Clinical trialPhase 3Ovarian cancer

Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial

Annals of Oncology · 2023806 patients (537 olaparib + bevacizumab, 269 placebo + bevacizumab; per the original NEJM 2019 report)

Ray-Coquard I, Leary A, Pignata S, Cropet C, González-Martín A, Marth C, et al. Annals of Oncology. 2023. 34:681-692

Study type: Clinical trial
Study name: PAOLA-1/ENGOT-ov25
Phase: Phase 3
Design: Randomised (2:1 ratio) placebo-controlled trial; prespecified final overall survival analysis
Sample size: 806 patients (537 olaparib + bevacizumab, 269 placebo + bevacizumab; per the original NEJM 2019 report)
Source: Annals of Oncology · 2023

In plain words

This study followed patients with advanced ovarian cancer who had responded well to their first chemotherapy for about 5 years. Across all patients, adding olaparib to bevacizumab did not make a significant difference to how long they lived. But in patients whose tumour had a defect in homologous recombination (HRD), survival was longer: 65.5% vs 48.4% were alive after 5 years. Serious blood-related side effects and new cancers were rare and similar in both groups.

Key results

61.7 vs 61.9 months

Median follow-up (olaparib vs placebo)

56.5 vs 51.6 months

Median overall survival in the intention-to-treat (ITT) population

HR 0.92; 95% CI: 0.76 to 1.12; P = 0.4118

105 patients (19.6%) vs 123 patients (45.7%)

Subsequent PARP inhibitor therapy

Olaparib group vs placebo group

HR 0.62

Overall survival in the HRD-positive population

95% CI: 0.45 to 0.85

65.5% vs 48.4%

5-year overall survival rate in the HRD-positive population

Olaparib + bevacizumab vs placebo + bevacizumab

46.1% vs 19.2%

5-year PFS rate in the HRD-positive population

HR 0.41; 95% CI: 0.32 to 0.54

Drugs in this study:Bevacizumab (Avastin)Olaparib (Lynparza)

Dose and schedule cards

Olaparib + bevacizumab maintenance (PAOLA-1)

HRD-positive (BRCA mutation and/or genomic instability), advanced disease, with complete or partial response to first-line platinum-based chemotherapy plus bevacizumabEach drug’s schedule in the tableOn the page “Ovarian cancer” · First line: maintenance therapy (based on BRCA and HRD)

HRD-positive (BRCA mutation and/or genomic instability), advanced disease, with complete or partial response to first-line platinum-based chemotherapy plus bevacizumab

Drug	Dose	Route	Schedule
Olaparib	300 mg twice daily	Oral	Continuously
Bevacizumab	15 mg/kg	IV	Day 1 every 21 days

Cycle schedule: Olaparib continuously; bevacizumab every 21 days
Duration: Olaparib up to 2 years (stopping rules as in SOLO-1); bevacizumab for a total of 15 months, including the period given with chemotherapy

Olaparib monitoring and dose modification as in the previous row. Pan-Asian ESMO guideline: for BRCA-mutated and HRD-positive disease [I, A].

On the page “Ovarian cancer” · First line: maintenance therapy (based on BRCA and HRD)

First-line maintenance in HRD-positive advanced ovarian cancer, with bevacizumab (PAOLA-1)

Complete or partial response to first-line platinum chemotherapy; HRD-positive (BRCA mutation and/or genomic instability)On the page “Olaparib (Lynparza)” · Standard dosing (FDA label)

Complete or partial response to first-line platinum chemotherapy; HRD-positive (BRCA mutation and/or genomic instability)

Drug	Dose	Route	Schedule
Continuous
Olaparib	300 mg	Oral (with or without food)	Twice daily (about every 12 hours)
Every 3 weeks
Bevacizumab	15 mg/kg	IV	Every 3 weeks

Cycle length: Continuous; bevacizumab every 21 days
Duration: Olaparib up to 2 years (as above); bevacizumab 15 months in total including the period with chemotherapy

On the page “Olaparib (Lynparza)” · Standard dosing (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Olaparib plus bevacizumab

Olaparib 300 mg orally twice daily for up to 24 months, plus bevacizumab 15 mg/kg IV every 3 weeks for a total of 15 months (including the period with first-line chemotherapy).

2Placebo plus bevacizumab

Placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg IV every 3 weeks for a total of 15 months.

Source of the regimen details: Abstract of the paper (olaparib 300 mg twice daily for up to 24 months; bevacizumab 15 mg/kg every 3 weeks for a total of 15 months) and the FDA label for Lynparza

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with newly diagnosed advanced ovarian cancer who had a clinical response after first-line platinum-based chemotherapy plus bevacizumab; regardless of surgical status. Analyses were also done by molecular biomarker status, including BRCA1/BRCA2 mutation and homologous recombination deficiency (HRD).

Endpoints

Overall survival (OS) was a key secondary endpoint in hierarchical testing. The OS analysis was planned at about 60% data maturity or 3 years after the primary analysis. Updated progression-free survival (PFS) and analyses by HRD status were also reported.

Safety and side effects

The incidence of myelodysplastic syndrome, acute myeloid leukaemia, aplastic anaemia and new primary malignancy remained low and balanced between the two groups. Grade ≥3 adverse event data are not given in the abstract.

Clinical significance and place in guidelines

Based on the abstract, an overall survival benefit of olaparib plus bevacizumab was shown in HRD-positive patients, and the authors consider this combination one of the standards of care for first-line maintenance in this group. In the whole ITT population the overall survival improvement was not significant, so HRD testing matters for patient selection. The HRD analyses were exploratory and prespecified. The status of drug approvals and clinical guidelines should be checked separately.

Limitations

Analyses by HRD status were exploratory. In the placebo group a high proportion of patients (45.7%) received a PARP inhibitor after disease progression, which may affect the overall survival comparison. In the ITT population the OS difference was not significant. Other details (including the total number of patients and grade ≥3 adverse events) are not given in the abstract.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.