Isabelle Ray-Coquard, MD, PhD
In women with newly diagnosed ovarian cancer, front-line maintenance therapy with olaparib plus bevacizumab reduced the risk of disease progression by 41% overall and by 69% in the subset of patients with BRCA-mutated disease, vs bevacizumab and placebo, in the phase III PAOLA-1/ENGOT-ov25 trial presented at the European Society for Medical Oncology (ESMO) Congress 2019.1 “This study reports the greatest hazard ratio (0.59) and longest progression-free survival we have ever seen [in women with newly diagnosed ovarian cancer],” said lead investigator Isabelle Ray-Coquard, MD, PhD, of the Centre Leon Bérard, Université Claude Bernard, Lyon, and President of the GINECO group, in an ESMO press release.
PAOLA-1 evaluated olaparib plus bevacizumab maintenance in 806 patients who responded to first-line platinum-based chemotherapy plus bevacizumab. Outcomes were evaluated according to homologous recombination deficiency (HRD) and BRCA-mutation status.
“Patient selection was not restricted by surgical outcome or BRCA-mutation status, so participants represent the general population of women with advanced ovarian cancer. Previous studies of relapse have suggested benefits from combining antiangiogenic agents and PARP inhibitors, and these results appear to support this,” added Dr. Ray-Coquard.
This was the first randomized trial to explore the efficacy and safety of the combination of olaparib and bevacizumab, vs bevacizumab and placebo, in patients with newly diagnosed ovarian cancer, according to the investigators. In the previous phase III SOLO-1 trial, olaparib monotherapy reduced the risk of disease progression by 70% (P < .0001) in patients with germline BRCA mutations.2 As background on the combination therapy, Dr. Ray-Coquard pointed out that PARP (poly [ADP ribose] polymerase) inhibitor activity has been observed beyond BRCA-mutated disease in platinum-sensitive relapse, especially when combined with an antiangiogenic agent.
PAOLA-1 Design
The PAOLA-1 trial enrolled 806 women with newly diagnosed stage III or IV high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer. Patients were randomly assigned 2:1 to receive olaparib (300 mg twice daily for up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks on day 1 for 15 months) or placebo. Patients were eligible regardless of the type or extent of surgery. All had received prior platinum-based chemotherapy (for at least four cycles) and bevacizumab (for at least three cycles) and responded to treatment. The median time from the first cycle of chemotherapy to randomization was 7 months.
HRD status was determined by the myChoice HRD Plus assay. An HRD score of ≥ 42 was considered positive.
Primary Endpoint Met
“PAOLA-1 met its primary objective, demonstrating a statistically significant improvement in progression-free survival in the intent-to-treat population when olaparib, compared with placebo, was added to first-line standard-of-care bevacizumab maintenance treatment,” Dr. Ray-Coquard reported. Compared with bevacizumab and placebo, maintenance therapy with the combination improved the median progression-free survival from 16.6 months to 22.1 months (hazard ratio = 0.59; P < .0001) in the overall population, regardless of BRCA-mutation status.
The analysis is based on 59% maturity of the data. The time to second disease progression data were not mature at the time of this analysis. Although all patient subsets benefited from treatment (Table 1), the magnitude was greatest for those whose tumors tested positive for BRCA1/2 mutations: 37.2 vs 21.7 months (hazard ratio = 0.31; 95% confidence interval [CI] = 0.20–0.47). The median progression-free survival was also noteworthy among HRD-positive patients (which included both patients with BRCA-mutated and BRCA wild-type disease; hazard ratio = 0.33; 95% CI = 0.25–0.45).
No significant difference was observed between the two arms in the homologous recombination–proficient groups. Surprisingly, the median progression-free survival of 16 months in the control arm (with bevacizumab alone) was quite similar to that observed in the HRD group, suggesting particular activity of bevacizumab in this population of patients.
“Prespecified subgroup analyses showed that patients with tumor BRCA mutations and those with a positive HRD status had the greatest progression-free survival benefits,” said Dr. Ray-Coquard. “The results reveal a patient population beyond patients with tumor BRCA-mutated disease—those who are HRD-positive—who experience substantial benefit from maintenance treatment with olaparib and bevacizumab.”
PAOLA-1 vs SOLO-1
Olaparib monotherapy was approved as front-line maintenance for patients with germline or somatic BRCA-mutated tumors, based on findings from the phase III SOLO-1 trial. In this trial, olaparib reduced the risk of disease progression or death by 70% compared with placebo (hazard ratio = 0.30; P < .0001).2 The median progression-free survival was not reached with olaparib but was 13.8 months with placebo.
Although patients in PAOLA-1 more frequently had FIGO stage IV disease, residual disease, and interval surgery, the hazard ratios are similar between the PAOLA-1 trial (0.31) and SOLO-1 (0.30) in the population with BRCA-mutated disease. The median progression-free survival was also longer with bevacizumab alone in PAOLA-1’s control arm (21.7 months) than with placebo in SOLO-1 (13.8 months). According to Dr. Ray-Coquard, this prolongation is probably due to the use of bevacizumab in the control arm of PAOLA-1 and reveals potentially interesting activity of bevacizumab in this BRCA-mutated population.
Safety Profile
Grade ≥ 3 adverse events occurred in 57% vs 51% of patients receiving olaparib/bevacizumab and placebo/bevacizumab, respectively, most commonly hypertension (19% vs 30%) and anemia (17% vs < 1%). There were five fatal treatment-emergent adverse events—one in the olaparib arm and four in the placebo arm.
Dose interruptions for experimental therapy were required for 54% of patients treated with the combination vs 24% treated with bevacizumab alone. Dose reductions were recorded in 41% and 7%, respectively, and dose discontinuations (including those due to adverse events or the patient’s decision) were needed in 20% and 6%, respectively. No differences were observed in health-related quality of life. ■
DISCLOSURE: Dr. Ray-Coquard has received honoraria from, served as an advisor or consultant for, and has received travel funds from AstraZeneca, Clovis Oncology, Tesaro, PharmaMar, Roche, Genmab, MSD, and Pfizer.
REFERENCES
1. 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 with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy plus bev. ESMO Congress 2019. Abstract LBA2_PR. Presented September 28, 2019.
2. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379:2495-2505, 2018.
