In a phase III DUO-E study durvalumab in combination with first-line carboplatin and paclitaxel followed by maintenance durvalumab with or without olaparib resulted in significantly lower risk of disease progression or death than chemotherapy alone among patients with newly diagnosed advanced or recurrent endometrial cancer. It is the first phase III study to examine the combination of immunotherapy and PARP inhibition in endometrial cancer.
Predefined, exploratory subgroup analyses suggest the addition of maintenance olaparib to the combination of durvalumab plus chemotherapy may improve outcomes in the mismatch repair (MMR)-proficient (pMMR) and PD-L1-positive patient populations. The safety profiles were generally consistent with individual agents. The findings were presented during the ESMO 2023 Congress and simultaneously published in JCO on 21 October by Dr. Shannon N. Westin of the University of Texas MD Anderson Cancer Center in Houston, TX, US, and colleagues.
The authors wrote in the background that RUBY and NRG-GY018 studies recently demonstrated efficacy of immune checkpoint inhibitors in combination with chemotherapy as first-line treatment for patients with primary advanced or recurrent endometrial cancer. The results from RUBY led to approval of dostarlimab in combination with carboplatin and paclitaxel followed by dostarlimab alone for the treatment of MMR-deficient (dMMR) or microsatellite instability high, primary advanced or recurrent endometrial cancer. However, a high unmet need remains, especially in patients with pMMR tumours, who comprise approximately 75% of patients with endometrial cancer.
The DUO-E investigators hypothesised that combining a PARP inhibitor with an immune checkpoint inhibitor may improve outcomes in endometrial cancer, including in patients with pMMR tumours. The phase III, global, double-blind, placebo-controlled DUO-E/GOG-3041/ENGOT-EN10 study investigated whether the addition of the anti-PD-L1 antibody durvalumab to carboplatin plus paclitaxel, followed by maintenance durvalumab with or without the addition of olaparib, improved outcomes in patients with newly diagnosed advanced or recurrent endometrial cancer. Primary endpoints were progression-free survival (PFS) for durvalumab and durvalumab plus olaparib arms versus control.
A total of 718 patients were randomised. In the intent-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.57 to 0.89; p = 0.003) and durvalumab plus olaparib arms (HR 0.55, 95% CI 0.43 to 0.69; p < 0.0001) versus control.
Pre-specfied, exploratory subgroup analyses showed PFS benefit in dMMR (HR 0.42 for durvalumab versus control, 95% CI 0.22 to 0.80 and HR 0.41 for durvalumab plus olaparib versus control, 95% CI 0.21 to 0.75) and pMMR subgroups (HR 0.77 for durvalumab versus control, 95% CI 0.60 to 0.97 and HR 0.57 for durvalumab plus olaparib versus control, 95% CI 0.44 to 0.73) and in PD-L1-positive subgroups (HR 0.63 for durvalumab versus control, 95% CI 0.48 to 0.83 and HR 0.42 for durvalumab plus olaparib versus control, 95% CI 0.31 to 0.57).
Interim overall survival results with maturity of approximately 28% were supportive of the primary outcomes (HR 0.77 for durvalumab versus control, 95% CI 0.56 to 1.07; p = 0.120 and HR 0.59 for durvalumab plus olaparib versus control, 95% CI 0.42 to 0.83; p = 0.003).
While there was a higher rate of grade 3 or higher adverse events in the durvalumab plus olaparib arm, the safety profiles of each arm were generally consistent with the known profiles of individual components of the regimen.
The authors concluded that these data confirm the clinical benefit of integrating immunotherapy into first-line chemotherapy, and are the first to indicate that the addition of a PARP inhibitor may offer further benefit in this setting.
Drs. Shannon N. Westin and Kathleen Moore contributed equally to this work.
The study was funded by AstraZeneca.
