myriad genomic instability score (GIS) used as HRD assessment in the trial. Progression free survival (PFS) was compared using log rank tests. Results: Among 1140 VELIA participants, biomarker analysis could be performed for 487 cases. Of these, 255 (52%) were BRCAm, 60 (12%) were BRCAwt HRDefine+, and 172 (35%) were BRCAwt HRDefine-. BRCAwt HRDefine+ was driven by promoter methylation (57%), germline (40%), or somatic (3%) PVs. Median PFS (months, all arms combined) was 26 months (BRCAm), 27 months (BRCAwt HRDefine+), and 15 months (BRCAwt HRDefine-), with corresponding hazard ratios (HR) of 0.50 (95% CI: 0.39-0.65) and 0.50 (0.34-0.73) versus HRDefine-. All HRDefine+ molecular subgroups were associated with longer PFS, including RAD51C/D mutations (HR 0.44, 0.25-0.77) and promoter methylation (HR 0.60, 0.36-0.97). HRDefine positivity was significantly associated with improved PFS compared to HRDefine-/GIS low (n=60 vs n=111, median PFS 27 versus 14 months, HR 0.44, 0.30-0.65), while the HRDefine- cases with high GIS demonstrated a trend toward an intermediate PFS (n=56, median 18 months, HR 0.67, 0.45-1.01). When compared by treatment arm, median PFS was significantly longer in the veliparib throughout arm compared to control only for the BRCAm group (32 months vs 23 months, HR 0.61, 0.42-0.87), though the analysis was underpowered for the BRCAwt HRDefine+ sub-group (30 months vs 25 months, HR 0.79, 0.4-1.57). Conclusions: HRDefine identifies BRCAwt OC associated with a PFS that is like that of BRCAm cases and may improve stratification for PARP inhibitor therapy beyond current HRD assays. GIS may have some, albeit reduced, prognostic implication that is independent of HRDefine. Citation Format: Isabel V. Rodriguez, Marc Radke, Ronit Katz, Persephone Miller, Paula Ladd, Nithisha Khasnavis, Jennifer Ochoa, Melanie Dillon, Heather Lankes, Peter Ansell, Carol Aghajanian, Gini Fleming, Michael Birrer, Scott Kaufmann, Charles Leath, Kathleen Moore, Theresa Werner, Linda Van Le, Robert L. Coleman, Elizabeth M. Swisher. Application of HRDefine: a biomarker for identifying root causes of homologous recombination deficiency to a phase 3, randomized, placebo-controlled trial of veliparib in front-line treatment of advanced ovarian cancer (VELIA/GOG-3005) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A044.