Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer

Abstract

Background: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes.Patients and methods: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression.Results: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P ¼ 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P ¼ 0.002) and OS (37.8 versus 23.0 months, P ¼ 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P ¼ 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension.Conclusions: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinumsensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status.

New strategies in ovarian cancer treatment

“…21 The most striking benefit of bevacizumab comes when one separates the balanced backbones of the AURELIA results, which demonstrated an improvement in PFS from 3.9 months to 10.4 months (hazard ratio [HR], 0.46) with the addition of bevacizumab to weekly paclitaxel. Similarly strong results were observed in the phase 2 trial of the addition of the VEGF receptor inhibitor cediranib to olaparib for women with platinumsensitive disease 22,23 ; the definitive phase 3 NRG GY004 trial currently is maturing and the results are expected this year. Both the Gynecologic Oncology Group (GOG)-0213 trial and the initial trial of the combination of cediranib and olaparib have demonstrated a trend and/or effect of the addition of the angiogenesis inhibitor for overall survival (HR, 0.83 [P = .056] and HR, 0.64 [P = .11], respectively).…”

“…Both the Gynecologic Oncology Group (GOG)-0213 trial and the initial trial of the combination of cediranib and olaparib have demonstrated a trend and/or effect of the addition of the angiogenesis inhibitor for overall survival (HR, 0.83 [P = .056] and HR, 0.64 [P = .11], respectively). 20,23 To our knowledge, no overall survival advantage of the addition of antiangiogenic therapy has otherwise been demonstrated to date for ovarian cancer. Another tumor microenvironment target is the immune microenvironment.…”

“…The addition of bevacizumab has led to incremental benefits in PFS in patients undergoing primary therapy, 17,18 those with a first recurrence of platinum-sensitive disease, 19,20 20,23 To our knowledge, no overall survival advantage of the addition of antiangiogenic therapy has otherwise been demonstrated to date for ovarian cancer. That, coupled with intratumoral heterogeneity, has led researchers in several directions.…”

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

“…That this combination was effective even in PARPi-resistant cases may be due to cediranib-mediated suppression of BRCA1/2 and RAD51 expression, both indirectly through induction of hypoxia, and directly through transcriptional repression [117]. In a similar patient population of germline BRCAwt platinum sensitive recurrent EOC, combination cediranib/olaparib had greater activity compared to olaparib alone in post-hoc analyses of a phase II trial, prolonging median PFS from 5.7 months to 23.7 months (p = 0.002) and median OS from 23.0 months to 37.8 months (p = 0.047) [118]. In prespecified subset analysis in a subsequent phase III trial (GY-004), however, the population with germline BRCAwt platinum sensitive recurrent EOC performed comparably to platinum-based chemotherapy (ORR 64% cediranib/olaparib versus 72% chemotherapy; HR 0.97, 95% CI 0.73-1.30) [119].…”

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

“…In an exploratory subgroup analysis, patients that were germline BRCA wild-type seemed to potentially benefit more from this treatment, with progression-free survival and overall survival improvement only seen in that subgroup of patients. 36 Nevertheless, grade ≥3 adverse events were reported by 70% of patients in the combination arm, mainly hypertension, diarrhea, and fatigue. Our group assessed the combination of olaparib (300 mg, tablets twice daily) and cediranib (20 mg once daily) in a single-arm phase II study in patients having progressed to prior PARPi treatment, regardless of platinum sensitivity, and showed a signal of activity.…”