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.

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“…However, the fact that LGSOCs are relatively chemoresistant has stimulated the search for alternative therapies. Hitherto, different treatment options such as bevacizumab, PARP inhibitors [ 43 ], or hyperthermic intraperitoneal chemotherapy [ 44 ] have been used to increase survival in patients with ovarian cancer (including LGSOCs). However, the results obtained are not completely satisfactory.…”

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“…84 Recent evaluation of this combination in platinum sensitive ovarian cancer indicated that the combination shows clinical activity but failed to improve progression-free survival compared with chemotherapy and had reduced patient reported outcomes. 85 The three additional arms to this trial are the combinations of olaparib and capivasertib (an oral pan-AKT inhibitor targeting the PI3K/ AKT/mTOR pathway), olaparib and durvalumab, and finally cediranib with durvalumab.…”

Efficacy evaluation of multi-immunotherapy in ovarian cancer: From bench to bed

“…In 2014, a phase 2 study revealed that Cediranib plus Olaparib could prolong PFS ( 33 ). Later, a phase 3 clinical study NRG-GY004 showed that combining Cediranib and Olaparib did not prolong PFS compared with chemotherapy and resulted in reduced patient-reported outcomes (PRO) ( 34 ). Besides, other combinational strategies are being investigated too.…”