Durvalumab Regimens Are Recommended for EU Approval for pMMR, dMMR Endometrial Cancer

A statistically significant and clinically meaningful improvement in progression-free survival in the phase 3 trial DUO-E support the recommendation.

The combination of durvalumab (Imfinzi) plus olaparib (Lynparza) has been recommended for approval in the European Union to treat patients with mismatch repair–proficient (pMMR) primary advanced or recurrent endometrial cancer, according to a press release from the developer, AstraZeneca.¹

Additionally, durvalumab plus chemotherapy followed by durvalumab alone has been recommended for patients with mismatch repair–deficient (dMMR) disease.

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) recommendation was made based on statistically significant and clinically meaningful improvements in progression-free survival (PFS) for both regimens, as seen in exploratory analyses in the phase 3 DUO-E trial (NCT04269200) published in the Journal of Oncology.²

Results of this analysis showed that the durvalumab plus olaparib arm had a 43% reduction in the risk of disease progression or death compared with the control arm, with a median PFS of 15.0 months compared with 9.7 months, respectively, in the pMMR subgroup (HR, 0.57; 95% CI, 0.44-0.73).

Additionally, for the dMMR subgroup, the reduction in the risk of disease progression or death in the durvalumab arm vs control arm was 58%, with a median PFS of not reached vs 7.0 months, respectively (HR, 0.42; 95% CI, 0.22-0.80).

“Patients with advanced or recurrent endometrial cancer currently have a very poor prognosis, especially those with mismatch repair proficient disease,” study investigator Els Van Nieuwenhuysen, MD, gynecological oncologist at the UZ Leuven, stated in the news release.¹ “This recommendation underscores the significant benefit shown with durvalumab as well as with the olaparib and durvalumab combination for patients with both mismatch repair deficient and mismatch repair proficient status. This marks an important step toward improving outcomes for these patients in Europe.”

In the international, double-blind, placebo-controlled DUO-E trial, investigators enrolled patients with newly diagnosed advanced or recurrent endometrial cancer and randomized them 1:1:1 to receive carboplatin/paclitaxel plus placebo followed by maintenance placebo (control arm), carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab (durvalumab alone), or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus placebo (durvalumab/olaparib arm).

The dual primary end points of the trial were investigator-assessed PFS for both the durvalumab arm vs control and the durvalumab plus olaparib arm vs control. Secondary end points included overall survival (OS), patient-reported outcomes, and safety.

At a data cutoff date of April 12, 2023 of all patients in the DUO-E trial (n = 718), 312 PFS events (65% maturity) for the durvalumab vs control comparison and 299 events (62% maturity) for the durvalumab plus olaparib vs control comparison were recorded. The median duration of follow-up in patients censored for PFS was 12.6 months (0.0-31.6) in the control arm, 15.4 months (0.0-29.1) in the durvalumab arm, and 15.4 months (0.0-31.7) in the durvalumab plus olaparib arm.

In the intent-to-treat (ITT) population, data showed that there was a 45% reduction in the risk of disease progression or death compared with the control arm, with a median PFS of 15.1 months compared with 9.6 months, respectively (HR, 0.55; 95% CI, 0.43-0.69; P < .0001).

Additionally, there was a 29% reduction in the risk of disease progression or death in the durvalumab arm vs control (HR, 0.71; 95% CI, 0.57-0.89; P = .003); the median PFS was 10.2 months vs 9.6 months, respectively.

Sensitivity analysis of PFS by blinded independent central review reinforced investigator results for both durvalumab vs control (HR, 0.74; 95% CI, 0.58-0.94) and durvalumab plus olaparib vs control (HR, 0.55; 95% CI, 0.42-0.70) comparisons.

In an exploratory analysis of both durvalumab-based arms, the investigator-assessed median PFS was 15.1 with durvalumab/olaparib vs 10.2 months with durvalumab alone (HR, 0.78; 95% CI, 0.61-0.99).

At the time of the primary PFS analysis, 199 (28%) deaths had occurred in the ITT population. The median duration of follow-up in OS-censored patients were 18.6 months (05-32.9), 18.4 months (2.1-33.0), and 18.7 months (1.1-33.4) in the control, durvalumab, and durvalumab plus olaparib arms, respectively. At the first interim analysis for OS, the HR favored investigational arms without reaching statistical significance in comparing durvalumab vs control (HR, 0.77; 95% CI, 0.56-1.07; P = .120) and durvalumab/olaparib vs control (HR, 0.59; 95% CI, 0.42-0.83; P = .003).

Regarding safety, the most common any-grade adverse effects (AEs) included anemia, nausea, fatigue or asthenia, and alopecia throughout the study period. The overall incidence of grade 3 or higher treatment-emergent AEs was 56.4%, 54.9%, and 67.2% in the control, durvalumab, and durvalumab plus olaparib arms, respectively.

References

1. Lynparza and Imfinzi combination recommended for approval in the EU by CHMP for patients with mismatch repair proficient advanced or recurrent endometrial cancer. Press release. AstraZeneca. Published July 1, 2024. Accessed July 8, 2024. https://tinyurl.com/msk9azn6
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: the phase III DUO-E trial. J Clin Oncol. 2023;42(3). doi:10.1200/JCO.23.02132