The PAOLA-1/ENGOT-ov25 is the first study with PARP inhibitor to show a clinically meaningful overall survival (OS) benefit in newly diagnosed patients with homologous recombination deficiency (HRD)-positive advanced ovarian cancer, irrespective of BRCA mutation. 5-year OS rate in patients with HRD-positive tumours was 66% with olaparib plus bevacizumab versus 48% with placebo plus bevacizumab despite >50% of patients with HRD-positive tumours in the placebo arm receiving subsequent PARP inhibitor. After 5 years, 46% of patients with HRD-positive tumours on olaparib plus bevacizumab versus 19% on placebo plus bevacizumab were alive and had not progressed.
No new safety signals were observed, and the incidence of myelodysplastic syndrome (MSD)/acute myeloid leukaemia (AML) remained low. The findings are published by Prof. Isabelle Ray-Coquard of the GINECO group, Centre Léon Bérard, Université Claude Bernard Lyon Est in Lyon, France, and colleagues on 19 May 2023 in the Annals of Oncology.
The phase III PAOLA-1/ENGOT-ov25 study evaluated maintenance treatment with PARP inhibitor olaparib plus bevacizumab, compared with placebo plus bevacizumab, in patients with newly diagnosed advanced ovarian cancer, irrespective of biomarker or surgical status, who were in clinical response after first-line platinum-based chemotherapy plus bevacizumab.
In primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed advanced ovarian cancer who were in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation or HRD (defined as a tumour with BRCA mutation and/or genomic instability). In the latest article, published in the Annals of Oncology, the authors report the prespecified final OS analysis, including analyses by HRD status.
Patients were randomised 2:1 to olaparib 300 mg bid (up to 24 months) plus bevacizumab 15 mg/kg q3w (15 months in total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for approximately 60% maturity or 3 years after the primary analysis.
After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, median OS was 56.5 versus 51.6 months in the intention-to-treat (ITT) population (hazard ratio [HR] 0.92, 95% confidence interval CI 0.76-1.12; p = 0.4118). Subsequent PARP inhibitor was received by 105 patients (19.6%) in the olaparib arm versus 123 patients (45.7%) in the placebo arm.
In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85) with 5-year OS rate of 65.5% versus 48.4%. At 5 years, updated PFS also showed a higher proportion of patients who received olaparib plus bevacizumab without relapse (HR 0.41, 95% CI 0.32-0.54) and 5-year PFS rate was 46.1% versus 19.2%.
MSD, AML, aplastic anaemia, and new primary malignancy incidence remained low and balanced between arms.
The authors concluded that this final, prespecified OS analysis demonstrates that the PFS advantage in the primary analysis, which established the combination of olaparib plus bevacizumab as one of the standards of care for patients with HRD-positive tumours in this setting, also translates to a clinically meaningful OS benefit in first-line treatment.
The addition of maintenance olaparib to bevacizumab modestly numerically prolonged OS versus bevacizumab alone in patients with newly diagnosed advanced ovarian cancer in the ITT population. However, in the subset of patients with HRD-positive tumours, where PARP inhibitors are expected to be biologically active, olaparib plus bevacizumab provided a clinically meaningful, numerical OS advantage at 5 years, despite 50% of patients in the control arm receiving PARP inhibitors post progression.
The OS benefit observed in patients with HRD-positive tumours was, in part, driven by the BRCA mutation subgroup (HR 0.60, 95% CI 0.39-0.93). Because PAOLA-1 lacked an olaparib monotherapy arm, it is difficult to draw conclusions on the effect of combining olaparib and bevacizumab versus olaparib alone. In PAOLA-1, a numerical OS benefit was also observed in patients with HRD-positive tumours excluding BRCA mutation (HR 0.71, 95% CI 0.45-1.13). The small subgroup size (97 in the olaparib plus bevacizumab and 55 in the placebo plus bevacizumab arms) may explain the large confidence intervals observed. For those patients classified as HRD-negative, there was no benefit observed with the addition of olaparib to bevacizumab (HR 1.19, 95% CI 0.88-1.63).
The PAOLA-1 results highlight the importance of refining biomarker testing to better distinguish patient populations likely to respond to PARP inhibitors. Future analyses of PAOLA-1 data evaluating OS by location and type of BRCA mutation may provide clearer assessment of individuals most likely to derive benefit. The absence of benefit observed in patients with HRD-negative tumours in PAOLA-1 also underlines an important unmet need in this population with a high rate of disease progression observed during PARP inhibitor treatment, emphasising the importance of refining HRD testing to better detect all patients with HRD, and highlighting the need for research into treatment options for patients with HRD-negative disease.
This work was supported by Association de Recherche Cancers Gynécologiques (ARCAGY) Research, AstraZeneca, Merck Sharp & Dohme (a subsidiary of Merck), and F. Hoffmann–La Roche.
Ray-Coquard I, Leary A, Pignata S, et al. for the PAOLA-1/ ENGOT-ov25 investigators. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Annals of Oncology; Published online 19 May 2023. DOI: https://doi.org/10.1016/j.annonc.2023.05.005