Adding Cediranib to Olaparib Improves Progression-Free Survival and Increases Toxicity in Recurrent Platinum-Sensitive Ovarian Cancer
In a randomized phase II trial reported in The Lancet Oncology, Liu et al found a significant improvement in progression-free survival and an increase in toxicity with the addition of the antiangiogenic agent cediranib (VEGFR-1,-2,-3 inhibitor) to the PARP inhibitor olaparib in women with recurrent platinum-sensitive ovarian cancer.
Study Details
In the open-label trial, 90 women with measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer or with deleterious germline BRCA1/2 mutations from nine U.S. centers were randomly assigned between October 2011 and June 2013 to receive olaparib 400 mg twice daily (n = 46) or cediranib 30 mg once daily and olaparib 200 mg twice daily (n = 44). The primary endpoint was progression-free survival in the intention-to-treat population.
Improved Progression-Free Survival
Median duration of follow-up in surviving patients was 16.6 months. Median progression-free survival was 17.7 months (95% confidence interval [CI] = 14.7 months–not reached) in the cediranib/olaparib group vs 9.0 months (95% CI = 5.7–16.5 months) in the olaparib monotherapy group (hazard ratio [HR] = 0.42, P = .005). A post hoc exploratory analysis suggested a greater treatment effect of the combination among women with wild-type BRCA or unknown mutation status, with median progression-free survival of 16.5 vs 5.7 months (HR = 0.32, P = .008). Among all patients, objective response was observed in 79.6% vs 47.8% (odds ratio = 4.24, P = .002).
Greater Toxicity
Treatment-related grade 3 adverse events were more common with combination therapy, including hypertension (39% vs 0%), fatigue (27% vs 11%), diarrhea (23% vs 0%), nausea (5% vs 0%), and headache (5% vs 0%). Grade 4 hypertension was observed in a combination group patient (2%). Dose reductions were required in 77% of the combination group (for cediranib in 77% and olaparib in 23%) and 24% of the monotherapy group. Adverse events led to discontinuation of treatment in four combination group patients (9%).
The investigators concluded: “Cediranib plus olaparib seems to improve [progression-free survival] in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy.”
Joyce F. Liu, MD, of Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.
The study was funded by the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit www.thelancet.com.
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