A randomized Phase III trial of durvalumab with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib in newly diagnosed advanced ovarian cancer (DUO-O): Updated trial endpoint and inclusion of China cohort (329)

Abstract

Objectives: Maintenance therapy with the PARP inhibitor olaparib (with or without the antiangiogenic agent bevacizumab) leads to significant progression-free survival (PFS) benefits in patients with newly diagnosed advanced ovarian cancer (OC) (with or without a BRCA’ and/or BRCA2 mutation [BRCAm]) (Moore et al. N Eng J Med 2018; Ray-Coquard et al. N Eng J Med 2019). Preclinical data have shown a potential synergistic antitumor effect when combining an immune checkpoint inhibitor with an antiangiogenic agent and a PARP inhibitor. The combination has shown promise as a treatment in platinum-sensitive relapsed non-germline BRCAm OC patients (Drew et al. ESMO 2020). The Phase III DUO-O trial (NCT03737643) began global enrollment in January 2019 and will evaluate the efficacy and safety of combinations of the standard of care platinumbased chemotherapy, bevacizumab, and the anti-PD-L1 antibody durvalumab, followed by maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced OC (Harter et al. ASCO 2019). The China cohort will evaluate these combinations in a standalone analysis of patients with non-BRCAm tumors. Methods: Eligible patients must have newly diagnosed stage III or IV high-grade ovarian, epithelial, fallopian, or primary peritoneal cancer and have undergone upfront primary surgery or be planned to have interval debulking surgery. From sites in China, ~120 patients with a non-BRCAm tumor (using a China-based central laboratory to determine BRCAm status) will be randomized 1:1:1 to: chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + olaparib maintenance; chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + placebo maintenance; or chemotherapy + bevacizumab + placebo, followed by bevacizumab + placebo. Olaparib (300 mg bid) and durvalumab (1120 mg q3w) will be administered for up to 24 months, and bevacizumab (15 mg/kg q3w) for up to 15 months, or until disease progression. The primary endpoints are investigator-assessed PFS (modified RECIST v1.1) in all patients with a non-BRCA tumor and patients with a non-BRCA, homologous recombination deficiency-positive tumor. A key secondary efficacy endpoint is overall survival, and safety will be summarized descriptively. Local China protocol amendments are in progress, and relevant updates will be presented. Enrollment in China began in April 2021. Objectives: Maintenance therapy with the PARP inhibitor olaparib (with or without the antiangiogenic agent bevacizumab) leads to significant progression-free survival (PFS) benefits in patients with newly diagnosed advanced ovarian cancer (OC) (with or without a BRCA’ and/or BRCA2 mutation [BRCAm]) (Moore et al. N Eng J Med 2018; Ray-Coquard et al. N Eng J Med 2019). Preclinical data have shown a potential synergistic antitumor effect when combining an immune checkpoint inhibitor with an antiangiogenic agent and a PARP inhibitor. The combination has shown promise as a treatment in platinum-sensitive relapsed non-germline BRCAm OC patients (Drew et al. ESMO 2020). The Phase III DUO-O trial (NCT03737643) began global enrollment in January 2019 and will evaluate the efficacy and safety of combinations of the standard of care platinumbased chemotherapy, bevacizumab, and the anti-PD-L1 antibody durvalumab, followed by maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced OC (Harter et al. ASCO 2019). The China cohort will evaluate these combinations in a standalone analysis of patients with non-BRCAm tumors. Methods: Eligible patients must have newly diagnosed stage III or IV high-grade ovarian, epithelial, fallopian, or primary peritoneal cancer and have undergone upfront primary surgery or be planned to have interval debulking surgery. From sites in China, ~120 patients with a non-BRCAm tumor (using a China-based central laboratory to determine BRCAm status) will be randomized 1:1:1 to: chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + olaparib maintenance; chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + placebo maintenance; or chemotherapy + bevacizumab + placebo, followed by bevacizumab + placebo. Olaparib (300 mg bid) and durvalumab (1120 mg q3w) will be administered for up to 24 months, and bevacizumab (15 mg/kg q3w) for up to 15 months, or until disease progression. The primary endpoints are investigator-assessed PFS (modified RECIST v1.1) in all patients with a non-BRCA tumor and patients with a non-BRCA, homologous recombination deficiency-positive tumor. A key secondary efficacy endpoint is overall survival, and safety will be summarized descriptively. Local China protocol amendments are in progress, and relevant updates will be presented. Enrollment in China began in April 2021.