Durvalumab plus chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib, in newly diagnosed advanced ovarian cancer patients

The phase III DUO-O trial evaluates paclitaxel/carboplatin plus bevacizumab and durvalumab, followed by maintenance bevacizumab, durvalumab and olaparib in patients with non-BRCA-mutated ovarian cancer in the first-line setting.  This regimen resulted in a statistically significant and clinically meaningful improvement in progression-free survival as compared to standard-of-care, with a safety profile that is generally consistent with the known profiles of each agent.

Maintenance therapy with olaparib with or without bevacizumab has improved outcomes in the first-line treatment of advanced ovarian cancer (OC). Unfortunately however, unmet needs remain, especially in some non-BRCA mutated patient subgroups. To date, phase III trials investigating the addition of immuno-oncology agents to standard-of-care in the newly diagnosed advanced OC setting have yet to demonstrate clinical benefit. The phase III DUO-O study evaluates paclitaxel/carboplatin plus bevacizumab plus durvalumab, followed by maintenance therapy with bevacizumab, durvalumab and olaparib in patients with newly diagnosed non-BRCA mutated advanced OC. At ASCO 2023, results of the preplanned interim PFS analysis from the DUO-O study were presented.

Study design

DUO-O is an international, phase III, randomised clinical trial among 1,130 newly diagnosed patients with stage III or IV high-grade epithelial ovarian tumours that did not have BRCA mutations and were either homologous recombination deficiency (HRD)-positive or negative. Patients could not have received prior systemic therapy for OC but had completed primary surgery or plan to have interval debulking surgery. During the run-in phase, patients received one cycle of chemotherapy. Patients were randomised (1:1:1) before cycle 2 to one of three arms: arm 1) chemotherapy + bevacizumab + placebo (for 6 cycles) followed by bevacizumab (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets, standard-of-care arm); arm 2) chemotherapy + bevacizumab + durvalumab (6 cycles) followed by bevacizumab + durvalumab (1,120 mg Q3W [total 15 months]) + placebo (tablets) maintenance treatment; or arm 3) chemotherapy + bevacizumab + durvalumab (6 cycles) followed by bevacizumab + durvalumab + olaparib (300 mg twice a day tablets [24 months]) maintenance treatment. Treatment was continued until disease progression, study treatment was complete or other discontinuation criteria were met. Primary endpoint was progression-free survival (PFS) in arm 3 vs. arm 1 in both non-BRCA mutated HRD-positive patients and in the intention-to-treat (ITT) population.

Results

Across all arms, roughly 90% of patients completed all planned cycles of chemotherapy. At the interim analysis, there was no significant difference in PFS between the standard-of-care (SOC) arm and the durvalumab arm. However, PFS increased in patients receiving durvalumab plus olaparib, as compared to the SOC arm. For the HRD-positive patients, PFS increased from 23.0 months for those in the SOC arm to 37.3 months for those receiving durvalumab plus olaparib (HR[95%CI]: 0.49[0.34-0.69], p< 0.0001). For patients in the ITT population, PFS was 24.2 months in the olaparib arm vs. 19.3 months for those in the SOC arm (HR[95%CI]: 0.63[0.52-0.76], p< 0.0001). A numerical, although not statistically significant, improvement in PFS was observed in arm 2 vs. arm 1 (HR[95%CI]: 0.87[0.73-1.04], p= 0.13). The PFS benefit was observed across subgroups, including those patients with HRD-negative disease (HR[95%CI]: 0.68[0.54-0.86]).

Safety was generally consistent with the known profiles of each individual agent. Serious adverse events were reported in 34% of patients in the SOC arm, 43% in the durvalumab arm and 39% in the olaparib arm. The rate of myelodysplastic syndromes and acute myeloid leukaemia was very low across all three arms.

Conclusion

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 and durvalumab, followed by maintenance bevacizumab, durvalumab and olaparib compared with standard-of-care in patients with non-BRCA mutated advanced OC.

Reference

Harter P, et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): Results from the randomized, placebo (pbo)-controlled phase III DUO-O trial. Presented at ASCO 2023; Abstract LBA5506.