Predictive value of BRCA1/RAD51C methylation in HGSOC – An ancillary study of the PAOLA-1/ENGOT-ov25 phase 3 trial
In high-grade serous ovarian cancer (HGSOC) bevacizumab (bev)/olaparib (ola) maintenance was approved for patients with homologous recombination DNA repair deficiency (HRD+) tumors. Although different methods exist to score genomic instability, DNA quality, tumor cell content, and costs may impair our ability to identify patients that will benefit from treatment. We analyzed BRCA1 and RAD51C methylation as an HRD determination tool in patients newly diagnosed of HGSOC (n = 519) based on data from the PAOLA-1/ENGOT-ov25 trial phase III prospective trial. Methylation was analyzed using quantitative methylation specific PCR, correlated to HRD scores, PFS and OS. 67 (12.9 %) were BRCA1 and 25 (4.8 %) were RAD51C methylated. Of the 81 samples with a failed HRD score, 13 were methylated. Methylated samples were HRD+ (mean score [95 % CI]; 65.9 [62.7-69.1] and 53.3 [48.0-58.6]) and almost mutually exclusive of BRCA1&2 mutations. A significant PFS1 benefit independently of methylation ratios was observed in patients with methylated tumors with bev-ola maintenance compared to bev alone (HR=0.49, 95 % CI 0.29-0.83, P = 0.008). An OS benefit was shown for patients defined as "all-HRD" (including methylation) (HR=0.59, 95 % CI 0.41-0.86, P = 0.007). This study confirms the feasibility and clinical value of BRCA1/RAD51C methylation for predicting response to ola-bev maintenance in newly diagnosed HGSOC. Assessment of methylation in parallel to mutation testing allowed the identification of nearly 85 % of HRD+ samples at low costs. This study suggests that methylation testing could be easily implemented to optimize the selection of patients that benefit from olaparib+bevacizumab maintenance.