A novel combination of durvalumab, olaparib, and bevacizumab improves progression-free survival (PFS) compared to standard of care for newly diagnosed advanced ovarian cancer without BRCA mutations.
In an interim analysis of the large international, randomized, Phase III DUO-O trial after a median follow-up of about 2 years, the results showed that the triple combination reduced the hazard for disease progression or death by 51 percent versus the standard of care of upfront paclitaxel/carboplatin chemotherapy plus bevacizumab, followed by maintenance bevacizumab arm. In homologous recombination deficiency (HRD)-positive patients, PFS was reduced by 37 percent in an intent-to-treat (ITT) analysis.
"DUO-O met its primary endpoint at the planned PFS interim analysis, demonstrating statistically significant and clinically meaningful improvement in PFS with first-line chemotherapy plus bevacizumab plus durvalumab followed by maintenance bevacizumab plus durvalumab and olaparib when compared with the control," said senior author Carol Aghajanian, MD, Chief of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center. "The PFS benefit was seen across subgroups, including those patients with HRD-negative disease." She presented the interim analysis results at the 2023 ASCO Annual Meeting (Abstract LBA5506).
Maintenance therapy with olaparib, a PARP inhibitor, with or without bevacizumab, an antiangiogenic agent, has improved outcomes in first-line advanced ovarian cancer. However, "unmet need remains, especially in some non-BRCA-mutated subgroups. To date, Phase III trials investigating the addition of immuno-oncology agents to standard of care in the newly diagnosed advance ovarian cancer setting have yet to demonstrate clinical benefit," Aghajanian said.
Two recent studies have shown that maintenance olaparib benefits newly diagnosed patients with a BRCA mutation and that bevacizumab benefits patients with HRD-positive tumors. This led researchers to explore the novel combination of bevacizumab and durvalumab, a checkpoint inhibitor, with the addition of olaparib to the maintenance therapy regimen to see whether this could enhance the antitumor effect.
The 1,130 DUO-O patients with Stage III or IV high-grade epithelial tumors that did not have BRCA mutations, including 531 patients with HRD-positive tumors, were randomized to three regimens:
* Arm 1: Paclitaxel-carboplatin chemotherapy, bevacizumab, and durvalumab placebo followed by maintenance with bevacizumab, durvalumab placebo, and olaparib placebo.
* Arm 2: Chemotherapy plus bevacizumab and durvalumab followed by bevacizumab, durvalumab, and olaparib placebo.
* Arm 3: Chemotherapy, bevacizumab, and durvalumab, followed by bevacizumab, durvalumab, and olaparib.
PFS increased in patients in Arm 3 compared to Arm 1. For HRD-positive patients, PFS was 37.3 months versus 23 months for those in the standard-of-care arm. For patients in the ITT population, PFS was 24.2 months in the triple therapy arm versus 19.3 for those in the standard-of-care arm. The risk of the disease progressing was 32 percent lower in all subsets of patients, including both HRD-positive and HRD-negative patients compared to the standard-of-care arm.
Arm 2 resulted in a median PFS of 20.6 months in the ITT analysis, which did not achieve significance versus Arm 1. Separate analyses by HRD status showed Arm 3 had a higher PFS in HRD-negative patients (20.9 months) than Arm 1 (17.4 months), as well as the HRD-positive subgroup. Arm 2 did not achieve statistical superiority in either subgroup versus Arm 1 and had a numerically lower median PFS in the HRD-negative group (15.4 vs. 17.4 months). The relative contribution of durvalumab to Arm 3 requires further investigation, Aghajanian noted.
The safety was generally consistent with the known profiles of each individual agent. "Adverse events were as expected. The incidence of MDS and AML was low, consistent with previous phase III trials in the first-line setting," Aghajanian noted. "Overall, discontinued rates differed between the treatment arms with a numerically higher proportion of patients discontinuing any treatment because of an adverse event in Arm 3."
Serious adverse events were reported in 34 percent of patients in the standard-of-care arm, 43 percent in the durvalumab arm, and 39 percent in the olaparib arm. Adverse events in the chemotherapy and maintenance phases combined occurred more often with Arm 3, particularly nausea and anemia. The most common Grade >=3 adverse events were neutropenia, ranging from 28 to 31 percent across all arms, and anemia (24% for Arm 3 vs. 8% for Arms 1 and 2). The trial is ongoing and final PFS, OS, and other key secondary endpoints will be reported when available.
ASCO Expert Merry Jennifer Markham, MD, FACP, FASCO, Chief of the Division of Hematology and Oncology at the UF Health Cancer Center, commented: "There is no early detection method for ovarian cancer, and over two-thirds of patients are diagnosed with advanced disease that frequently recurs. While more research is needed, this trial's finding that a novel combination of therapies can prolong PFS is indeed promising for patients with advanced ovarian cancer."
Mark L. Fuerst is a contributing writer.