Findings from the Phase III DUO-E trial, unveiled at ESMO 2023, demonstrated that the amalgamation of durvalumab and chemotherapy, followed by maintenance with either durvalumab alone or durvalumab combined with olaparib, could improve outcomes compared to chemotherapy alone for individuals with advanced or recurrent endometrial cancer.

It was found that individuals who were administered durvalumab alongside chemotherapy, followed by either durvalumab alone or durvalumab combined with olaparib, experienced notable advancements in progression-free survival (PFS) compared to those who solely underwent chemotherapy. Additionally, there was a tendency towards enhanced overall survival (OS) with the use of durvalumab or durvalumab-olaparib; however, the data for OS are still pending maturation.

Patients were randomly allocated to one of the following groups:

• Placebo plus chemotherapy followed by placebo maintenance (n=241)
• Durvalumab plus chemotherapy followed by durvalumab maintenance (n=238)
• Durvalumab plus chemotherapy followed by durvalumab plus olaparib maintenance (n=239).

The DUO-E study, marking the first Phase III trial to establish the progression-free survival (PFS) advantages of durvalumab in combination with olaparib, introduces novel treatment possibilities for individuals with advanced or recurrent endometrial cancer. The study involved 718 patients diagnosed with recurrent or newly identified stage III/IV endometrial cancer, all of whom had not undergone any prior systemic therapy for advanced disease and were unfamiliar with both PARP inhibitors and immune-mediated therapy.

The durvalumab arm and the durvalumab-olaparib arm both exhibited significantly longer median progression-free survival (PFS) compared to the control arm. Specifically, the median PFS was 9.6 months in the control group, 10.2 months in the durvalumab group, and notably extended to 15.1 months in the durvalumab-olaparib group. The overall data maturity for PFS reached 61.0%. In a comparative analysis, durvalumab-olaparib demonstrated a significantly prolonged PFS in comparison to durvalumab alone.

The median overall survival (OS) was 25.9 months in the control group, not reached in the durvalumab group, and also not reached in the durvalumab-olaparib group. In an exploratory analysis, there was an indication of a potential improvement in overall survival with durvalumab-olaparib compared to durvalumab alone. The data maturity for overall survival reached 27.7%.

In the subgroup analysis, all-hazard rate-point estimates favored the durvalumab arm over the control arm. Smaller hazard ratios were observed in the mismatch repair-deficient subgroup compared to the mismatch repair-proficient subgroup, and in patients with PD-L1 positive status compared to those with negative disease. Additionally, durvalumab plus olaparib also demonstrated superiority over placebo. Generally, we observed smaller hazard ratios than those seen in the durvalumab vs control comparison, except for the mismatch repair-deficient group, especially notable in patients with homologous recombination repair mutation (HRRm).

In a pre-specified exploratory analysis of progression-free survival (PFS) based on MMR status, both durvalumab monotherapy and durvalumab plus olaparib outperformed placebo in both the mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) arms. Similarly, in a pre-specified exploratory analysis of PFS based on PD-L1 status, both durvalumab monotherapy and durvalumab plus olaparib demonstrated superiority over placebo in both positive and negative PD-L1 groups.

The rate of Grade 3 or higher adverse events (AEs) was 56.4% in the placebo group, 54.9% in the durvalumab group, and 67.2% in the durvalumab-olaparib group.

The majority of adverse events (AEs) occurred during the chemotherapy phase of the study. The most common AEs in the control, durvalumab, and durvalumab-olaparib groups, respectively, were anemia (54%, 48%, and 62%), alopecia (50%, 50%, and 51%), fatigue and asthenia (44%, 43%, and 54%), nausea (44%, 41%, and 55%), and neutropenia (42%, 36%, and 42%).

KOL insights

“These findings showcase, for the first time, the potential of combining immunotherapy with a PARP inhibitor to deliver significant clinical improvements for these patients. These DUO-E data may offer oncologists novel avenues to enhance outcomes for endometrial cancer patients.” – Professor, United States.

“DUO-E is the first Phase 3 study to demonstrate that durvalumab plus olaparib confers PFS benefit and provides new treatment options for patients with advanced or recurrent endometrial cancer”– Professor, United States.

Conclusion

The DUO-E study demonstrates overall positive outcomes across the entire trial population, successfully achieving its primary endpoint for both the doublet and triplet treatment regimens. The incorporation of IMFINZI and LYNPARZA, in addition to chemotherapy, resulted in a 45% reduction in the risk of disease progression or death in patients newly diagnosed with advanced or recurrent endometrial cancer. Furthermore, the addition of IMFINZI alone to chemotherapy reduced the same risk by 29%.

The FDA has intensified its examination of PARP inhibitors such as LYNPARZA. Clinical data in advanced treatment stages hint at potential long-term adverse effects on patient survival, particularly in tumors lacking homologous recombination repair mutations, despite an initial advantage in disease progression. Additionally, the appropriateness of IMFINZI as the optimal immunotherapy companion for LYNPARZA in the endometrial cancer population raises questions. 

For more insight into the endometrial cancer, their respective geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• Synchronous Endometrial and Ovarian Cancer (SEOC) Market Insight and Market Forecast
• Endometrial Cancer Market Insight and Market Forecast