Maintenance Therapy with Olaparib plus Bevacizumab in Newly Diagnosed Advanced High‐Grade Ovarian Carcinoma

An investigation of whether adding a maintenance therapy regimen of olaparib combined with bevacizumab provided a benefit beyond first progression in patients with newly diagnosed advanced high‐grade ovarian carcinoma.

Although demonstrated clinically significant benefits of olaparib had been shown when used as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation, the effect of combined maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status was unknown until results of the PAOLA-1/ENGOT-ov25 study were published in 2019.¹ In the primary analysis of this phase 3 clinical trial to evaluate the safety and efficacy of the combination of olaparib plus bevacizumab as first-line maintenance treatment for patients with ovarian cancer with and without a BRCA mutation, the combination showed that in patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival (PFS) benefit, which was substantial in patients with homologous recombination deficiency (HRD)-positive tumors, including those without a BRCA mutation.

In a mini oral presentation at the European Society for Medical Oncology Virtual Congress 2020, Antonio González-Martín, MD, PhD, Co-Director, Medical Oncology, Cliníca Universidad de Navarra, Pamplona, Spain, discussed recent findings from a final analysis of second PFS (PFS2) of the phase 3 PAOLA-1/ENGOT-ov25 clinical trial. As in the original study, this study looked at the use of maintenance therapy (olaparib plus bevacizumab) in patients with newly diagnosed advanced high‐grade ovarian carcinoma. Based on the original study parameters, regardless of surgical outcome or BRCA mutation status, eligible patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months. Bevacizumab was administered at a dose of 15 mg/kg every 3 weeks up to 15 months in total. The time from randomization until investigator-assessed disease progression or death was the primary end point.¹

The investigators noted that there was significant benefit in PFS. In patients with HRD-positive tumors, including those without a BRCA mutation, this was particularly important. Specifically, adding olaparib to maintenance bevacizumab after first-line platinum-based chemotherapy led to a significant PFS benefit in a patient population with advanced high‐grade ovarian carcinoma (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.49-0.72).¹ PFS2 data at the time of publication were not fully developed.

In this most recent analysis presented by Dr González-Martín and colleagues at the European Society for Medical Oncology Virtual Congress 2020, patients with newly diagnosed, high‐grade ovarian carcinoma (stage III-IV) who were responsive to platinum-based chemotherapy plus bevacizumab were randomized to receive olaparib (300 mg for 24 months twice daily) plus bevacizumab (15 mg/kg every 3 weeks for 15 months) or placebo plus bevacizumab. Time to second subsequent therapy (TSST) or death and PFS2 were the key secondary end points.

These patient cohorts who received olaparib and bevacizumab (N = 537) or who received placebo and bevacizumab (N = 269) had a median PFS2 corresponding follow-up of 35.5 and 36.5 months. A statistically significant reduction in the risk for second progression or death compared with placebo and bevacizumab was shown: the median PFS2 was 36.5 months for the olaparib plus bevacizumab cohort and 32.6 months for the placebo plus bevacizumab cohort (HR, 0.78; 95% CI, 0.64-0.95; P = .0125). TSST was longer in the olaparib plus bevacizumab cohort compared with the placebo plus bevacizumab cohort (median, 38.2 vs 31.5 months; HR, 0.78; 95% CI, 0.64-0.95; P = .0115). In the active arm, no new safety signals were seen with longer follow-up.

In this study, adding a maintenance therapy regimen of olaparib plus bevacizumab provided a benefit beyond first progression. Most notably, a substantial PFS2 benefit was found in the BRCA mutation–positive and HRD-positive cohorts, reinforcing significant benefit to these patient populations. This conclusion is based on a subanalysis, demonstrating that the median PFS2 benefit was 50.3 months for all patients with HRD-positive disease receiving olaparib plus bevacizumab versus 35.3 months for placebo plus bevacizumab (HR, 0.56; 95% CI, 0.41-0.77). The statistically significant improvement in PFS2 seen with olaparib plus bevacizumab when compared with placebo plus bevacizumab was supported by a similar TSST benefit.

Lastly but importantly, HRs for PFS2 by biomarker status with olaparib plus bevacizumab compared with placebo plus bevacizumab were 0.53 in patients with BRCA mutation–positive disease, 0.56 in patients with HRD-positive disease, 1.04 in patients with HRD-negative disease, and 0.60 in patients with HRD-positive disease without a BRCA mutation.

Because at the time of final PFS2 analysis overall survival data were considered immature, Dr González-Martín and colleagues reinforced that definitive conclusions still cannot be made. “The prespecified final overall survival analyses will be conducted once approximately 60 percent of events have occurred or 3 years after the primary PFS analysis (March 2022),” the investigators noted.²

Source: González-Martín A, et al. Ann Oncol. 2020;31(4_suppl). Abstract LBA33.

References
1. Ray-Coquard I, Pautier P, Pignata S, et al; for the PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381:2416-2428.
2. Nalley C. Maintenance olaparib + bevacizumab provides continued benefit in ovarian cancer. http://know.lww.com/oncology-times/esmoarticles/maintenance-olaparib.html. Accessed November 14, 2020.