Background: The PAOLA-1/ENGOT-ov25 trial showed that adding olaparib (ola) to maintenance bevacizumab (bev) after first-line therapy led to a progression-free and overall survival benefit in advanced ovarian high-grade carcinoma (AOC) patients with homologous recombination deficiency (HRD) (Myriad MyChoice^R Genomic Instability Score) or BRCA1/2 mutations (BRCAmut). Here, we address the impact of BRCA1 and RAD51C epimutations to improve our understanding of GIS beyond BRCAmut.Methods:BRCA1 and RAD51C methylation analysis was assessed and quantified in pre-treatment biopsies (66%), after neoadjuvant chemotherapy (NACT) (20%) or unknown (14%) from bisulfite converted DNAs using fluorescent methylation specific PCR and methylation specific droplet digital PCR (ddPCR). Methylation status was correlated to clinical data, BRCA1/2 mutations, GIS and HRD scores, PFS (PFS1, PFS2) and OS. R (r-project.org) was used for statistical analysis. Results: Among the 537 patients randomized to maintenance ola + bev and 269 to placebo (pbo) + bev, 348 and 171 were available for methylation analysis. Their baseline molecular and clinical characteristics were well balanced with those of the entire cohort. Promoter methylation was identified in 67 (12.9%) samples for BRCA1 and 25 (4.8%) for RAD51C (4 were methylated on both genes). Methylation and BRCAmut were mutually exclusive except for 3 samples. Mean GIS scores were 62.5 [59.6-65.5]; 59.4 [57.2-61.5]; 54.2 [50.5-57.8]; 23.4 [21.6-25.2] for BRCA1 or RAD51C methylated (met-tumors), BRCAmut, non-mut/non-met HRD+ (b-/m-HRD+) and HRP (proficient) tumors respectively. Among met-tumors 92% (66/72) were GIS positive (>42). The mean GIS score of Met-tumors were significantly higher than that of b-/m- HRD+ samples (p=0,009). Benefit of adding ola maintenance to bev was in a similar between patients with met AOC and those with b-/m- HRD+ tumors (table). Conclusions: Methylated BRCA1/RAD51 tumors are HRD+ and provide to ovarian cancer patients a similar clinical benefit of ola+bev as patients with b-/m- HRD+ tumors. Methylation assessment represents a rapid and cost effective tool; which coupled with BRCA1-2 somatic testing allows the identification of the majority (81%) of HRD+ AOC. Clinical trial information: NCT02477644.

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