PAOLA-1 Supports Olaparib–Bevacizumab Maintenance For HRD-Positive Advanced Ovarian Cancer

medwireNews: Findings from the PAOLA-1/ENGOT-ov25 study indicate that patients derive a significant benefit from the use of the PARP inhibitor olaparib alongside maintenance bevacizumab after first-line treatment for stage III–IV ovarian cancer with a homologous recombination deficiency (HRD). 

The progression-free survival (PFS) trial findings were reported at the ESMO Congress 2019 in Barcelona, Spain, by Isabelle Ray-Coquard, from Centre Léon Bérard in Lyon, France.  

Speaking to medwireNews, the presenter said she believes the PAOLA-1 findings are “changing practice, as we report that [HRD-positive] patients in first-line treatment need to receive a PARP inhibitor in combination with bevacizumab.” 

Patients with newly diagnosed high-grade serous or endometrioid disease were treated with surgery and platinum–taxane chemotherapy and at least three cycles of bevacizumab 15 mg/kg every 3 weeks before randomisation to receive maintenance treatment with olaparib 300 mg twice daily for 2 years plus bevacizumab for up to 15 months (n=537), or to receive placebo plus maintenance bevacizumab (n=269). 

Intention-to-treat analysis of the primary endpoint revealed a median PFS duration of 22.1 months for the patients given olaparib–bevacizumab versus 16.6 months for those given placebo–bevacizumab, with a significant hazard ratio (HR) for death or progression of 0.59. 

Time to first subsequent therapy or death also significantly favoured the olaparib–bevacizumab arm (24.8 vs 18.5 months, HR=0.59) and there was a trend towards improved time to second progression at interim analysis (32.2 vs 30.1 months), although this did not reach significance. Overall survival data are yet to mature, the presenter said. 

Analysis confirmed that olaparib–bevacizumab achieved a PFS benefit across all the clinical subgroups of age, FIGO stage, ECOG performance status, cytoreductive surgery timing and outcome, and response to first-line chemotherapy. 

When patients were assessed by biomarkers, median PFS among the patients with a BRCA mutation was significantly higher with olaparib–bevacizumab versus placebo–bevacizumab (37.2 vs 21.7 months, HR=0.31). 

Isabelle Ray-Coquard told delegates this PFS was longer than observed in the SOLO1 trial findings for olaparib monotherapy in BRCA-mutated patients despite a higher proportion of patients in PAOLA-1 having stage IV or residual disease, “and this is probably due to the bevacizumab administration.” 

PFS was also significantly longer with olaparib–bevacizumab for patients without a BRCA mutation or whose status was unknown (18.9 vs 16.0 months, HR=0.71), although the benefit was smaller, as well as for the subgroup of HRD-positive patients whether including or excluding those with a BRCA mutation (HR=0.33 and 0.43, respectively). 

However, there was no significant gain in PFS with olaparib use for patients with unknown or HRD-negative status, the investigator said. 

Safety analysis showed a comparable rate of grade 3 or more severe treatment-related adverse events in the olaparib–bevacizumab and placebo–bevacizumab arms (57 vs 51%), although there was a higher rate of dose interruptions, reductions and discontinuations because of adverse events with olaparib. Quality of life did not differ between the treatment groups. 

“The PAOLA-1 population is representative of the majority of patients with newly advanced ovarian cancer as patient selection was not restricted by surgical outcome or BRCA mutation”, summarised Isabelle Ray-Coquard. 

While acknowledging that the prespecified biomarker analysis showed that the greatest benefit was in patients with a BRCA mutation, the presenter emphasized that “the results reveal a new population beyond BRCA–HRD-positive [patients] who experienced a substantial benefit with the combination of olaparib and bevacizumab.” 

Reference  

Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian treated with platinum-based chemotherapy (PCh) plus bev. ESMO Congress 2019; Barcelona, Spain: 27 September–1 October. LBA2_PR