In the phase III DUO-E trial, a first-line treatment regimen that includes chemotherapy plus the checkpoint inhibitor durvalumab followed by maintenance durvalumab, with or without the PARP inhibitor olaparib, significantly improved progression-free survival in patients with advanced or recurrent endometrial cancer. These findings were reported at the European Society for Medical Oncology (ESMO) Congress 2023 by Shannon N. Westin, MD, MPH, FACOG, Professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, Houston.1 These findings were simultaneously published in the Journal of Clinical Oncology.2
Shannon N. Westin, MD, MPH, FACOG
“DUO-E is the first phase III study to demonstrate that durvalumab plus olaparib confers a progression-free survival benefit and provides new treatment options for patients with advanced or recurrent endometrial cancer,” Dr. Westin commented.
DUO-E assessed the benefit of adding immunotherapy to chemotherapy. It also evaluated whether the addition of a PARP inhibitor to maintenance durvalumab would further enhance benefit. The addition of durvalumab to chemotherapy, followed by durvalumab maintenance, reduced the risk of disease progression by 29% compared with chemotherapy alone, and adding olaparib to maintenance reduced the risk by 45%.
The population of patients with mismatch repair–proficient (pMMR) tumors seemed to derive the most benefit from the addition of olaparib to immunotherapy, obtaining a 43% reduction in risk. As Dr. Westin noted, phase III trials have shown that immunotherapy in combination with chemotherapy has activity in endometrial cancer, particularly in mismatch repair–deficient (dMMR) disease, and this patient subset accounts for about 30% of the advanced-disease population.
The global DUO-E/GOG-3041/ENGOT-EN10 trial enrolled 718 patients with newly diagnosed, stage III/IV or recurrent endometrial cancer, naive to first-line systemic treatment for advanced disease and naive to PARP inhibitors and immune mediators. About 80% of patients had pMMR tumors, and 70% had PD-L1–positive tumors. The primary endpoints were investigator-assessed progression-free survival for the durvalumab arm vs control and durvalumab plus olaparib arm vs control. The study did not formally compare the two durvalumab-containing regimens.
All patients received up to six cycles of chemotherapy in combination with placebo or durvalumab. Those without evidence of disease progression were then transitioned to the maintenance phase. The arms follow:
Significant Benefit Shown
A statistically significant progression-free survival benefit was observed in the durvalumab arm (hazard ratio [HR] = 0.71; P = .003) and durvalumab/olaparib arm (HR = 0.55; P < .0001) vs control, based on medians of 9.6 months for the control arm, 10.2 months for the durvalumab arm, and 15.1 moths for the durvalumab/olaparib arm. At 18 months, 21.7%, 37.8%, and 46.3% of patients, respectively, were progression-free. For the exploratory analysis of durvalumab vs durvalumab/olaparib, the hazard ratio was 0.78 (95% confidence interval [CI] = 0.61–0.99).
Dr. Westin commented on this finding: “Note the doubling in progression-free survival in the durvalumab/olaparib arm vs control and the clear plateaus observed at the tail of the curves.” These benefits were generally consistent across subgroups, with the exception of a lack of additional benefit from durvalumab alone in those with PD-L1–negative disease and in patients from Asia; the addition of olaparib boosted the benefit somewhat.
Predefined exploratory analyses helped refine the observed progression-free survival benefit, showing the benefit offered by durvalumab was greatest in the dMMR subgroup, and the addition of olaparib to durvalumab enhanced the benefit in the pMMR and PD-L1–positive subgroups. Specifically, for patients with dMMR and pMMR tumors, respectively, hazard ratios for durvalumab vs controls were 0.42 (95% CI = 0.22–0.80) and 0.77 (95% CI = 0.60–0.97), respectively; for durvalumab/olaparib, the hazard ratios were 0.41 (95% CI = 0.21–0.75) and 0.57 (95% CI = 0.44–0.73).
In the control, durvalumab, and durvalumab/olaparib arms, the overall incidence of grade ≥ 3 treatment-emergent adverse events was 56.4%, 54.9%, and 67.2%, respectively; the incidence in the maintenance phase was 16.6%, 16.4%, and 41.1%, respectively. The overall incidence of grade ≥ 3 neutropenia was 23.3%, 21.7%, and 26.0%, respectively, and grade ≥ 3 anemia was seen in 14.4%, 15.7%, and 23.5%. The two durvalumab arms had similar rates of immune-mediated adverse events. Treatment discontinuations were similar across arms, but patients receiving durvalumab/olaparib had more dose reductions and interruptions.
DISCLOSURE: Dr. Westin reported financial relationships with and/or support from AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis Oncology, GSK, Mereo, Novartis, Roche/Genentech, Zentalis, Caris, Eisai, EQRX, Gilead Sciences, ImmunoGen, Jazz Pharmaceuticals, Eli Lilly, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.
1. Westin SN, Moore KN, Lee J, et al: Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab ± olaparib as a first-line treatment for newly diagnosed advanced or recurrent endometrial cancer. ESMO Congress 2023. Abstract LBA 41. Presented October 21, 2023.
2. Westin SN, Moore K, Chon HS, et al: Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. J Clin Oncol. October 21, 2023 (early release online).
Domenica Lorusso, MD, PhD
Invited discussant of the DUO-E trial, Domenica Lorusso, MD, PhD, commented: “Looking at the data, it’s clear to me that we are entering a new era of clinical research” in endometrial cancer. Patient populations are becoming molecularly refined, which will pave the...