Chicago, IL—Oral cediranib, an investigational vascular endothelial growth factor (VEGF) inhibitor, in combination with a poly ADP-ribose polymerase (PARP) inhibitor or with chemotherapy, shows survival benefit in women with relapsed platinum-sensitive ovarian cancer, according to data from 2 studies presented at the 2017 American Society of Clinical Oncology meeting.
Survival Advantage in Phase 2 Study
In an update of an open-label, randomized phase 2 clinical trial of cediranib in combination with olaparib (Lynparza), the use of the combination doubled the median progression-free survival (PFS) versus olaparib alone—16.5 months versus 8.2 months (hazard ratio [HR], 0.50; P = .007), reported Joyce F. Liu, MD, MPH, Director of Clinical Research, Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, at the meeting.
The PFS was superior with the combination of cediranib and olaparib in women without a known germline BRCA mutation, in whom the updated median PFS was 23.7 months compared with 5.7 months in the olaparib monotherapy group, which did not quite achieve significance (HR, 0.48; P = .074). A nonsignificant trend toward an improvement in overall survival (OS) was also observed by adding cediranib in the women without a germline BRCA mutation.
In noncarriers of germline BRCA mutation or in patients in whom germline BRCA mutation status was unknown, the median OS was 23.0 months with the cediranib plus olaparib combination versus 37.8 months in the olaparib monotherapy arm (HR, 0.48; P = .074).
The PFS and OS durations were similar in the 2 arms in known carriers of a BRCA mutation.
The hypothesized mechanism driving the synergy “is that in the setting of hypoxia that’s induced by a VEGF inhibitor, for example, we downregulate genes of homologous recombination. So, we induce a homologous recombination deficiency,” said Dr Liu. “In a patient who’s either not a germline BRCA mutation carrier or a somatic BRCA mutation carrier…by adding an antiangiogenic, you induce the homologous recombination deficiency, and now you get synergy with a PARP inhibitor.”
The study included 90 patients with measurable platinum-sensitive relapsed high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer. They were randomized to olaparib 400 mg twice daily or the combination of cediranib 30 mg daily and olaparib 200 mg twice daily.
Second Study Confirms Results
In a second study, known as ICON6, cediranib combined with chemotherapy followed by maintenance cediranib led to an improvement in median OS of 7.4 months compared with chemotherapy plus placebo in a phase 3 trial of more than 400 women with platinum-sensitive relapsed ovarian cancer.
The OS analysis demonstrated a median OS of 27.3 months in the cediranib arm versus 19.9 months in the placebo arm (HR, 0.85; 95% confidence interval, 0.66-1.10), but the study was underpowered to show a significant difference, according to lead investigator Jonathan A. Ledermann, MD, FRCP, Professor of Medical Oncology, University College London Cancer Institute, England.
“There is a clear evidence that cediranib extends PFS, and the consistent trend in favor of OS benefit suggests a promising future for cediranib, particularly when you look at the time from histological diagnosis to death, where there was an 8-month increase in median survival,” said Dr Ledermann.
The median PFS was 11.1 months in the cediranib arm and 8.7 months in the placebo arm (HR, 0.57; P = .00001). The maintenance strategy is being explored further in the ICON9 trial.
Although the PFS advantage with cediranib in combination is promising, the OS advantage “didn’t quite make the cut,” said Ronald J. Buckanovich, MD, PhD, Associate Professor, Obstetrics and Gynecology, University of Michigan, Ann Arbor. In addition, toxicity was an issue, and adherence to cediranib, especially as maintenance therapy, was poor, with nearly 40% of patients discontinuing the drug because of toxicities such as fatigue, diarrhea, hypertension, and hypothyroidism, Dr Buckanovich added.