Adding olaparib to bevacizumab delays disease progression in patients with newly diagnosed advanced ovarian cancer beyond BRCA mutation status

The phase III PAOLA-1/ENGOT-ov25 study investigated the addition of olaparib to maintenance bevacizumab in patients with advanced ovarian cancer who are receiving first-line standard of care including bevacizumab. Importantly, this study included a broad patient population, which was not restricted by surgical outcome or BRCA mutation status. The study met its primary endpoint by demonstrating a statistically significant improvement in the progression-free survival in the overall study population when olaparib compared with placebo was added to bevacizumab maintenance treatment. The clinical benefit of olaparib was not limited to BRCA mutated patients alone, as also BRCA wild type patients with homologous recombination deficiency experienced substantial benefit from maintenance treatment with olaparib and bevacizumab.

Background

First-line bevacizumab in combination with chemotherapy and followed by bevacizumab maintenance has been shown to increase the response rate and prolongs the progression-free survival (PFS) and overall survival (OS) in high-risk subgroups of newly diagnosed advanced ovarian cancer. In the phase III SOLO-1 trial, the PARP inhibitor olaparib showed an unprecedented PFS benefit as first line maintenance monotherapy for advanced ovarian cancer patients harbouring a BRCA mutation. Interestingly, in platinum sensitive ovarian cancer, PARP inhibitor activity was observed beyond the BRCA mutation status and this activity was increased when it was combined with an anti-angiogenic agent. These findings formed the rationale for the phase III PAOLA 1/ENGOT-ov25 trial evaluating the efficacy and safety of maintenance therapy with olaparib in patients with advanced ovarian cancer regardless of BRCA mutation status who are receiving first line standard of care treatment including bevacizumab.

Trial set-up

In the study at hand, 806 patients with newly diagnosed, FIGO stage III-IV high-grade serous/endometrioid ovarian, fallopian tube, or primary peritoneal cancer who received platinum-taxane based chemotherapy and at least 3 cycles of bevacizumab were randomized (2:1) to maintenance therapy with bevacizumab (15 mg/kg every 3 weeks for a total of 15 months) either in combination with olaparib (300 mg BID for 2 years), or with placebo. The primary endpoint of the study was investigator-assessed PFS, with the time to first subsequent therapy (TFST), time to second progression (PFS2), overall survival (OS), quality of life (QoL) and safety as secondary objectives.

Results

The median age of patients in the study was 61 years, 70% had an ECOG performance status 0 and the ovary was the primary tumour location in approximately 85% of patients. The vast majority (96%) of patients had a serous histology, 70% had FIGO stage III disease and 30% of study participants harboured a BRCA mutation (BRCA wild type or unknown status in 70%). Half of the patients in the trial underwent upfront surgery and 42% had interval cytoreductive surgery (no surgery in 7%). At the time of the analysis, 62% and 73% of patients discontinued therapy in the olaparib and placebo arm, respectively. The main reasons for treatment discontinuation in the olaparib arm were disease progression (34%) and treatment emergent adverse events (TEAE; 20%), while disease progression was responsible for almost all treatment discontinuations in the placebo arm (58%).

In the overall study population, olaparib-bevacizumab maintenance was associated with a median PFS of 22.1 months, which was significantly longer than the 16.6 months median PFS seen in the control arm (HR [95%CI]: 0.59 [0.49-0.72]; p<0.0001). Also with respect to the TFST, the addition of olaparib to maintenance bevacizumab resulted in a significant improvement (median TFST: 24.8 vs 18.5 months; HR [95% CI]: 0.59 [0.49-0.71]; p<0.0001). The PFS benefit of olaparib was particularly pronounced in the subgroup of patients with BRCA mutations (median PFS: 37.2 vs 21.7 months; HR [95% CI]: 0.31 [0.20-0.47]), but also patients without BRCA mutations seemed to derive benefit from the addition of olaparib (median PFS: 18.9 vs 16.0 months; HR [95% CI]: 0.71[0.58-0.88]). Of particular interest was the presentation of the PFS data in function of the homologous recombination deficiency (HRD) status. This analysis revealed that HR deficient patients with a BRCA mutation derived the largest benefit from adding olaparib (median PFS: 37.2 vs 17.7 months; HR [95% CI]: 0.33 [0.25-0.45]), while HR proficient patients did not seem to benefit from olaparib maintenance (median PFS: 16.9 vs 16.0 months; HR [95% CI]: 0.92 [0.72-1.17]). Interestingly, the subgroup of patients with HRD tumours without a BRCA mutation experienced a pronounced PFS benefit from olaparib-bevacizumab maintenance compared to placebo-bevacizumab. In this subgroup of patients, the addition of olaparib to bevacizumab resulted in a 57% reduction in the risk of disease progression or death (median PFS: 28.1 vs 16.6 months; HR [95% CI]: 0.43 [0.28-0.66]).

Grade ≥3 adverse events (AEs) occurred in 57% vs 51% of patients receiving olaparib and placebo. The most commonly reported AEs were hypertension (19% vs 30%) and anaemia (17% vs <1%). There were five fatal treatment emergent AEs, one with olaparib and 4 in the placebo arm. Dose interruptions occurred in 54% vs 24%, while dose reductions occurred in 41% vs 7%, and treatment discontinuation occurred in 20% vs 6% of patients receiving olaparib and placebo, respectively.

Conclusions

PAOLA-1/ENGOT-ov25 met its primary objective, demonstrating a statistically significant and clinically meaningful improvement in PFS in the overall study population when olaparib compared with placebo was added to first-line standard of care bevacizumab maintenance treatment. This PFS benefit was especially pronounced in the subgroup of patients with a BRCA mutation, but also in HR deficient patients without a BRCA mutation.

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 cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Presented at ESMO 2019; Abstract LBA2_PR.