DUO-E/GOG-3041/ENGOT-EN10 trial

Medical oncologist Prof Christine Gennigens from CHU de Liège and gynaeco-oncologist Prof Els Van Nieuwenhuysen, the last author of the complete publication of the DUO-E/GOG-3041/ENGOT-EN10 trial in JCO 2023, shared insights into their research.

The DUO-E/GOG-3041/ENGOT-EN10 trial is a phase 3, three-arm, randomised, double-blind, placebo-controlled multicenter study in endometrial cancer. Newly diagnosed FIGO stage III/IV or recurrent endometrial cancer patients, naive to systemic treatment, were randomly assigned to three arms: a control arm with carboplatin/paclitaxel chemotherapy followed by a placebo; a second arm with chemotherapy plus durvalumab, followed by durvalumab maintenance and placebo; and a third arm with a triplet regimen of chemotherapy, durvalumab, and olaparib maintenance. The primary endpoint was investigator-assessed PFS in the ITT  population, with a prespecified subgroup analysis based on MMR status.

In total, 718 patients were randomized with a median follow-up between 12 and 15 months. The triplet regimen showed a 45% reduction in PFS (HR 0.55), while adding durvalumab alone to chemotherapy achieved a 29% reduction compared to chemotherapy alone (HR 0.71). Prespecified exploratory subgroup analyses by MMR status demonstrated comparable PFS benefits in patients with dMMR disease in the durvalumab arm (58%) and in the durvalumab plus olaparib arm (59%) compared to the control arm. An additional clinical benefit was observed when olaparib maintenance was added to durvalumab in the pMMR subgroup (43% vs. 23%; HR < 1, but not statistically significant). Both experimental arms showed a manageable safety profile.

The discussion then delved into the rationale for combining immunotherapy and a PARP inhibitor in endometrial cancer. About 30 to 40% of endometrial cancers have HRR mutations, and adding PARP can increase genomic instability, leading to the activation of the STING pathway, upregulating inflammatory genes and enhancing sensitivity to immunotherapy.

Prof Gennigens queried Prof Van Nieuwenhuysen about the trial’s weaknesses. Prof Van Nieuwenhuysen acknowledged that they should have powered the study for PFS in the MMR populations, especially in the pMMR population, where DUO-E makes a difference. The outcomes align with previous studies (RUBY, NRG GY018, AtTEnd), indicating the benefits of adding immunotherapy in the dMMR population. However, DUO-E demonstrates that the PFS benefit can be further increased by adding a PARP inhibitor to the combination for the pMMR population.

Prof Gennigens sought Prof Van Nieuwenhuysen’s strategy in daily practice with the new data, regardless of reimbursement criteria. In the dMMR population, she would add immunotherapy to platinum-based chemotherapy but wouldn’t add a PARP inhibitor. However, for a pMMR patient, she would opt for the triplet combination in the front line. Considering a recurrent patient who has already undergone immunotherapy, genetic profiling would be crucial to determine the optimal second-line treatment strategy—an interesting field developing in this context.