Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial

Objectives: In the Phase III PAOLA-1/ENGOT-ov25 (NCT02477644) trial, the addition of the PARP inhibitor olaparib to bevacizumab maintenance therapy led to a significant progression-free survival (PFS) benefit in patients with newly diagnosed advanced ovarian cancer (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.49-0.72), particularly in patients who were homologous recombination deficiency (HRD) positive, both including patients with BRCA1 and/or BRCA2 mutations (BRCAm; HR 0.33; 95% CI 0.25-0.45) and patients without a BRCAm (HR 0.43; 95% CI 0.28-0.66; Ray-Coquard et al. NEJM 2019). We explored the role of mutations in genes involved in homologous recombination repair (HRRm) excluding BRCAm as a predictive biomarker in patients with newly diagnosed advanced ovarian cancer who received olaparib + bevacizumab maintenance therapy in PAOLA-1. Methods: Patients with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer were randomized (2:1) to olaparib + bevacizumab maintenance or placebo + bevacizumab maintenance following response to platinum-based chemotherapy + bevacizumab. In an exploratory analysis, PFS was assessed in patients harboring a tumor mutation in a wide range of HRR gene panels (excluding tumor BRCAm [tBRCAm]): a panel with 13 pre-defined genes involved in HRR, an expanded panel with five additional genes involved in HRR, a restricted panel using five selected genes with the highest median genomic instability scores, and three published panels (Table). Tumors were analyzed using the Myriad myChoice HRD plus assay. Results: Of the 806 patients randomized in PAOLA-1, 235/806 (29.2%) had a tBRCAm. The percentage of patients harboring deleterious mutations involved in HRR excluding tBRCAm ranged from 3.7% to 9.8% depending on the HRR gene panel (Table). For each gene panel, the number of patients with an HRRm in each treatment arm and HRD status are shown in the Table. PFS using different gene panels for HRRm is summarized in the Table; using the 13-gene panel, in patients with an HRRm excluding tBRCAm (n=54), the HR for PFS was 0.95 (95% CI 0.49-1.94). Expansion of this panel to include five other genes (n=72) demonstrated an HR (95% CI) for PFS of 1.01 (0.55-1.95). Consistent results were seen in patients with HRRm excluding tBRCAm using the three other published HRR gene panels (Table). Conclusions: Acknowledging limitations of small subgroup sizes, HRRm (excluding tBRCAm) was not predictive of PFS benefit with maintenance olaparib in combination with bevacizumab, compared with bevacizumab alone, in PAOLA-1, regardless of the gene panel used. Mutation analysis using HRRm gene panels did not have utility beyond tBRCAm for selecting patients who may benefit from maintenance olaparib plus bevacizumab in PAOLA-1 and should not be considered a substitute for HRD determined by BRCA and/or genomic instability testing. Download : Download high-res image (309KB) Download : Download full-size image