Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial

Abstract

Objective: In 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.

Methods: Patients 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.

Results: Of 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.

Conclusion: This 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.

Keywords: Ovarian Cancer.

Figure 1

Kaplan-Meier estimate of progression-free survival in (A) higher-risk patients with HRD-positive tumors, (B) lower-risk patients with HRD-positive tumors, (C) higher-risk patients with a BRCA mutation, (D) lower-risk patients with a BRCA mutation, (E) higher-risk patients with HRD-positive tumors without a BRCA mutation, and (F) lower-risk patients with HRD-positive tumors without a BRCA mutation. Five-year progression-free survival data from the final overall survival data cut-off (March 22, 2022). The end of the curves should be interpreted with caution because of the small number of patients at risk at these time points. Tumor BRCAm status was determined by one of five central French academic laboratories before trial entry, and HRD status was determined retrospectively by the MyChoice HRD Plus assay. HRD-positive defined as a tumor BRCA mutation and/or GIS ≥42; HRD-positive without a BRCAm defined as GIS ≥42 and no tumor BRCA mutation. The number of patients in the tumor BRCAm and HRD-positive without tumor BRCAm subgroups does not equal the total number of patients in the HRD-positive subgroup because of these different testing methods. *Kaplan-Meier estimates. ^†Unstable median due to lack of events. ^‡Too few events and/or survival curves cross; interpret HRs with caution. BRCA, BRCA1 and/or BRCA2; GIS, genomic instability score; HRD, homologous recombination deficiency; PFS, progression-free survival.

Figure 2

Kaplan-Meier estimate of overall survival in (A) higher-risk patients with HRD-positive tumors, (B) lower-risk patients with HRD-positive tumors, (C) higher-risk patients with a BRCA mutation, (D) lower-risk patients with a BRCA mutation, and (E) higher-risk patients with HRD-positive tumors without a BRCA mutation. Data in panel E are shown for higher-risk patients with HRD-positive tumors without a BRCA mutation; in lower-risk patients with HRD-positive tumors without a BRCA mutation, median overall survival was not reached in either treatment group, and the HR was not reported because of too few events; 5-year overall survival was 82% in the olaparib plus bevacizumab group versus 54% in the bevacizumab group (Kaplan-Meier estimates). The end of the curves should be interpreted with caution because of the small number of patients at risk at these time points. Tumor BRCAm status was determined by one of five central French academic laboratories before trial entry and HRD status was determined retrospectively by the MyChoice HRD Plus assay. HRD-positive defined as a tumor BRCA mutation and/or GIS ≥42; HRD-positive without a BRCA mutation defined as GIS ≥42 and no tumor BRCA mutation. The number of patients in the tumor BRCAm and HRD-positive without tumor BRCAm subgroups does not equal the total number of patients in the HRD-positive subgroup because of these different testing methods. *Unstable median due to lack of events. ^†Kaplan-Meier estimates. BRCA, BRCA1 and/or BRCA2; GIS, genomic instability score; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival.