Background
Phase III RCT (PAOLA-1/ENGOT-OV25). 806 patients with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer who received first-line standard chemotherapy (carboplatin + paclitaxel) plus bevacizumab and had no disease progression. Randomized 2:1 to olaparib 300 mg BID + bevacizumab 15 mg/kg q3wk (up to 15 months) vs placebo + bevacizumab (up to 15 months) maintenance. Olaparib continued for 24 months total from maintenance start. Prospectively stratified by HRD status and tumor BRCA status.
Interventions and follow up
Arm A: Olaparib 300 mg BID + bevacizumab 15 mg/kg q3wk maintenance (olaparib 24 months; bevacizumab up to 15 months)
Arm B: Placebo + bevacizumab 15 mg/kg q3wk (up to 15 months)
Primary endpoint: PFS by investigator assessment
mFollow up: 22.9 month
Arm B: Placebo + bevacizumab 15 mg/kg q3wk (up to 15 months)
Primary endpoint: PFS by investigator assessment
mFollow up: 22.9 month
Results
Median PFS — overall: 22.1 months (olaparib + bev) vs 16.6 months (placebo + bev), HR 0.59 (95% CI 0.49–0.72), P<.001
Median PFS — HRd (includes BRCA-mutated): 37.2 vs 17.7 months, HR 0.33 (95% CI 0.25–0.45)
Median PFS — BRCA-mutated: Not reached vs 21.7 months, HR 0.31
Median PFS — HRd non-BRCAm: 28.1 vs 16.6 months, HR 0.43
Median PFS — HRp: 16.9 vs 16.0 months, HR 0.92 (95% CI 0.72–1.17) — not significant
Median PFS — HRd (includes BRCA-mutated): 37.2 vs 17.7 months, HR 0.33 (95% CI 0.25–0.45)
Median PFS — BRCA-mutated: Not reached vs 21.7 months, HR 0.31
Median PFS — HRd non-BRCAm: 28.1 vs 16.6 months, HR 0.43
Median PFS — HRp: 16.9 vs 16.0 months, HR 0.92 (95% CI 0.72–1.17) — not significant
Adverse events
Main adverse events: Grade ≥3 AEs: 57% (olaparib + bev) vs 51% (placebo + bev). Grade ≥3 hypertension: 19% vs 18%. Grade ≥3 anemia: 17% vs 6%. Grade ≥3 fatigue: 5% vs 4%. Discontinuation due to AEs: 20% vs 5%.
Conclusions
Olaparib + bevacizumab maintenance dramatically improved PFS in HRd/BRCAm patients (HR 0.33; 37.2 vs 17.7 months) with minimal benefit in HRp patients (HR 0.92), establishing this combination as standard in HRd/BRCAm patients receiving bevacizumab first-line.
Key Limitations
Key Limitations: No OS benefit demonstrated at primary analysis (immature). The bevacizumab backbone in both arms means this trial does not address whether olaparib alone (without bevacizumab) would be equivalent — olaparib alone (SOLO1) performs similarly in BRCA-mutated patients without bevacizumab. HRp patients gained no meaningful PFS benefit. HRD testing adds cost and complexity. Real-world applicability requires confirming bevacizumab was used in the first-line chemo.
Clinical Context
PAOLA-1 led to FDA approval (2020) of olaparib + bevacizumab maintenance for newly diagnosed HRd advanced ovarian cancer. In practice: for BRCA-mutated patients who received bevacizumab first-line, olaparib + bevacizumab (PAOLA-1) or olaparib alone (SOLO1) are both options; for non-BRCA HRd patients with bevacizumab, olaparib + bevacizumab is preferred; for HRp patients, bevacizumab alone is the maintenance backbone.
References
References: Ray-Coquard I et al, N Engl J Med 2019 (PAOLA-1)