Olaparib/Cediranib Combination Leads to Continued PFS Improvement in Ovarian Cancer

Joyce F. Liu, MD, MPH

Progression-free survival (PFS) continues to be superior with the combination of cediranib maleate and olaparib (Lynparza) compared with olaparib alone in patients with recurrent platinum-sensitive ovarian cancer in a randomized open-label study with follow-up to December 2016.¹The improvement in PFS remains pronounced in the subset of women without a knownBRCAmutation, reported Joyce F. Liu, MD, MPH, at the 2017 meeting of the American Society of Clinical Oncology.

The primary analysis, which was performed on March 31, 2014 after 47 events occurred, demonstrated a median PFS of 17.7 months for the women treated with cediranib plus olaparib compared with 9.0 months for those treated with olaparib monotherapy (HR, 0.42;P= .005).²

The updated analysis was conducted after 67 PFS events, at which time the median PFS in the entire study cohort was 8.2 months in the olaparib alone arm and 16.5 months in the cediranib/olaparib arm (HR, 0.50;P= .007). In the patients who were known carriers of a germline BRCA mutation, the updated median PFS was nearly identical between the 2 arms (16.5 vs 16.4 months;P= .42). In those patients without a known germlineBRCAmutation, updated median PFS was superior in the cediranib/olaparib arm compared with olaparib monotherapy, at 23.7 versus 5.7 months (HR, 0.32;P= .002).

“This has told us that the updated PFS is very consistent with what we originally saw; that there is a PFS benefit in adding the cediranib to the olaparib. What is interesting about this, even more so than in our original analysis, is that this benefit is most pronounced in those patients who do not have a known germlineBRCAmutation,” said Liu, assistant professor of medicine and director of clinical research for gynecologic oncology, Dana-Farber Cancer Institute, Boston. “That also is reflected in a nonsignificant trend toward an overall survival [OS] benefit, keeping in mind that this is a small study not powered to show OS advantage. The OS curve does separate in the patients without a known germlineBRCAmutation, with a difference of almost 14 months.”

Ninety patients with measurable platinum-sensitive relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer were enrolled in the phase II study and were randomized in a 1:1 ratio to olaparib, 400 mg twice daily, or the combination of cediranib, 30 mg/day, and olaparib, 200 mg twice daily. High-grade tumors of other histologies were allowed if patients carried a known deleterious germlineBRCA1/2mutation. Treatment continued with imaging every 8 weeks until disease progression by RECIST v1.1 criteria. PFS in the intent-to-treat population was the primary endpoint.

There were 24 patients withBRCAmutations in the olaparib monotherapy arm and 23 patients in the cediranib/olaparib arm. In the olaparib monotherapy arm and the cediranib/olaparib combination arm, 37.0% and 58.1%, respectively, received 1 prior line of therapy; 39.1% and 22.7% received 2 prior lines; and 23.9% and 8.2% received 3 prior lines.

There was a trend toward improved median OS in patients randomized to cediranib/olaparib versus olaparib monotherapy (44.2 vs 33.3 months; HR, 0.64;P= .11). Within known germlineBRCAmutation carriers, OS was 40.1 and 44.2 months in the olaparib and cediranib/olaparib arms, respectively (HR, 0.79;P= .55). In non-carriers of germlineBRCAmutation or patients in whom germlineBRCAmutation status was unknown, median OS was 23.0 versus 37.8 months in the 2 arms, respectively (HR, 0.48;P= .074).

“The mechanism that we hypothesized that is 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 [HR]. So we induce an HR deficiency,” said Liu. “For someone who is a germlineBRCAmutation carrier, especially if they are platinum-sensitive, they likely still have an amount of HR deficiency with vulnerability to a PARP inhibitor alone. But in a patient who is either not a germlineBRCAmutation carrier or a somaticBRCAmutation carrier, in somebody who does not have intrinsic HR deficiency in their tumor, by adding an antiangiogenic [agent], you induce the HR deficiency, and now you get synergy with a PARP inhibitor.”

Phase III trials of the combination in both the platinum-sensitive and platinum-resistant settings are accruing, she said. “It is important that we are going to be looking at the biomarkers to help distinguish whether it is the non-carriers of germlineBRCAmutations who are going to benefit the most from an antiangiogenic and a PARP inhibitor.”

References:

1. Liu J, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.J Clin Oncol.2017;35 (suppl; abstr 5535).
2. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.Lancet Oncol.2014;15:1207-1214.