Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial

Abstract

Purpose: The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)-positive tumors. We explored whether mutations in non-BRCA1 or BRCA2 homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1.

Methods: Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non-BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non-BRCA HRR gene panels, three devised for this analysis and three previously published.

Results: The non-BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non-BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non-BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes (BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non-BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43).

Conclusion: Acknowledging limitations of small subgroup sizes, non-BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

Trial registration: ClinicalTrials.gov NCT02477644.

FIG 1.

Prevalence of HRRm within HRD-positive, HRD-negative, and HRD-unknown tumors. (A) OncoPrint of mutated HRR genes with annotated positive, negative, and unknown status for HRD and tBRCAm. Percentages on the basis of the total number of enrolled patients in PAOLA-1 (n = 806). Genes are arranged in descending order of median GIS. HRD-positive was defined as a GIS of ≥ 42, and HRD-negative as a GIS of < 42. (B) Expanded panel. The expanded panel included mutated genes in the predefined panel plus five additional selected genes involved in homologous recombination repair. HRD-positive was defined as a GIS of ≥ 42, and HRD-negative as a GIS of < 42. BRCAm, BRCA1, and/or BRCA2 mutation; GIS, genomic instability score; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; tBRCAm, tumor BRCAm.

FIG 2.

Distribution of GISs and proportion of biallelic loss and heterozygous alterations. (A) Distribution of GISs and gene-specific zygosity per HRR gene in BRCA1, BRCA2, and the expanded panel. Of non-BRCA genes analyzed in the expanded gene panel, the genes with the highest median GISs were BLM, BRIP1, RAD51C, PALB2, and RAD51D, forming the basis of the restricted gene panel. Patients with mutations in more than one gene (ie, co-occurring genes) are excluded from this analysis. (B) Proportion of biallelic loss and heterozygous alterations per gene where gene-specific zygosity could be assessed for BRCA1, BRCA2, and the expanded panel. Patients with mutations in more than one gene (ie, co-occurring genes) are excluded from this analysis. BRCAm, BRCA1, and/or BRCA2 mutation; GIS, genomic instability score; HRRm, homologous recombination repair mutation; tBRCAm, tumor BRCAm.

FIG 3.

PFS for patients with non-BRCA homologous recombination repair gene mutation detected using six different gene panels: (A) predefined panel, (B) expanded panel, (C) restricted panel, (D) panel used in Study 19, (E) panel used in the NOVA study, and (F) panel used in the ARIEL3 study. The expanded panel included five additional genes involved in homologous recombination repair; the restricted panel used the five genes with the highest genomic instability scores. bev, bevacizumab; HR, hazard ratio; NC, not calculated (< 20 events); PFS, progression-free survival.

FIG 4.

PFS for patients with mutations in non-BRCA genes involved in homologous recombination repair using the expanded panel by HRD status: (A) HRD-positive (GIS of ≥ 42) tumors and (B) HRD-negative (GIS of < 42) or unknown tumors. bev, bevacizumab; GIS, genomic instability score; HRD, homologous recombination deficiency; PFS, progression-free survival.