Joyce F. Liu, MD, MPH
In follow-up results to data first presented in December 2016, investigators found that the combination of olaparib (Lynparza) and cediranib maleate continued to show superior progression-free survival (PFS) compared with olaparib alone for women with BRCA-negative recurrent platinum-sensitive ovarian cancer.1
In the primary analysis, performed in March 2014 after 47 events occurred, median PFS was 17.7 months for women treated the combination compared with 9.0 months for those treated with olaparib alone (HR, 0.42; P
In this updated analysis, conducted after 67 PFS events, PFS again favored the combination over monotherapy (8.2 months versus 16.5 months; HR, 0.50; P
= .007). In patients without a known germline BRCA mutation (n = 23), updated median PFS was superior in the cediranib/olaparib arm compared with monotherapy, 23.7 months versus 5.7 months (HR, 0.32; P
Known carriers of the BRCA mutation (n = 24) did not derive the same benefit from the combination. For those patients, the updated median PFS was nearly identical between the 2 arms (16.5 vs 16.4 months; P
Joyce F. Liu, MD, MPH, assistant professor of medicine and director of clinical research for gynecologic oncology at Dana-Farber Cancer Institute, presented the results at the 2017 ASCO Annual Meeting.
“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 germline BRCA mutation,” she said. “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 germline BRCA mutation, with a difference of almost 14 months.”
Patients with measurable platinum-sensitive relapsed high-grade serous or endometroid ovarian fallopian tube, or primary peritoneal cancer (N = 90) were randomized in a 1:1 ratio to twice daily 400 mg olaparib or the combination of daily 30 mg cediranib and twice-daily 200 mg olaparib. Treatment continued with imaging every 8 weeks until disease progression. The primary endpoint was PFS in the intent-to-treat population.
High-grade tumors of other histologies were allowed if patients carried a known deleterious germline BRCA1/2 mutation.
More than one-third of patients (37.0%) in the olaparib monotherapy arm received 1 prior line of therapy, 39.1% received 2 lines, and 23.9% received 3 lines. In the combination arm, 58.1% had received 1 line of therapy, 22.7% received 2 lines, and 8.2% received 3.
As Liu noted, investigators observed a trend toward improved OS in the combination arm (44.2 vs 33.3 months; HR, 0.64; P
= .11), though the study was not powered to detect that outcome. OS was 40.1 months among women known to carry the germline BRCA mutation in the monotherapy arm versus 44.2 months with the combination (HR, 0.79; P
= .55). Median OS favored the combination, 23.0 months versus 37.8 months (HR, 0.48; P
= .074), in non-carriers or patients with unknown mutation status,.
“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,” Liu said. “For someone who is a germline BRCA mutation 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 germline BRCA mutation carrier or a somatic BRCA mutation 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.”
Liu said that investigators are recruiting patients for phase III trials of the combination in both the platinum-sensitive and platinum-resistant settings. “It is important that we are going to be looking at the biomarkers to help distinguish whether it is the non-carriers of germline BRCA mutations who are going to benefit the most from an antiangiogenic and a PARP inhibitor.”
- 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).
- 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.