Isabelle Ray-Coquard, MD, PhD
As reported inThe New England Journal of Medicine by Isabelle Ray-Coquard, MD, PhD, of the Céntre Léon 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.
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.