As reported in The New England Journal of Medicine by Isabelle Ray‑Coquard, MD, PhD, of the Centre Leon Berard, University Claude Bernard Lyon 1 and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Paris, and colleagues, the phase III PAOLA-1 trial has shown a progression-free survival benefit with the addition of olaparib to bevacizumab maintenance in patients with advanced ovarian cancer responding to first-line platinum-taxane chemotherapy plus bevacizumab.1 The benefit was greatest in patients with homologous recombination deficiency (HRD)-positive tumors.
Isabelle Ray‑Coquard, MD, PhD
In the double-blind trial, 806 women from sites in 11 countries who had newly diagnosed advanced (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV) high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer who responded to first-line platinum-taxane chemotherapy plus bevacizumab were randomly assigned 2:1 between July 2015 and September 2017 to receive olaparib at 300 mg twice daily (n = 537) or placebo (n = 269) for up to 24 months. All patients received bevacizumab maintenance at 15 mg/kg every 3 weeks, for up to a total of 15 months. Patients were enrolled irrespective of BRCA status. Randomization was stratified according to outcome of first-line treatment at screening and BRCA status. The primary endpoint was investigator-assessed progression-free survival.
For the olaparib vs placebo groups: the median age was 61 vs 60 years; the primary tumor location was the ovaries in 85% vs 88%; the FIGO stage was III in 70% vs 69%; the histologic type was serous in 97% vs 94%; history of cytoreductive surgery was upfront in 50% vs 51% (macroscopic residual disease in 41% vs 38%), interval in 42% vs 41% (macroscopic residual disease in 29% vs 32%), and no surgery in 7% vs 8%; response after first-line chemotherapy with no evidence of disease in 54% vs 52%, complete response in 20% vs 20%, and partial response in 26% vs 28%; deleterious BRCA mutations were present in 30% vs 30%; and tumor HRD status was positive in 47% vs 49%, negative in 36% vs 32%, and unknown in 17% vs 19%.
The median follow-up was 22.9 months. The median progression-free survival was 22.1 months in the olaparib group vs 16.6 months in the placebo group (hazard ratio [HR] = 0.59, P < .001).
In an analysis by BRCA status, the median progression-free survival was 37.2 months vs 21.7 months among 157 patients treated with olaparib vs 80 patients who received placebo and had a BRCA mutation (HR = 0.31, 95% confidence interval [CI] = 0.20–0.47) and 18.9 vs 16.0 months among 380 vs 189 patients without a BRCA mutation (HR = 0.71, 95% CI = 0.58–0.88).
In an analysis by HRD status, the median progression-free survival was 37.2 months in the olaparib group vs 17.7 months in the placebo group (HR = 0.33, 95% CI = 0.25–0.45) among 255 vs 132 patients with HRD-positive tumors including those with a BRCA mutation and 28.1 vs 16.6 months among 97 vs 55 patients with HRD-positive tumors without a BRCA mutation (HR = 0.43, 95% CI = 0.28–0.66). Among 192 vs 85 patients with HRD-negative tumors, the median progression-free survival was 16.6 months in the olaparib group vs 16.2 months in the placebo group (HR = 1.00, 95% CI = 0.75–1.35).
In an analysis by response to first-line chemotherapy, hazard ratios were 0.53 (95% CI = 0.40–0.70) among patients with no evidence of disease, 0.44 (95% CI = 0.29–0.66) among those with a complete response, and 0.86 (95% CI = 0.63–1.19) among those with a partial response.
Interim analysis at data maturity of 39% showed Kaplan-Meier estimates of the rate of freedom from second disease progression and death at 18 months of 79% vs 80% (HR = 0.86, 95% CI = 0.69–1.09). Overall survival data were not mature at the time of analysis.
During maintenance therapy, the most common adverse events of any grade occurring more frequently in the olaparib/bevacizumab group were fatigue (53% vs 32%), nausea (53% vs 22%), and anemia (41% vs 10%); hypertension was more common in the placebo/bevacizumab group (60% vs 46%). Grade ≥ 3 adverse events occurred in 57% vs 51% of patients, with the most common in the olaparib/bevacizumab group being hypertension (19% vs 30%) and anemia (17% vs < 1%), and hypertension being the most common in the placebo/bevacizumab group.
Serious adverse events occurred in 31% of both groups, with the most common occurring at a higher incidence in the olaparib/bevacizumab group being anemia (6% vs < 1%), and the most common occurring at a higher incidence in the placebo/bevacizumab group being hypertension (13% vs 9%). Adverse events led to dose interruption in 54% vs 24% of patients, dose reduction in 41% vs 7%, and treatment discontinuation in 20% vs 6%. Myelodysplastic syndromes, acute myeloid leukemia, or aplastic anemia occurred in 1% vs < 1% of patients, and new primary cancers occurred in 1% of each group.
The investigators concluded: “In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation.”
Dr. Ray-Coquard told The ASCO Post: “The addition of maintenance olaparib to bevacizumab in the first-line setting provided a significant progression-free survival benefit in a broad, front-line population of patients with advanced ovarian cancer, which was not restricted by surgical outcome. The median progression-free survival observed in the combination arm has never before been seen in this population with ovarian carcinoma that is not limited to BRCA-mutated disease.”
DISCLOSURE: The study was funded by Arcagy Research, AstraZeneca, Merck Sharp & Dohme, and F. Hoffmann–La Roche. 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.
1. Ray‑Coquard I, Pautier P, Pignata S, et al: Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381:2416-2428, 2019.
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