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Clinical Trial
. 2024 Jan 20;42(3):283-299.
doi: 10.1200/JCO.23.02132. Epub 2023 Oct 21.

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

Shannon N Westin  1 , Kathleen Moore  2 , Hye Sook Chon  3 , Jung-Yun Lee  4 , Jessica Thomes Pepin  5 , Michael Sundborg  6 , Ayelet Shai  7 , Joseph de la Garza  8 , Shin Nishio  9 , Michael A Gold  10 , Ke Wang  11 , Kristi McIntyre  12 , Todd D Tillmanns  13 , Stephanie V Blank  14 , Ji-Hong Liu  15 , Michael McCollum  16 , Fernando Contreras Mejia  17 , Tadaaki Nishikawa  18 , Kathryn Pennington  19 , Zoltan Novak  20 , Andreia Cristina De Melo  21 , Jalid Sehouli  22 , Dagmara Klasa-Mazurkiewicz  23 , Christos Papadimitriou  24 , Marta Gil-Martin  25 , Birute Brasiuniene  26 , Conor Donnelly  27 , Paula Michelle Del Rosario  28 , Xiaochun Liu  29 , Els Van Nieuwenhuysen  30 ; DUO-E Investigators
Collaborators, Affiliations
Clinical Trial

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

Shannon N Westin et al. J Clin Oncol. .

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.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
CONSORT diagram of patients. AE, adverse event; DCO, data cutoff.
FIG 2.
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.
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.
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.
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