Olaparib With or Without Cediranib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer (NRG-GY004): A Randomized, Open-Label, Phase III Trial

Abstract

Purpose: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy.

Patients and methods: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs).

Results: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed.

Conclusion: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.

Trial registration: ClinicalTrials.gov NCT02446600.

FIG 1.

CONSORT diagram. Only patients in the chemotherapy arm completed planned treatment (completed chemotherapy course, followed by surveillance), as olaparib and olaparib + cediranib were continued until the time of disease progression. As of the data cutoff date (November 13, 2019). AE, adverse event; ITT, intention-to-treat.

FIG 2.

Progression-free survival by randomized treatment. Distributions were estimated by means of the Kaplan-Meier method for progression-free survival by investigator assessment.

FIG 3.

PFS in BRCA1/2-mutation subgroups. Progression-free survival estimates by Kaplan-Meier method are shown for (A) participants with a deleterious germline BRCA1/2 mutation and (B) participants without a deleterious germline BRCA1/2 mutation.

FIG 4.

Mean NFOSI-DRS-P scores over time. Larger scores suggest a better or preferable state of health.

FIG A1.

Sensitivity analysis for PFS censoring patients in the chemotherapy arm at the time of receipt of PARP inhibitor maintenance. The results were consistent with the primary analysis, with a median PFS on the chemotherapy arm of 10.2 months. The HR for PFS for combination cediranib/olaparib compared with chemotherapy was 0.90 (95% CI, 0.69 to 1.18), with a P value of .124. HR, hazard ratio; PARP, poly (ADP-ribose) polymerase; PFS, progression-free survival.