Durvalumab-Based Combos Win EU Approval for Advanced/Recurrent Endometrial Cancer

The European Commission has approved first-line durvalumab (Imfinzi) plus chemotherapy, followed by durvalumab plus olaparib (Lynparza), for the treatment of patients with mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer. Additionally, durvalumab plus chemotherapy, followed by durvalumab alone, has been approved for the treatment of patients with mismatch repair–deficient (dMMR) disease.¹

These approvals follow a positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use and are supported by data from a prespecified exploratory subgroup analysis by mismatch repair status from the phase 3 DUO-E study (NCT04269200).

Results published in the Journal of Clinical Oncology showed that the durvalumab plus olaparib regimen reduced the risk of disease progression or death by 43% for patients with pMMR disease (n = 191; HR, 0.57; 95% CI, 0.44-0.73).^1,2 In this group, the median progression-free survival (PFS) was 15.0 months (95% CI, 12.4-18.0) with the doublet vs 9.7 months (95% CI, 9.2-10.1) in the control arm (n = 192).2 The 12-month PFS rates in the doublet and control arms were 59.4% (95% CI, 52.0%-66.0%) and 40.8% (33.6%-47.8%), respectively; respective rates at 18 months were 42.0% (95% CI, 34.1%-49.6%) and 20.0% (14.1%-26.7%).

Moreover, the durvalumab regimen reduced the risk of disease progression or death by 58% (HR, 0.42; 95% CI, 0.22-0.80) among patients with dMMR disease. The median PFS for patients in the dMMR group was not reached (NR; 95% CI, NR-NR) in the durvalumab arm (n = 46) vs 7.0 months (95% CI, 6.7-14.8) in the control arm (n = 49).

Both regimens were well tolerated and exhibited generally manageable safety profiles that were broadly consistent with the known profiles of the individual agents.¹

“This approval is welcome news for patients with advanced or recurrent endometrial cancer in Europe, especially those with pMMR disease who have limited options,” Els Van Nieuwenhuysen, MD, PhD, a gynecological oncologist at UZ Leuven in Belgium and an investigator in the DUO-E trial, stated in a news release. “The olaparib and durvalumab as well as the durvalumab regimens now have the potential to improve outcomes for all patients in this setting in Europe, regardless of MMR status.”

In the same news release, Dave Fredrickson, executive vice president of the Oncology Business Unit at AstraZeneca, added that, “this approval of [durvalumab] and [olaparib] regimens marks the first-ever approval for a combination of an immunotherapy and PARP inhibitor in endometrial cancer and a major step forward for patients. In Europe, endometrial cancer is the fourth most common cancer in women, and until now, the 70% to 80% of patients who have pMMR disease have had few available treatment options.”

In June 2024, the FDA approved durvalumab plus carboplatin/paclitaxel, followed by single-agent durvalumab, for the treatment of adult patients with primary advanced or recurrent endometrial cancer and dMMR disease based on data from DUO-E.³ Regulatory submissions for durvalumab plus olaparib are currently under review in Japan and several other countries based on these trial data.¹

DUO-E Trial

The double-blind, global, placebo-controlled DUO-E study was conducted in 253 study locations across 22 countries including the United States, Europe, South America, and Asia.1,2 The trial enrolled patients with newly diagnosed International Federation of Gynecology and Obstetrics stage III/IV or recurrent endometrial cancer.2 Those with newly diagnosed stage III disease were required to have measurable disease, known MMR status, and no prior exposure to frontline systemic therapy for advanced disease or PARP inhibitors and immune-mediated therapy. Prior adjuvant chemotherapy was permitted if at least 1 year had passed since last treatment relapse. All histologies except for sarcomas were included.

A total of 699 patients were randomly assigned 1:1:1 to receive either 1120 mg of durvalumab or placebo every 3 weeks alongside twice-daily carboplatin plus paclitaxel.¹ Following 4 to 6 cycles of chemotherapy, patients who had not experienced disease progression (PD) received either 1500 mg of durvalumab or placebo every 4 weeks as maintenance therapy alongside either 300 mg of olaparib twice daily vs placebo. Treatment continued until PD, intolerable toxicity, or other discontinuation criteria were met.²

Stratification factors included MMR status (pMMR vs dMMR), disease status (newly diagnosed vs recurrent), and geographic region (Asia vs non-Asia). PFS by investigator assessment and RECIST v1.1 criteria for the durvalumab arm vs the control arm and the doublet arm vs the control arm served as the study’s dual primary end points. Secondary end points comprised overall survival (OS), patient-reported outcomes, and safety.

Assessment of OS for both arms in the overall trial population is ongoing.¹

References

1. Lynparza and Imfinzi combination approved in the EU for patients with mismatch repair proficient advanced or recurrent endometrial cancer. News release. AstraZeneca. August 14, 2024. Accessed August 14, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/lynparza-and-imfinzi-combination-approved-in-the-eu-for-patients-with-mismatch-repair-proficient-advanced-or-recurrent-endometrial-cancer.html
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. 2024;42(3):283-299. doi:10.1200/JCO.23.02132
3. FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer. FDA. June 14, 2024. Accessed August 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-chemotherapy-mismatch-repair-deficient-primary-advanced-or-recurrent