PAOLA-1 Trial: Olaparib Plus Bevacizumab Maintenance Therapy
The PAOLA-1 trial demonstrated that adding olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy plus bevacizumab significantly improves progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer, with the most substantial benefit seen in patients with homologous recombination deficiency (HRD)-positive tumors. 1
Primary Efficacy Results
Overall Population:
- Median PFS was 22.1 months with olaparib plus bevacizumab versus 16.6 months with placebo plus bevacizumab (HR 0.59; 95% CI 0.49-0.72; P<0.001) 2
- This represents a 41% reduction in the risk of disease progression or death 2
HRD-Positive Tumors (Including BRCA Mutations):
- The combination showed remarkable efficacy with HR 0.33 (95% CI 0.25-0.45) 2
- Median PFS was 37.2 months versus 17.7 months with bevacizumab alone 2
- This represents a 67% reduction in risk of progression or death 3
- Five-year PFS rates were 35% versus 15% in higher-risk patients and 72% versus 28% in lower-risk patients 4
HRD-Positive Without BRCA Mutations:
HRD-Negative Tumors:
Overall Survival Data
Updated mature overall survival analysis demonstrates clinically meaningful improvements in HRD-positive patients:
Higher-Risk HRD-Positive Patients:
- HR for overall survival 0.70 (95% CI 0.50-1.00) 4
- Five-year overall survival: 55% with olaparib plus bevacizumab versus 42% with bevacizumab alone 4
Lower-Risk HRD-Positive Patients:
- HR for overall survival 0.31 (95% CI 0.14-0.66), representing a 69% reduction in risk of death 4
- Five-year overall survival: 88% versus 61% 4
- This suggests an increased potential for cure, with particular benefit in lower-risk HRD-positive patients 4
Clinical Risk Stratification
The trial stratified patients into two risk categories: 5
Higher-Risk (74% of patients):
- Stage III with upfront surgery and residual disease 5
- Stage III with neoadjuvant chemotherapy 5
- Stage IV disease 5
Lower-Risk (26% of patients):
- Stage III with upfront surgery and no residual disease 5
Both risk groups benefited from olaparib plus bevacizumab in the HRD-positive population, with lower-risk patients showing particularly impressive results (85% reduction in risk of progression or death). 5
Treatment Regimen
Dosing Schedule:
- Olaparib 300 mg orally twice daily for up to 24 months 2
- Bevacizumab 15 mg/kg intravenously every 3 weeks for up to 15 months total (including treatment during chemotherapy) 2
- Patients must be in complete or partial response after first-line platinum-taxane chemotherapy plus bevacizumab 2
Safety Profile
Common Adverse Events (Any Grade):
- Anemia: 63% with combination versus 18% with bevacizumab alone 1
- Nausea: 57% versus 28% 1
- Neutropenia: 26% versus 7% 1
- Platelet count decreased: 28% versus 1% 1
Grade ≥3 Hematologic Events:
Study Drug Discontinuation:
- 12.0% with olaparib plus bevacizumab versus 2.5% with bevacizumab alone discontinued due to adverse events 1
The safety profile was consistent with the established profiles of both agents and was generally manageable. 6, 2
FDA Approval and Companion Diagnostics
FDA approved olaparib in combination with bevacizumab on May 8,2020, for first-line maintenance treatment of HRD-positive advanced ovarian cancer. 3
Myriad myChoice CDx was designated as the companion diagnostic device for identifying HRD-positive status for use of olaparib plus bevacizumab combination. 3
NCCN Guideline Recommendations
The NCCN Guidelines incorporate PAOLA-1 results with specific recommendations: 1
- For BRCA1/2-mutated tumors: Olaparib plus bevacizumab maintenance for 2 years is recommended 7
- For BRCA1/2-wild-type/HRD-positive tumors: Olaparib plus bevacizumab maintenance for 2 years is recommended 7
- For HRD-negative tumors: Bevacizumab maintenance alone is recommended 7
Critical caveat: The combination should not be limited to higher-risk patients, as lower-risk HRD-positive patients demonstrated particularly impressive benefits. 4
Key Clinical Implications
HRD testing is essential before initiating maintenance therapy to identify patients who will benefit from the combination versus bevacizumab alone. 3
Hematologic monitoring is crucial, particularly for anemia, neutropenia, and thrombocytopenia, which may require dose modifications. 1
The five-year PFS and overall survival data support the potential for long-term remission and suggest an increased potential for cure, especially in lower-risk HRD-positive patients. 4