Dataset Information

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.

SUBMITTER: Pujade-Lauraine E

PROVIDER: S-EPMC9928987 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Pujade-Lauraine Eric E Brown Jessica J Barnicle Alan A Wessen Jonathan J Lao-Sirieix Pierre P Criscione Steven W SW du Bois Andreas A Lorusso Domenica D Romero Ignacio I Petru Edgar E Yoshida Hiroyuki H Vergote Ignace I Colombo Nicoletta N Hietanen Sakari S Provansal Magali M Schmalfeldt Barbara B Pignata Sandro S Martín Lorente Cristina C Berton Dominique D Runnebaum Ingo B IB Ray-Coquard Isabelle I

JCO precision oncology 20230101

<h4>Purpose</h4>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-<i>BRCA1</i> or <i>BRCA2</i> homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in ...[more]

PMID: 36716415

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Project description:ObjectiveIn the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status.MethodsPatients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status.ResultsOf 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk.ConclusionThis post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Project description:IntroductionIn 2023, the final PAOLA-1 trial (NCT02477644) survival data were published documenting the benefits of therapy consisting of olaparib plus bevacizumab for patients with advanced ovarian cancer (AOC) as a function of molecular status. In light of these new data, the present study was conducted with the goal of evaluating the cost-effectiveness of olaparib plus bevacizumab for the treatment of the overall AOC patient population and for homologous recombination deficiency (HRD)-positive patients, patients with a breast cancer susceptibility gene (BRCA) mutations, homologous recombination proficiency (HRD)-positive, or patients not harboring BRCA mutations AOC from a US payers perspective.MethodsA Markov state-transition model with a 15-year time horizon was used to evaluate outcomes of patients administered Olaparib plus bevacizumab versus bevacizumab. Life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-effectiveness ratio (ICER) values were evaluated in this study in light of a $150,000/QALY of willingness-to-pay (WTP) threshold. The stability of the established model was evaluated through sensitivity analyses.ResultsRelative to bevacizumab alone, Olaparib plus bevacizumab was associated with mean incremental costs and QALYs (LYs) of olaparib plus bevacizumab versus bevacizumab were $293,656 and 1.85 (2.16), $265,668 and 3.34 (4.02), $242,746 and 1.71 (2.06), and $193,792 and 0.97 (1.14) for overall, BRCA mutation-positive, HRD-positive, and HRD-positive BRCA mutation-negative AOC patients, respectively. The corresponding ICER values for these patient subgroups were $158,729 ($136,218), $79,434 ($66,120), $141,636 ($117,747), and $200,595 ($169,733) per QALY (LY) gained Utility value and the price of olaparib were identified in sensitivity analyses as the primary factors influencing these results.ConclusionAt current pricing levels, maintenance treatment with olaparib plus bevacizumab treatment may represent a cost-effective therapeutic option for BRCA mutations and HRD-positive AOC patients in the USA.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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