August 2017 VOL 8, NO 8

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2017 American Society of Clinical Oncology Annual Meeting

Promising Survival Signal with Cediranib as Combination in Relapsed Ovarian Cancer

Promising Survival Signal with Cediranib as Combination in Relapsed Ovarian CancerOral cediranib, an investigational VEGF inhibitor, in combination with a PARP or chemotherapy inhibitor, appears to have a survival benefit in women with relapsed platinum-sensitive ovarian cancer, according to data from 2 studies presented at the 2017 ASCO Annual Meeting.

In an update of an open-label randomized phase 2 trial of cediranib combined with olaparib, patients treated with the combination had a median progression-free survival (PFS) of 16.5 months compared with 8.2 months in patients who received olaparib alone (hazard ratio [HR], 0.50; P = .007), reported Joyce Liu, MD, Director of Clinical Research, Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA.

PFS was preferentially 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 with olaparib alone, which did not 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 patients without a germline BRCA mutation or patients in whom germline BRCA mutation status was unknown, median OS was 37.8 months in the cediranib/olaparib arm versus 23 months in the olaparib monotherapy arm (HR, 0.48; P = .074).

Both PFS and OS 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 endometroid ovarian, fallopian tube, or primary peritoneal cancer. They were randomized to olaparib 400 mg twice daily, or the combination of cediranib, 30 mg/day, and olaparib, 200 mg twice daily.

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), but the study was underpowered to show a significant difference, said lead investigator Jonathan A. Ledermann, MD, Gynecologic Cancer Specialist, University College London Cancer Institute, UK.

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 survival advantage with cediranib in combination is promising, compliance with cediranib, especially as maintenance, was poor, with nearly 40% of patients discontinuing the drug because of toxicities such as fatigue, diarrhea, hypertension, and hypothyroidism, noted Ronald J. Buckanovich, MD, PhD, Associate Professor of Obstetrics and Gynecology, University of Michigan, Ann Arbor.

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