Durvalumab, Olaparib Combination Improves Progression-Free Survival in Patients With Advanced Ovarian Cancer

Durvalumab (Imfinzi; AstraZeneca) combined with chemotherapy, followed by maintenance therapy with olaparib (Lynparza; AstraZeneca), durvalumab (Imfinzi; AstraZeneca), and bevacizumab (Avastin; Genentech), demonstrated a clinically meaningful and significant improvement in progression-free survival (PFS) compared to chemotherapy plus bevacizumab (control) in newly diagnosed patients with advanced high-grade epithelial ovarian cancer (OC) who do not have BRCA mutations.

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At the pre-specified interim analysis, the quadripartite combination treatment reduced the relative risk of disease progression or death by 37% compared to the control. Median PFS was 24.2 months in the treatment arm.

“Data from the DUO-O trial interim PFS analysis provide evidence for further improvement with olaparib and durvalumab combination versus chemotherapy and bevacizumab alone in patients without tumor BRCA mutations,” said lead investigator Philipp Harter, Director, Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte, Germany, in a press release.

DUO-O is a phase 3, double-blind, randomized, placebo-controlled, multi-center trial that evaluated the safety and efficacy of the durvalumab combination treatment and durvalumab combination as maintenance therapy. The trial enrolled more than 1200 patients with newly diagnosed OC, including those without BRCA tumor mutations and homologous recombination deficiency (HRD)-positive disease. Patients were randomized in 3 arms (1:1:1):

• Arm 1 (control) received induction therapy of platinum-based chemotherapy with bevacizumab and placebo, followed by maintenance therapy of bevacizumab and placebo.
• Arm 2 received induction therapy of platinum-based chemotherapy, bevacizumab, and durvalumab followed by maintenance therapy of durvalumab and bevacizumab plus placebo.
• Arm 3 received combination induction therapy of platinum-based chemotherapy, bevacizumab, and durvalumab followed by maintenance therapy of durvalumab and bevacizumab plus olaparib.

The primary outcome was PFS (arm 1 vs arm 3), and key secondary outcomes were PFS of arm 2 compared to control and overall survival (OS). Investigators also performed a subgroup analysis of HRD-positive and -negative disease. Patients with positive disease had a 51% reduced relative risk of disease or death and higher median PFS than the control (37.3 months vs 23 months). Patients with HRD-negative disease experienced a relative reduced risk of death by 32% and higher median PFS than the control (20.9 months and 17.4 months).

The safety and tolerability profile of the combination treatments were consistent across trials. The most common adverse events (AEs) were nausea (57%), anemia (55%), neutropenia (51%), fatigue/asthenia (49%), arthralgia (34%), constipation (30%), diarrhea (30%), thrombocytopenia (28%), hypertension (26%), vomiting (26%), leukopenia (24%), headache (22%), abdominal pain (21%), and hypothyroidism (20%).

Globally, OC is the eighth most common cancer in women. More than 66% of patients are diagnosed with advanced stage disease, which increases the risk of death in 5 years to 70%. Outcomes are worse for patients with HRD-negative disease. Estimates suggest that OC will rise by approximately 42% by 2040, increasing the expected patient diagnoses to 445,000 and deaths to 314,000.

Durvalumab works by binding to the programmed death-ligand 1 (PD-L1) protein to prevent the tumor from blocking the immune response. Olaparib is a novel poly (ADP-ribose) polymerase (PARP) inhibitor that can block DNA damage response in homologous recombination repair-deficient tumors, including those that contain BRCA mutations, to hopefully cause cancer cell death.

“These results are an important milestone in our ongoing journey to address unmet need in ovarian cancer,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in a press release. “The DUO-O trial demonstrates the potential of combining PARP inhibition with immunotherapy and we look forward to seeing more mature data and key secondary endpoints results.”

Reference

AstraZeneca. Lynparza and Imfinzi combination reduced risk of disease progression or death by 37% vs. chemotherapy and bevacizumab in patients with advanced ovarian cancer without tumour BRCA mutations in the DUO-O Phase III trial. News Release. June 3, 2023. Accessed on June 5, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/lynparza-and-imfinzi-combination-reduced-risk-of-disease-progression-or-death-vs-chemotherapy-and-bevacizumab-in-patients-with-advanced-ovarian-cancer-without-tumour-brca-mutations-in-the-duo-o-phase-iii-trial.html