The DUO-E trial in endometrial cancer

Prof Van Nieuwenhuysen discusses insights from the DUO-E trial, which included first-line endometrial cancer patients and those with first relapse. The trial enrolled 718 patients randomised into three groups: Taxol-Carbo (TC) followed by placebo, TC combined with durvalumab (DURV) followed by DURV maintenance, and TC combined with DURV followed by DURV and olaparib maintenance. The trial showed positive results PFS in the intention-to-treat analysis, with the most significant benefit observed in the pMMR population receiving the triplet combination of TC, DURV, and olaparib, achieving an HR of 0.57. In comparison, the HR for TC and DURV alone in this population was 0.77, indicating a substantial benefit from adding olaparib.

The pMMR population, known for its heterogeneity, was further analysed to identify which patients benefitted most from the triplet combination. BRCA mutation analysis was conducted on the entire DUO-E population, revealing a 27% mutation rate in the MMRd population and 6% in the pMMR population. The higher mutation rate in the MMRd group may be attributed to the presence of more passenger mutations. Importantly, the benefit of combining chemotherapy, DURV, and olaparib was observed regardless of BRCA status in both MMRd and MMRp populations, suggesting that BRCA mutation alone does not explain the observed responses.

Regarding safety and tolerability, adding olaparib to the TC and DURV combination raised concerns. However, the DUO-E trial indicated no new safety signals from adding an immune checkpoint inhibitor to platinum-based chemotherapy. Common adverse events included hypothyroidism and skin rash. In the olaparib-added group, the main additional toxicity was anaemia, with 18.8% of patients experiencing grade 3 anaemia compared to only 0.6% in the TC plus placebo arm. Despite the increased anaemia risk, the triplet combination of TC, DURV, and olaparib remains manageable in recurrent or advanced endometrial cancer. However, dose interruptions or reductions were necessary for some patients due to anaemia.