J Clin Oncol. 2023 Oct 21:101200JCO2302132. doi: 10.1200/JCO.23.02132. Online ahead of print.
PURPOSE: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a PARP inhibitor may improve outcomes, especially in pMMR disease.
METHODS: This phase III, global, double-blind, placebo-controlled trial randomized eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab+olaparib arm). Primary end points were progression-free survival (PFS) for durvalumab and durvalumab+olaparib arms versus control.
RESULTS: 718 patients were randomized. In the intent-to-treat population, statistically significant PFS benefit was observed in the durvalumab (HR, 0.71; 95% CI, 0.57 to 0.89; P=.003) and durvalumab+olaparib arms (HR, 0.55; 0.43 to 0.69; P<.0001) versus control. Pre-specfied, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42; 0.22 to 0.80; HR [durvalumab+olaparib v control], 0.41; 0.21 to 0.75) and pMMR subgroups (HR [durvalumab v control], 0.77; 0.60 to 0.97; HR [durvalumab+olaparib v control] 0.57; 0.44 to 0.73); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63; 0.48 to 0.83; HR [durvalumab+olaparib v control], 0.42; 0.31 to 0.57). Interim overall survival results (maturity ∼28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77; 0.56 to 1.07; P=.120; durvalumab+olaparib v control: HR, 0.59; 0.42 to 0.83; P=.003). The safety profiles of the experimental arms were generally consistent with individual agents.
CONCLUSIONS: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.