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

Abstract

Purpose: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease.

Methods: This phase III, global, double-blind, placebo-controlled trial randomly assigned 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). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control.

Results: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT04269200.

FIG 1.

CONSORT diagram of patients. AE, adverse event; DCO, data cutoff.

FIG 2.

Intention-to-treat analyses of (A) PFS, as assessed by the investigator according to RECIST v1.1, and (B) OS. For the PFS analysis, the HRs and CIs were estimated from a Cox proportional hazards model stratified by MMR and disease status. For the OS analysis, the HRs and CIs were estimated from an unstratified Cox proportional hazards model. P values were calculated using a stratified log-rank test. Tick marks indicate a censored observation. Patients without an event were censored at the latest evaluable RECIST assessment. HR, hazard ratio; MMR, mismatch repair; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 3.

Subgroup analysis of PFS in (A) the durvalumab arm and (B) the durvalumab + olaparib arm. The HR and CI were estimated from an unstratified Cox proportional hazards model. An HR <1 favored the treatment arm of interest over the control arm. ^aStratification factors are per the randomization code. ^bHRs are not calculated because of the small number of patients. ^cIncludes patients with race not reported. ^dAs determined at the time of initial diagnosis of disease under investigation. ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; HRRm, homologous recombination repair mutation; MMR, mismatch repair; NC, not calculated.

FIG 4.

Exploratory PFS analyses, as assessed by the investigator according to RECIST v1.1, in (A) dMMR, (B) pMMR, (C) PD-L1–positive, and (D) PD-L1–negative subgroups. For dMMR and pMMR subgroup analyses, MMR status is as per the randomization code. The HR and 95% CI were estimated from an unstratified Cox proportional hazards model. Tick marks indicate a censored observation. Patients without an event were censored at the latest evaluable RECIST assessment. PD-L1 expression was assessed using the Ventana SP263 immunohistochemical assay (Roche Diagnostics). PD-L1–positive was defined as TAP ≥1%. PD-L1–negative was defined as TAP <1%. Unknown included patients who withdrew consent or due to sample unavailability. dMMR, mismatch repair-deficient; HR, hazard ratio; MMR, mismatch repair; NR, not reached; PFS, progression-free survival; pMMR, mismatch repair-proficient; TAP, tumor area positivity.