DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.

Abstract

TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

“…The emergence of poly (ADP-ribose) polymerase (PARP) inhibition as a treatment for EOC has provided justification to explore triplet therapy with a CPI, anti-VEGF, and PARP inhibitor (174). A Phase III study of durvalumab, bevacizumab, and olaparib is ongoing (175).…”

Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer

“…A major effort for advanced ovarian cancer tumor therapy using targeted small molecule inhibitors with a candidate anti-PD-1 antibody is also ongoing (NCT03737643, ClinicalTrials.gov). This study evaluates the use of durvalumab treatment in combination with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab, and olaparib treatment 37 . When conducted with appropriate biobanking techniques, these and similar studies could immediately apply the methodologies we have proposed in this report and eventually produce novel biomarkers for improved clinical decision-making.…”

Front-Line Maintenance Therapy in Advanced Ovarian Cancer—Current Advances and Perspectives

“…Immune checkpoint inhibitor (ICI) such as anti-programmed-death ligand-1 (PD-L1) are being evaluated in front-line and maintenance therapy, in combination with chemotherapy, bevacizumab and PARPi. Four clinical trials are still recruiting patients: ATHENA trial (ClinicalTrials.gov Identifier: NCT03522246 ATHENA) [ 62 ], DUO-O trial (ClinicalTrials.gov Identifier: NCT03737643 DUO-O) [ 63 ], from AGO group, ENGOT-ov43 (ClinicalTrials.gov Identifier: NCT03740165 ENGOT-ov43) [ 64 ], from BGOG and FIRST trial (ClinicalTrials.gov Identifier: NCT03602859 FIRST) [ 65 ], from GINECO group ( Table 2 ). PARP inhibition might increase cancer antigens, the number of DNA mutations and the production of interferon type I, therefore enhance the immune response against cancer cells [ 66 ].…”