Maintenance olaparib plus bevacizumab after first-line chemotherapy as a standard of care for advanced ovarian cancer

In the PAOLA-1/ENGOT-ov25 primary analysis, adding olaparib to maintenance bevacizumab after first-line platinum-based chemotherapy plus bevacizumab led to a significant progression-free survival (PFS) benefit in patients with advanced ovarian cancer. The final overall survival (OS) analysis of this trial now demonstrates that this benefit also translates into a clinically meaningful OS improvement in the first-line treatment of patients with a homologous recombination deficiency (HRD), irrespective of the presence of a BRCA mutation.

The PAOLA-1/ENGOT-ov25 trial compared the efficacy of maintenance olaparib plus bevacizumab with placebo plus bevacizumab in patients with newly diagnosed advanced ovarian cancer who had received first-line standard-of-care treatment including bevacizumab. In the primary analysis, adding olaparib to maintenance bevacizumab led to a significant progression-free survival (PFS) benefit in advanced ovarian cancer (HR[95%CI]: 0.59[0.49-0.72]; p< 0.001), with a more pronounced benefit in patients with homologous recombination deficiency (HRD-positive patients). The final PAOLA-1 analysis presented at ESMO 2022 investigated whether the PFS advantage observed in the primary analysis translates to a clinically relvant OS advantage at five years in the first-line setting.

Study design

Patients with newly-diagnosed high-grade advanced serous or endometrioid ovarian, fallopian tube and/or primary peritoneal cancer, in response after platinum-based chemotherapy plus bevacizumab, were randomised 2:1 to olaparib tablets (300 mg twice a day for up to 24 months) plus bevacizumab (15 mg/kg Q3W for 15 months total) or placebo plus bevacizumab. Primary endpoint was investigator-assessed PFS. Overall survival (intent-to-treat [ITT] population) was a key secondary endpoint, with analysis planned for three years after the primary analysis as part of hierarchical testing.

Results

In total, 537 patients were randomised to olaparib plus bevacizumab and 269 to placebo plus bevacizumab. Patient characteristics were well-balanced among the two treatment arms. Importantly, 30% of the patients had stage IV disease. In addition, 50% of patients had received upfront surgery, with approximately 40% of patients having residual disease. Some patients (7%) did not receive surgery at all. Over 25% of patients were in partial response after surgery and platinum-based chemotherapy.

After a median follow-up of respectively 61.7 and 61.9 months in the olaparib and placebo arms, median OS in the ITT population was 56.5 months in the olaparib arm vs. 51.6 months in the placebo arm (HR[95%CI]: 0.92[0.76-1.12], p= 0.4118). Of note, 45.7% of patients in the placebo arm and 19.6% of those in the olaparib arm received a PARP inhibitor during any subsequent treatment. OS rates at 5 years in the ITT population were 47.3% and 41.5%. Among HRD-positive patients, median OS was prolonged from 57.3 months with placebo to 75.2 months (still unstable due to data maturity <50%) with olaparib (HR[95%CI]: 0.62[0.45-0.85]; OS at 5 year, 65.5 vs. 48.4%). The OS-benefit observed in the HRD-positive population was supported by the updated PFS analysis for these patients (median PFS 46.8 vs. 17.6 months, HR[95%CI]: 0.41[0.32-0.54]). The OS benefit in HRD-positive patients was observed in patients with or without a tumour BRCA mutation. In contrast however, no OS benefit was seen in HRD-negative patients (HR[95%CI]: 1.19[0.88-1.63]).

All patients had discontinued treatment at the PFS2 data cut-off. Treatment-emergent adverse events have been reported previously and the olaparib safety profile has been well characterised. With longer follow-up, the rate of myeloid dysplastic syndrome, acute myeloid leukaemia and aplastic anaemia, as well as the incidence of new primary malignancies, were similar in both arms and relatively low.

Conclusion

Despite a high proportion of patients in the control arm receiving a PARP inhibitor post-progression, the addition of maintenance olaparib to bevacizumab still provided a clinically meaningful improvement in OS for first-line HRD-positive patients with and without a tumour BRCA mutation. These data confirm olaparib maintenance as standard of care in this setting, and further underscore the importance of precision medicine and biomarker testing to guide treatment decisions.

Reference

Ray-Coquard I, et al. Final overall survival (OS) results from the Phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). Presented at ESMO 2022; Abstract LBA29.