Clinical trialPhase 3Endometrial (womb) cancer

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

JCO · 2024718 patients

Westin SN, Moore K, Chon HS, Lee JY, Thomes Pepin J, Sundborg M, et al. JCO. 2024. 42:283-299

Study type: Clinical trial
Study name: DUO-E
Phase: Phase 3
Design: Global phase 3 trial, 1:1:1 randomisation, double-blind and placebo-controlled
Sample size: 718 patients
Source: JCO · 2024
Trial registration: NCT04269200

In plain words

In this large study, women newly diagnosed with advanced or recurrent endometrial cancer (cancer of the lining of the womb) were given, in addition to the usual chemotherapy (carboplatin and paclitaxel), the immunotherapy drug durvalumab, and in some groups also the drug olaparib. Adding these drugs lengthened the time during which the disease did not progress. This benefit was seen both in patients with a mismatch repair defect and in patients without this defect. Overall survival data are not yet complete, and treatment decisions should be made with the treating doctor.

Key results

HR 0.71 (95% CI 0.57–0.89)

Progression-free survival (all patients): durvalumab vs control

P=0.003

HR 0.55 (95% CI 0.43–0.69)

Progression-free survival (all patients): durvalumab + olaparib vs control

P<0.0001

HR 0.42 (0.22–0.80) / HR 0.41 (0.21–0.75)

PFS in the dMMR subgroup (durvalumab / durvalumab + olaparib vs control)

Prespecified exploratory analysis

HR 0.77 (0.60–0.97) / HR 0.57 (0.44–0.73)

PFS in the pMMR subgroup (durvalumab / durvalumab + olaparib vs control)

Prespecified exploratory analysis

HR 0.63 (0.48–0.83) / HR 0.42 (0.31–0.57)

PFS in the PD-L1-positive subgroup (durvalumab / durvalumab + olaparib vs control)

Prespecified exploratory analysis

HR 0.77 (95% CI 0.56–1.07)

Interim overall survival: durvalumab vs control

P=0.120; maturity about 28%

HR 0.59 (95% CI 0.42–0.83)

Interim overall survival: durvalumab + olaparib vs control

P=0.003; maturity about 28%

Drugs in this study:Carboplatin (Paraplatin)Olaparib (Lynparza)Paclitaxel (Taxol)Durvalumab (Imfinzi)

Dose and schedule cards

Durvalumab + carboplatin–paclitaxel (DUO-E, dMMR)

First line for primary advanced or recurrent dMMR disease (FDA indication)On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

First line for primary advanced or recurrent dMMR disease (FDA indication)

Drug	Dose	Route	Schedule
With chemotherapy: 6 cycles every 21 days
Durvalumab	1120 mg (60-minute infusion)	IV	Day 1
Carboplatin	AUC 5 or 6	IV	Day 1
Paclitaxel	175 mg/m²	IV	Day 1
Maintenance
Durvalumab	1500 mg	IV	Every 4 weeks

Cycle length: 21 days for the first 6 cycles, then every 4 weeks
Duration: Until progression or unacceptable toxicity

Body weight below 30 kg: 15 mg/kg with chemotherapy, then 20 mg/kg every 4 weeks. Dose source: the paper and the FDA label.

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

Durvalumab + carboplatin–paclitaxel, then durvalumab + olaparib (DUO-E, pMMR)

First line for primary advanced or recurrent disease; the benefit of adding olaparib was largest in pMMR; ESGO for non-MMRd [I, B]; olaparib has no endometrial cancer indication in the FDA labelEach drug’s schedule in the tableOn the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

First line for primary advanced or recurrent disease; the benefit of adding olaparib was largest in pMMR; ESGO for non-MMRd [I, B]; olaparib has no endometrial cancer indication in the FDA label

Drug	Dose	Route	Schedule
With chemotherapy: 6 cycles every 21 days
Durvalumab	1120 mg	IV	Day 1
Carboplatin	AUC 5 or 6	IV	Day 1
Paclitaxel	175 mg/m²	IV	Day 1
Maintenance
Durvalumab	1500 mg	IV	Every 4 weeks
Olaparib	300 mg twice daily (tablets)	Oral	Daily, continuously

Cycle schedule: Durvalumab every 3 weeks with chemotherapy, then every 4 weeks; olaparib daily and continuously during maintenance
Duration: Until progression or unacceptable toxicity

Dose source: full text of the paper. Olaparib dose reductions: 250 mg, then 200 mg twice daily. Grade 3 or worse adverse events: 67.2% over the whole treatment and 41.1% during maintenance.

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Control group

Carboplatin AUC 5 or 6 mg/mL/min and paclitaxel 175 mg/m² every 3 weeks for 6 cycles, with durvalumab placebo IV every 3 weeks (6 cycles); then maintenance with durvalumab placebo IV every 4 weeks plus olaparib placebo tablets twice daily. Treatment continued until radiological progression (RECIST 1.1, investigator-assessed), unacceptable toxicity or other discontinuation criteria; maintenance was started only in the absence of progression during the chemotherapy phase (241 patients).

2Durvalumab group

Carboplatin AUC 5 or 6 and paclitaxel 175 mg/m² every 3 weeks (6 cycles) with durvalumab 1120 mg IV every 3 weeks (6 cycles); then maintenance with durvalumab 1500 mg IV every 4 weeks plus olaparib placebo tablets twice daily; continuation and discontinuation criteria as in the control group (238 patients).

3Durvalumab + olaparib group

Carboplatin AUC 5 or 6 and paclitaxel 175 mg/m² every 3 weeks (6 cycles) with durvalumab 1120 mg IV every 3 weeks (6 cycles); then maintenance with durvalumab 1500 mg IV every 4 weeks plus olaparib 300 mg tablets twice daily; continuation and discontinuation criteria as in the control group (239 patients).

Source of the regimen details: Full text of the paper (PMC10824389, section Random Assignment and Study Treatment)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 years or older with newly diagnosed advanced (FIGO 2009 measurable stage III or newly diagnosed stage IV) or recurrent epithelial endometrial cancer (excluding sarcoma); in recurrent disease, the chance of cure by surgery was low, and prior systemic therapy was allowed only in the adjuvant setting with at least 12 months until recurrence. MMR status had to be known before randomisation. The trial was conducted in 22 countries, and results were examined in the dMMR and pMMR subgroups and in PD-L1-positive subgroups.

Endpoints

Primary endpoints: progression-free survival (PFS) for durvalumab versus control and for durvalumab + olaparib versus control. Overall survival (OS) was reported as an interim analysis (data maturity about 28%).

Safety and side effects

Treatment-emergent grade 3 or higher adverse events (whole period): 56.4% (control), 54.9% (durvalumab) and 67.2% (durvalumab + olaparib); in the maintenance phase 16.6%, 16.4% and 41.1%. Grade 3 or higher neutropenia 23.3%, 21.7% and 26.0%; grade 3 or higher anaemia 14.4%, 15.7% and 23.5%. Serious adverse events 30.9%, 31.1% and 35.7%, and fatal events 3.4%, 1.7% and 2.1%. Immune-mediated adverse events 6.8%, 28.1% and 23.5%. Pneumonitis (any grade) in 1, 4 and 12 patients (5.0% in the triplet group, mostly in the maintenance phase); 3 cases of pure red cell aplasia (1.6%, all grade 3) only in the durvalumab + olaparib group; no cases of MDS or AML were reported.

Clinical significance and place in guidelines

This trial showed that adding durvalumab to first-line chemotherapy and continuing it as maintenance, and adding olaparib in the maintenance phase, improves progression-free survival in advanced or recurrent endometrial cancer. Benefit was seen in the dMMR, pMMR and PD-L1-positive subgroups, but these analyses were exploratory. Overall survival data are still interim. The status of drug approvals and formal clinical guideline recommendations should be checked separately, as the abstract does not mention them.

Limitations

Subgroup analyses (dMMR, pMMR and PD-L1) were exploratory. Overall survival data are interim with about 28% maturity, and for durvalumab versus control the overall survival difference was not significant (P=0.120). Exact adverse event rates are not reported in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.