Multi-Agent Treatment Offers Hope in Advanced or Recurrent Endometrial Cancer

MADRID — Immunotherapy, chemotherapy, and a PARP inhibitor in the first line improved progression-free survival (PFS) in patients with advanced or recurrent endometrial cancer, according to the DUO-E trial.

The trial assessed the combination of durvalumab (Imfinzi) and platinum-based chemotherapy, followed by maintenance therapy with either durvalumab plus the PARP inhibitor olaparib (Lynparza) or durvalumab alone. Add-on durvalumab to chemotherapy, followed by durvalumab maintenance, reduced the risk of progression by 29% compared to chemotherapy alone, while adding olaparib to the maintenance portion of the regimen helped reduce that risk by 45%, reported Shannon Westin, MD, MPH, of MD Anderson Cancer Center in Houston.

Interim overall survival data showed a positive trend in both experimental arms, but were immature at the time of this analysis, she noted.

“DUO-E is the first phase III study to demonstrate that durvalumab plus olaparib confers PFS benefit and provides new treatment options for patients with advanced or recurrent endometrial cancer,” Westin said in a presentation at the European Society for Medical Oncology (ESMO) congress.

She observed that recently reported results from several phase III trials showed that immunotherapy in combination with chemotherapy has activity in endometrial cancer, particularly in mismatch repair deficient disease. However, a greater benefit has been observed in patients with mismatch repair deficient (dMMR) than MMR proficient (pMMR) disease, she said.

“Unfortunately that’s only about 30% of patients,” Westin told MedPage Today. “So we have this large group of patients that have mismatch repair proficiency and for those patients the addition of immunotherapy alone is better, but it’s not as impactful as in the population that has the biomarker.”

The hope was that the addition of a PARP inhibitor to immunotherapy and chemotherapy would improve outcomes, particularly in pMMR disease, she explained.

In the phase III DUO-E/GOG-3041/ENGOT-EN10 trial, 718 patients were randomized 1:1:1 to one of three arms:

• Control: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance
• Durvalumab: carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo
• Durvalumab/olaparib: carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib

In the intent-to-treat population, a statistically significant PFS benefit was observed in the durvalumab arm (HR 0.71, 95% CI 0.57-0.89, P=0.003) and durvalumab/olaparib arm (HR 0.55, 95% CI 0.43-0.69, P<0.0001) versus control.

“And when we teased out different molecular features, in the population that was mismatch repair proficient, that’s where the addition of olaparib to immunotherapy seemed to have the biggest impact,” Westin observed.

Specifically, analyses by MMR status showed a PFS benefit in both the dMMR and pMMR subgroups, respectively:

• Durvalumab: HR 0.42 (95% CI 0.22-0.80); HR 0.77 (95% CI 0.60-0.97)
• Durvalumab/olaparib: HR 0.41 (95% CI 0.21-0.75); HR 0.57 (95% CI 0.44-0.73)

ESMO discussant Domenica Lorusso, MD, PhD, of the Fondazione IRCCS National Cancer Institute of Milan, noted that the benefit was essentially the same in both experimental arms in the dMMR subgroup so adding olaparib may not be worthwhile. She noted that “that’s not surprising because the bar of immunotherapy plus chemo in this population is so high that it is very difficult to move forward.”

“But — very important — is the benefit that was reported in the pMMR population, where we see a clear additional benefit in the full treatment arm,” she said, stating that “this is a very heterogeneous population, so my suggestion…is to try to better understand who are these patients. What is the molecular profile of the pMMR patients that seems to gain benefit?”

An exploratory analysis according to PD-L1 status suggested a PFS benefit for both the durvalumab and durvalumab/olaparib arms compared to control in the PD-L1-positive subgroup, but no benefit in the PD-L1 negative group.

In another exploratory analysis of investigator-assessed PFS in the durvalumab/olaparib versus durvalumab arm, the HR was 0.78 (95% CI 0.61-0.99).

The fact that the trial was not powered to have a formal comparison between the two experimental arms was a main limitation of the trial, Lorusso commented. “What is the added benefit of olaparib to durvalumab, unfortunately, remains an unanswered question,” she said.

Regarding safety, Westin reported that in the control, durvalumab, and durvalumab/olaparib arms, the overall incidence of grade 3 or higher treatment-emergent adverse events (AEs) was 56.4%, 54.9%, and 67.2%, respectively, while the incidence in the maintenance phase was 16.6%, 16.4%, and 41.1%, respectively.

The overall incidence of grade 3 or higher neutropenia was 23.3%, 21.7%, and 26.0%, respectively, and the overall incidence of grade 3 or higher anemia was 14.4%, 15.7%, and 23.5%. Serious AEs occurred overall in 30.9%, 31.1%, and 35.7%, of patients in the control, durvalumab, and durvalumab/olaparib arms, respectively, and fatal events occurred in 3.4%, 1.7%, and 2.1%.

DUO-E was a randomized, double-blind, placebo-controlled multicenter trial conducted in 22 countries. Eligible patients had newly diagnosed advanced measurable stage III/newly diagnosed stage IV or recurrent endometrial cancer of epithelial histology (excluding sarcomas).

Median patient age was about 64 in the entire trial, and about 28% were from Asia, while around 48% had newly diagnosed disease. pMMR tumors were present in 80% of the control arm, 81% of the durvalumab arm, and 80% of the durvalumab/olaparib arm.