Genomic instability score (GIS) and benefit from olaparib (ola) and bevacizumab (bev) maintenance in high-grade ovarian cancer (HGOC): Phase III PAOLA-1 GINECO/ENGOT-ov25 trial exploratory analysis.

5576 Background: The PAOLA-1 trial showed that adding ola to bev as maintenance therapy improved overall survival (OS) of HGOC patients with BRCA1/2 mutations (BRCAm) or homologous recombination (HR) deficiency (HRD) defined by the MyChoice HRD Plus assay with a GIS threshold of 42. This post hoc analysis of PAOLA-1 explored if alternative thresholds could better identify patients who benefit most from ola. Methods: New cutoffs were determined through OS analyses using Cox proportional hazards models with an interaction term for GIS. Tumors were categorized into HRP (GIS<42), HRDlow (42–60 for BRCA1/2 wild-type [BRCAwt], 42–67 for BRCAm), and HRDhigh (>60 for BRCAwt, >67 for BRCAm). Genomic analyses included promoter methylation, BRCA loss of heterozygosity (LOH) and HR repair gene mutations. Results: Among 623 patients, 194 (31%) were BRCAm and 429 (69%) BRCAwt. Main clinical prognostic features were well-balanced across BRCAwt/HRDhigh, BRCAwt/HRDlow and BRCAwt/HRP as well as among BRCAm/HRDhigh, BRCAm/HRDlow and BRCAm/HRP. Ola+bev improved progression-free survival (PFS) and OS in BRCAwt/HRDhigh and BRCAm/HRDhigh (Table). Ola+bev improved PFS but not OS in BRCAwt/HRDlow and BRCAm/HRDlow. HRP tumors showed no PFS or OS benefit regardless of BRCA status. BRCA1 / RAD51C promoters were methylated in 75% of BRCAwt/HRDhigh, 47% of HRDlow, and 3% of HRP. HRDlow tumors had fewer HR repair gene mutations than HRDhigh. Among HRP/BRCAm, 37% lacked BRCA LOH, suggesting functional BRCA. Conclusions: Our post-hoc subgroup analyses suggest that refined GIS thresholds identify three distinct populations of HGOC patients with varying survival benefits from ola+bev maintenance. Optimized GIS cutoffs may further improve patient stratification in future PARP inhibitors trials. BRCA WT BRCA Mut HRP HRD low HRD high p HRP HRD low HRD high p N 277 72 80 19 124 51 BRCA mutation 0.36 BRCA1 ‐ ‐ ‐ 11 (57.9%) 82 (66.1%) 38 (74.5%) BRCA2 ‐ ‐ ‐ 8 (42.1%) 42 (33.9%) 13 (25.5%) No BRCA LOH ‐ ‐ ‐ 7 (36.8%) 1 (0.8%) 2 (4.0%) p<0.001 HR gene methylation (NA=134) p<0.001 No 187 (96.9%) 26 (53.1%) 13 (24.5%) ‐ ‐ ‐ BRCA1 1 (0.5%) 15 (30.6%) 34 (64.2%) ‐ ‐ ‐ RAD51C 5 (2.6%) 8 (16.3%) 6 (11.3%) ‐ ‐ ‐