A major phase III clinical trial has demonstrated significant benefits from adding immunotherapy and PARP inhibition to standard chemotherapy for advanced endometrial cancer. The global DUO-E study, published in the Journal of Clinical Oncology on October 21, 2023, found that combining the immune checkpoint inhibitor durvalumab and the PARP inhibitor olaparib with carboplatin and paclitaxel chemotherapy substantially improved progression-free survival compared to chemotherapy alone.
This randomized, double-blind, placebo-controlled trial enrolled 718 patients with newly diagnosed advanced (stage III/IV) or recurrent endometrial cancer across 22 countries. Funded by AstraZeneca, the study aimed to evaluate whether adding durvalumab immunotherapy, with or without olaparib maintenance therapy, could improve outcomes beyond standard platinum-based chemotherapy.
Patients were randomized 1:1:1 to three arms: 1) standard carboplatin/paclitaxel chemotherapy plus placebo, followed by placebo maintenance; 2) chemotherapy plus durvalumab, followed by durvalumab maintenance; or 3) chemotherapy plus durvalumab, followed by durvalumab and olaparib maintenance. The primary endpoints were progression-free survival (PFS) for the durvalumab arm versus control and the durvalumab plus olaparib arm versus control.
Importantly, the trial included patients regardless of mismatch repair (MMR) status, with about 80% having MMR-proficient tumors. This is noteworthy as previous immunotherapy studies have shown greater benefit in MMR-deficient endometrial cancers. The study population was globally representative, with 28% of patients from Asia. Median patient age was 63-64 years across the arms.
The results showed statistically significant and clinically meaningful improvements in PFS for both experimental arms compared to chemotherapy alone. The durvalumab plus olaparib arm demonstrated a 45% reduction in the risk of disease progression or death versus control (hazard ratio 0.55, p<0.0001), with median PFS extended from 9.6 months to 15.1 months. The durvalumab alone arm showed a 29% risk reduction (hazard ratio 0.71, p=0.003), with median PFS of 10.2 months.
Notably, PFS benefits were observed across key subgroups, including both MMR-proficient and MMR-deficient tumors. In the MMR-proficient subgroup, which comprised about 80% of patients, the hazard ratio was 0.77 for durvalumab alone and 0.57 for durvalumab plus olaparib versus control. The MMR-deficient subgroup showed even more pronounced benefits, with hazard ratios of 0.42 and 0.41 respectively.
The PD-L1 positive subgroup (defined as ≥1% tumor area positivity) derived particular benefit, with hazard ratios of 0.63 for durvalumab and 0.42 for durvalumab plus olaparib versus control. Benefits in the PD-L1 negative subgroup were less pronounced but still favored the experimental arms.
While overall survival data were still immature at this analysis (28% maturity), early trends supported the PFS findings. The hazard ratio for overall survival was 0.77 (p=0.120) for durvalumab alone and 0.59 (p=0.003) for durvalumab plus olaparib versus control.
Regarding safety, the experimental regimens were generally consistent with the known profiles of the individual agents. Grade 3 or higher adverse events occurred in 56.4% of the control arm, 54.9% of the durvalumab arm, and 67.2% of the durvalumab plus olaparib arm. The most common high-grade events were neutropenia and anemia. Immune-mediated adverse events were more frequent with durvalumab, occurring in 28.1% of the durvalumab arm and 23.5% of the durvalumab plus olaparib arm, versus 6.8% of controls.
Importantly, there were no cases of myelodysplastic syndrome or acute myeloid leukemia reported, which have been concerns with PARP inhibitors in other settings. New primary malignancies were rare across all arms. Pneumonitis of any grade occurred in 5% of the durvalumab plus olaparib arm, versus <2% in the other arms.
The study authors concluded that adding durvalumab to first-line carboplatin and paclitaxel, followed by durvalumab maintenance with or without olaparib, resulted in statistically significant and clinically meaningful improvements in PFS for patients with advanced or recurrent endometrial cancer. They noted that the addition of olaparib maintenance to durvalumab appeared to provide further benefit, particularly in MMR-proficient and PD-L1 positive subgroups.
This trial has several strengths, including its large size, global patient population, and inclusion of patients regardless of biomarker status. The double-blind, placebo-controlled design also adds rigor to the findings. However, there are some limitations to consider. The overall survival data are still immature, and longer follow-up will be needed to confirm durable benefits. Additionally, while the safety profile was generally as expected, the higher rate of grade 3-4 events in the durvalumab plus olaparib arm warrants careful consideration in clinical practice.
The potential clinical impact of these findings is substantial. Endometrial cancer is the most common gynecologic malignancy in developed countries, and advanced disease has a poor prognosis with limited treatment options. This study provides strong evidence for incorporating immunotherapy into first-line treatment, potentially changing the standard of care. The apparent benefit in MMR-proficient tumors is particularly notable, as these patients have had less dramatic responses to immunotherapy in previous studies.
The role of PARP inhibition in this setting is a novel finding that warrants further investigation. While PARP inhibitors have shown clear benefits in ovarian cancer, their role in endometrial cancer has been less defined. The additional PFS improvement seen with olaparib maintenance, especially in biomarker-selected subgroups, opens new avenues for tailoring treatment.
As with any practice-changing study, these results will need to be balanced against toxicity considerations and cost-effectiveness in real-world implementation. The higher rate of adverse events with the triplet regimen may impact quality of life and treatment adherence for some patients. Additionally, biomarker testing for MMR status and PD-L1 expression may become increasingly important for treatment selection.
In conclusion, the DUO-E trial represents a significant advance in the treatment of advanced endometrial cancer. By demonstrating substantial PFS improvements with the addition of immunotherapy and PARP inhibition to standard chemotherapy, it provides a strong rationale for updating treatment guidelines and clinical practice. As overall survival data mature and additional studies further refine optimal patient selection and sequencing, this approach has the potential to meaningfully improve outcomes for patients with this challenging malignancy.
References
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: The Phase III DUO-E Trial. J Clin Oncol. 2024;42(3):283-299. doi:10.1200/JCO.23.02132
