Analysis of the Phase 3 PAOLA-1/ENGOT-ov25 Trial by Disease Stage in Patients with Homologous Recombination Deficiency–Positive Newly Diagnosed Advanced Ovarian Cancer Receiving Bevacizumab with Olaparib/Placebo Maintenance

Results of the PAOLA-1/ENGOT-ov25 study demonstrated sustained progression-free survival benefit with the addition of maintenance olaparib to bevacizumab, compared with placebo and bevacizumab in homologous recombination deficiency-positive patients, irrespective of International Federation of Gynecology and Obstetrics stage and residual disease after up-front surgery.

Analyses of the phase 3 PAOLA-1/ENGOT-ov25 trial (NCT02477644), which evaluated the addition of maintenance olaparib or placebo to bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer (HGOC), were performed in homologous recombination deficiency (HRD)-positive patients by disease stage; these results were presented at the 2021 American Society of Clinical Oncology Annual Meeting.

The study enrolled patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III-IV HGOC in response after platinum-based chemotherapy plus bevacizumab. Eligible patients received bevacizumab (15 mg/kg every 3 weeks for 15 months) and either olaparib (300 mg twice a day for 24 months) or placebo. This exploratory analysis evaluated progression-free survival (PFS; data cutoff: March 22, 2019) and second PFS (PFS2; data cutoff: March 22, 2020) in HRD-positive patients (tumor BRCA1/BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage.

Of the 806 patients randomized in the study, 48% were HRD-positive. In the HRD-positive population, the majority (70%) had stage III disease, and 30% had stage IV disease; of whom 56% and 53% had a tBRCAm, respectively. Among patients with HRD-positive stage III disease, 63% had up-front surgery (of whom 30% had residual disease), and 33% had interval surgery (of whom 21% had residual disease). Among patients with HRD-positive stage IV disease, 45% had up-front surgery (of whom 65% had residual disease), and 48% had interval surgery (of whom 33% had residual disease).

Among patients with HRD-positive stage III disease, the olaparib/bevacizumab group (compared with the placebo/bevacizumab group) showed prolonged PFS (median follow-up: 24.8 months; median PFS: 39.3 vs 19.9 months) and PFS2 (median follow-up: 37.2 months; median PFS2: not reached vs 43.0 months). Among patients with HRD-positive stage IV disease, the olaparib/bevacizumab group showed prolonged PFS compared with the placebo/bevacizumab group (median follow-up: 24.0 months; median PFS: 25.1 vs 12.8 months, respectively), as well as PFS2 (median follow-up: 37.0 months; median PFS2: 37.8 vs 27.8 months, respectively). In lower-risk patients with stage III HRD-positive tumors, who benefited from complete resection following up-front surgery, the 2-year and 3-year PFS2 rates were >90% with olaparib/bevacizumab (94.7% and 91.9%, respectively) compared with placebo/bevacizumab (80.6% and 65.7%, respectively). Among higher-risk patients with stage III HRD-positive tumors and residual disease after up-front surgery, or those who received neoadjuvant chemotherapy, or those with HRD-positive stage IV disease, the 2-year PFS2 rate was 73.9%, and the 3-year PFS2 rate was 57.1% with olaparib/bevacizumab compared with placebo/bevacizumab (69.1% and 42.3%, respectively).

These results of the PAOLA-1 study demonstrate sustained PFS benefit with the addition of maintenance olaparib to bevacizumab compared with placebo plus bevacizumab in HRD-positive patients, irrespective of FIGO stage and residual disease after up-front surgery.

Source: Pautier P, Harter P, Pisano C, et al. Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial. J Clin Oncol. 2021;39(suppl_15). Abstract 5514.