Endometrial Neoplasms
Conditions
Keywords
Cancer of Endometrium, Cancer of the Endometrium, Carcinoma of Endometrium, Endometrial Cancer, Endometrial Carcinoma, Endometrium Cancer, Neoplasms, Endometrial
Brief summary
A study to assess the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin) followed by maintenance durvalumab with or without olaparib for patients with newly diagnosed advanced or recurrent endometrial cancer.
Detailed description
This Phase III study will assess the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin) followed by maintenance durvalumab with or without olaparib for patients with newly diagnosed advanced or recurrent endometrial cancer. Target patient population: Adult female patients with histologically confirmed diagnosis of epithelial endometrial carcinoma (excluding sarcomas): newly diagnosed Stage III, newly diagnosed Stage IV, or recurrent endometrial cancer
Interventions
DRUGolaparib
Olaparib tablets
BIOLOGICALdurvalumab
Durvalumab by intravenous infusion
Matching placebo for intravenous infusion
DRUGolaparib placebo
Placebo tablets to match olaparib
DRUGCarboplatin
Standard of care chemotherapy
DRUGPaclitaxel
Standard of care chemotherapy
Sponsors
AstraZeneca
GOG Foundation
European Network of Gynaecological Oncological Trial Groups (ENGOT)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
double-blind, placebo-controlled
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 150 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years at the time of screening and female. * Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies, including carcinosarcomas, will be allowed. Sarcomas will not be allowed. * Patient must have endometrial cancer in one of the following categories: 1. Newly diagnosed Stage III disease (measurable disease per RECIST 1.1 following surgery or diagnostic biopsy), 2. Newly diagnosed Stage IV disease (with or without disease following surgery or diagnostic biopsy) 3. Recurrence of disease (measurable or non-measurable disease per RECIST 1.1) where the potential for cure by surgery alone or in combination is poor. * Naïve to first line systemic anti-cancer treatment. For patients with recurrent disease only, prior systemic anti-cancer treatment is allowed only if it was administered in the adjuvant setting and there is at least 12 months from date of last dose of systemic anti-cancer treatment administered to date of subsequent relapse * FPPE tumor sample must be available for MMR evaluation. * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study treatment.
Exclusion criteria
* History of leptomeningeal carcinomatosis. * Brain metastases or spinal cord compression. * Prior treatment with PARP inhibitors. * Any prior exposure to immune-mediated therapy, including (but not limited to) other anti CTLA-4, anti-PD-1, anti-PD-L1, or anti-programmed-cell-death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | At baseline, every 9 weeks (wks) up to 18 wks, then every 12 wks until objective radiological disease progression. Assessed until 12 Apr 2023 DCO (08 Jul 2024 DCO for China cohort), up to 50 months | To demonstrate the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy by assessment of PFS (using investigator assessment according to Response Evaluation Criteria in Solid Tumours version 1.1 \[RECIST 1.1\]) in patients with newly diagnosed advanced or recurrent endometrial cancer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Analysis | Survival assessed every 2 months after RECIST defined radiological progression; assessed through study completion, up to 83 months | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of OS |
| Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | At baseline, every 9 to 18 wks, then every 12 wks until objective radiological disease progression. Assessments then per local practice every 12 wks until second progression. Assessed until 12Apr2023 DCO (08Jul2024 DCO for China cohort), up to 50 months | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of PFS2 |
| Objective Response Rate (ORR) Based on Investigator Assessment | At baseline, every 9 to 18 wks, then every 12 wks until objective radiological disease progression. Assessed until 12 Apr 2023 DCO (08 Jul 2024 DCO for China cohort), up to 50 months | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of ORR |
| Duration of Response (DoR) Based on Investigator Assessment | At baseline, every 9 wks up to 18 wks, then every 12 wks until objective radiological disease progression. Assessed until 12 Apr 2023 DCO, up to 35 months | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of DoR |
| Time From Randomisation to First Subsequent Therapy or Death (TFST) | Time elapsed from randomisation to first subsequent therapy or death. Assessed every 12 wks following treatment discontinuation, through study completion (up to 83 months) | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of TFST |
| Time From Randomisation to Second Subsequent Therapy or Death (TSST) | Time elapsed from randomisation to second subsequent therapy or death. Assessed every 12 wks following treatment discontinuation, through study completion (up to 83 months) | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of TSST |
| Time From Randomisation to Discontinuation of Treatment or Death (TDT) | Time elapsed from randomisation to study treatment discontinuation or death. Assessed through study completion, up to 83 months | To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of TDT |
| Serum Concentration of Durvalumab | PK sampling performed on Day 85 pre-dose, Day 183 pre-dose, and 3 months after study treatment discontinuation (up to 36 months) | To characterise the pharmacokinetics (PK) of durvalumab and durvalumab in combination with olaparib |
| Anti-drug Antibodies (ADA) to Durvalumab | Immunogenicity sampling performed on Day 1 pre-dose, Day 85 pre-dose, Day 183 pre-dose, and 3 and 6 months after study treatment discontinuation (up to 39 months) | To characterise the immunogenicity of durvalumab and durvalumab in combination with olaparib |
| Change From Baseline in Physical Functioning Score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients 30 (EORTC QLQ-C30) | At baseline, every 3 wks until Wk 18, and every 4 wks until the second progression. Assessed until 12 Apr 2023 DCO, up to 35 months. The average treatment effect over the first 12 months after randomisation is presented. | To determine effects on symptoms, functioning, and overall health related quality of life (HRQoL) of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy alone in newly diagnosed advanced or recurrent endometrial cancer patients. The physical functioning score is a score from 0 to 100. Higher scores on the physical functioning score indicate better health status/function. |
| Change From Baseline in Global Health Status/QoL Score of the EORTC QLQ-C30 | At baseline, every 3 wks until Wk 18, and every 4 wks until the second progression. Assessed until 12 Apr 2023 DCO, up to 35 months. The average treatment effect over the first 12 months after randomisation is presented. | To determine effects on symptoms, functioning, and overall HRQoL of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy alone in newly diagnosed advanced or recurrent endometrial cancer patients. The global health status/quality of life (QoL) is a score from 0 to 100. Higher scores on the global health status/QoL indicate better health status/function. |
Countries
Australia, Belgium, Brazil, Canada, China, Colombia, Estonia, Germany, Greece, Hong Kong, Hungary, India, Israel, Japan, Lithuania, Mexico, Poland, Russia, Singapore, South Korea, Spain, United States
Contacts
PRINCIPAL_INVESTIGATORShannon N. Westin, MD, MPH, FACOG
M.D. Anderson Cancer Center
Participant flow
Recruitment details
Global Cohort: 875 patients screened across 179 centres in 22 countries; 718 were randomised. Results were reported for analysis of progression-free survival (PFS) (data cut-off \[DCO\]: 12 Apr 2023). China Cohort: 172 patients screened across 25 sites; 129 were randomized. Results were reported for analysis of PFS (DCO: 08 Jul 2024). In total, 805 patients were randomised; 718 to the Global cohort, 129 to the China cohort, with 42 patients overlapping and belonging to both cohorts.
Pre-assignment details
It was planned that approximately 699 women from the Global cohort and 129 women from the China cohort, with newly diagnosed advanced or recurrent endometrial cancer, were to receive durvalumab/placebo in combination with platinum-based chemotherapy followed by maintenance durvalumab/placebo (same treatment as during chemotherapy phase) and olaparib/placebo in a 1:1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| SoC (Global Cohort & China Cohort) Platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for a maximum of 6 cycles with durvalumab placebo (IV) Q3W.
Following completion of chemotherapy treatment, patients without objective disease progression received durvalumab placebo (IV) Q4W and olaparib placebo (tablets) bd orally as maintenance treatment until disease progression. | 270 |
| SoC + Durvalumab (Global Cohort & China Cohort) Platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for a maximum of 6 cycles with 1120 mg durvalumab (IV) Q3W.
Following completion of chemotherapy treatment, patients without objective disease progression received 1500 mg durvalumab (IV) Q4W with olaparib placebo (tablets) bd orally as maintenance treatment until disease progression. | 267 |
| SoC + Durvalumab + Olaparib (Global Cohort & China Cohort) Platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for a maximum of 6 cycles with 1120 mg durvalumab (IV) Q3W.
Following completion of chemotherapy treatment, patients without objective disease progression received 1500 mg durvalumab (IV) Q4W with 300 mg olaparib (tablets) bd orally as maintenance treatment until disease progression. | 268 |
| Total | 805 |
Baseline characteristics
| Characteristic | Total | SoC (Global Cohort & China Cohort) | SoC + Durvalumab (Global Cohort & China Cohort) | SoC + Durvalumab + Olaparib (Global Cohort & China Cohort) |
|---|---|---|---|---|
| Age, Continuous China cohort | 58.4 Years STANDARD_DEVIATION 9.24 | 58.3 Years STANDARD_DEVIATION 8.73 | 57.6 Years STANDARD_DEVIATION 10.57 | 59.3 Years STANDARD_DEVIATION 8.41 |
| Age, Continuous Global cohort | 62.6 Years STANDARD_DEVIATION 10.03 | 62.1 Years STANDARD_DEVIATION 10.36 | 63.3 Years STANDARD_DEVIATION 9.82 | 62.4 Years STANDARD_DEVIATION 9.9 |
| Age, Customized China cohort <65 years | 95 Participants | 35 Participants | 30 Participants | 30 Participants |
| Age, Customized China cohort >=65 years | 34 Participants | 9 Participants | 13 Participants | 12 Participants |
| Age, Customized Global cohort <65 years | 381 Participants | 124 Participants | 122 Participants | 135 Participants |
| Age, Customized Global cohort >=65 years | 337 Participants | 117 Participants | 116 Participants | 104 Participants |
| Ethnicity (NIH/OMB) China cohort Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) China cohort Not Hispanic or Latino | 129 Participants | 44 Participants | 43 Participants | 42 Participants |
| Ethnicity (NIH/OMB) China cohort Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Global cohort Hispanic or Latino | 80 Participants | 20 Participants | 28 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Global cohort Not Hispanic or Latino | 632 Participants | 218 Participants | 208 Participants | 206 Participants |
| Ethnicity (NIH/OMB) Global cohort Unknown or Not Reported | 6 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized China cohort American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China cohort Asian | 129 Participants | 44 Participants | 43 Participants | 42 Participants |
| Race/Ethnicity, Customized China cohort Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China cohort Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China cohort Not reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China cohort Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China cohort White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Global cohort American Indian or Alaska Native | 12 Participants | 0 Participants | 6 Participants | 6 Participants |
| Race/Ethnicity, Customized Global cohort Asian | 215 Participants | 73 Participants | 72 Participants | 70 Participants |
| Race/Ethnicity, Customized Global cohort Black or African American | 35 Participants | 10 Participants | 11 Participants | 14 Participants |
| Race/Ethnicity, Customized Global cohort Native Hawaiian or Other Pacific Islander | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Global cohort Not reported | 11 Participants | 3 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Global cohort Other | 30 Participants | 10 Participants | 8 Participants | 12 Participants |
| Race/Ethnicity, Customized Global cohort White | 412 Participants | 143 Participants | 136 Participants | 133 Participants |
| Sex/Gender, Customized China cohort Female | 129 Participants | 44 Participants | 43 Participants | 42 Participants |
| Sex/Gender, Customized Global cohort Female | 718 Participants | 241 Participants | 238 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 82 / 241 | 65 / 238 | 52 / 239 | 12 / 44 | 11 / 43 | 14 / 42 |
| other Total, other adverse events | 233 / 236 | 228 / 235 | 236 / 238 | 44 / 44 | 41 / 41 | 39 / 41 |
| serious Total, serious adverse events | 73 / 236 | 73 / 235 | 85 / 238 | 14 / 44 | 8 / 41 | 19 / 41 |
Outcome results
Primary
Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments
To demonstrate the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy by assessment of PFS (using investigator assessment according to Response Evaluation Criteria in Solid Tumours version 1.1 \[RECIST 1.1\]) in patients with newly diagnosed advanced or recurrent endometrial cancer
Time frame: At baseline, every 9 weeks (wks) up to 18 wks, then every 12 wks until objective radiological disease progression. Assessed until 12 Apr 2023 DCO (08 Jul 2024 DCO for China cohort), up to 50 months
Population: Full Analysis Set (FAS) consisting of all patients randomised as part of global enrolment including patients from China who were randomised before the global recruitment was closed (up to and including 20 Apr 2022). China FAS includes all patients who were randomised at sites in China and Hong Kong.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Global Cohort - SoC | Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | 9.6 Months |
| Global Cohort - SoC + Durvalumab | Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | 10.2 Months |
| Global Cohort - SoC + Durvalumab + Olaparib | Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | 15.1 Months |
| China Cohort - SoC | Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | 9.7 Months |
| China Cohort - SoC + Durvalumab | Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | 9.9 Months |
| China Cohort - SoC + Durvalumab + Olaparib | Progression-free Survival (PFS) According to RECIST 1.1, Based on Investigator Assessments | 9.9 Months |
p-value: 0.00395% CI: [0.57, 0.89]Regression, Cox
p-value: <0.000195% CI: [0.43, 0.69]Regression, Cox
95% CI: [0.42, 1.25]Regression, Cox
95% CI: [0.57, 1.61]Regression, Cox
Secondary
Anti-drug Antibodies (ADA) to Durvalumab
To characterise the immunogenicity of durvalumab and durvalumab in combination with olaparib
Time frame: Immunogenicity sampling performed on Day 1 pre-dose, Day 85 pre-dose, Day 183 pre-dose, and 3 and 6 months after study treatment discontinuation (up to 39 months)
Population: ADA Analysis Set. This includes all patients who receive at least 1 dose of durvalumab and have non-missing baseline ADA and at least 1 post-baseline ADA result.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | ADA-positive at any visit (ADA prevalence) | 8 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-emergent ADA-positive (ADA incidence) | 2 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-boosted ADA | 0 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-induced ADA (positive post-baseline only) | 2 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive at baseline only | 6 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive post-baseline and positive at baseline | 0 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Persistently positive | 2 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Transiently positive | 0 Number of participants |
| Global Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Neutralising antibody positive at any visit | 1 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-boosted ADA | 0 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-induced ADA (positive post-baseline only) | 0 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive at baseline only | 9 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive post-baseline and positive at baseline | 0 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | Persistently positive | 0 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | Transiently positive | 0 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | ADA-positive at any visit (ADA prevalence) | 9 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-emergent ADA-positive (ADA incidence) | 0 Number of participants |
| Global Cohort - SoC + Durvalumab | Anti-drug Antibodies (ADA) to Durvalumab | Neutralising antibody positive at any visit | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive at baseline only | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive post-baseline and positive at baseline | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | Transiently positive | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | Persistently positive | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-boosted ADA | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | Neutralising antibody positive at any visit | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-emergent ADA-positive (ADA incidence) | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-induced ADA (positive post-baseline only) | 0 Number of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Anti-drug Antibodies (ADA) to Durvalumab | ADA-positive at any visit (ADA prevalence) | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-emergent ADA-positive (ADA incidence) | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive at baseline only | 1 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | ADA-positive at any visit (ADA prevalence) | 1 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | ADA positive post-baseline and positive at baseline | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-induced ADA (positive post-baseline only) | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Treatment-boosted ADA | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Neutralising antibody positive at any visit | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Persistently positive | 0 Number of participants |
| China Cohort - SoC | Anti-drug Antibodies (ADA) to Durvalumab | Transiently positive | 0 Number of participants |
Secondary
Change From Baseline in Global Health Status/QoL Score of the EORTC QLQ-C30
To determine effects on symptoms, functioning, and overall HRQoL of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy alone in newly diagnosed advanced or recurrent endometrial cancer patients. The global health status/quality of life (QoL) is a score from 0 to 100. Higher scores on the global health status/QoL indicate better health status/function.
Time frame: At baseline, every 3 wks until Wk 18, and every 4 wks until the second progression. Assessed until 12 Apr 2023 DCO, up to 35 months. The average treatment effect over the first 12 months after randomisation is presented.
Population: FAS consisting of all patients randomised as part of global enrolment including patients from China who were randomised before the global recruitment was closed (up to and including 20 Apr 2022). All participants with a baseline and post baseline global health status/QoL available were analysed. This endpoint was not assessed in the China cohort as it was not prespecified in the SAP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort - SoC | Change From Baseline in Global Health Status/QoL Score of the EORTC QLQ-C30 | -2.8 Score on a scale | Standard Error 0.93 |
| Global Cohort - SoC + Durvalumab | Change From Baseline in Global Health Status/QoL Score of the EORTC QLQ-C30 | -2.7 Score on a scale | Standard Error 0.92 |
| Global Cohort - SoC + Durvalumab + Olaparib | Change From Baseline in Global Health Status/QoL Score of the EORTC QLQ-C30 | -3.6 Score on a scale | Standard Error 0.88 |
95% CI: [-2.5, 2.6]Mixed model for repeated measures
95% CI: [-3.4, 1.6]Mixed model for repeated measures
Secondary
Change From Baseline in Physical Functioning Score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients 30 (EORTC QLQ-C30)
To determine effects on symptoms, functioning, and overall health related quality of life (HRQoL) of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy alone in newly diagnosed advanced or recurrent endometrial cancer patients. The physical functioning score is a score from 0 to 100. Higher scores on the physical functioning score indicate better health status/function.
Time frame: At baseline, every 3 wks until Wk 18, and every 4 wks until the second progression. Assessed until 12 Apr 2023 DCO, up to 35 months. The average treatment effect over the first 12 months after randomisation is presented.
Population: FAS consisting of all patients randomised as part of global enrolment including patients from China who were randomised before the global recruitment was closed (up to and including 20 Apr 2022). All participants with a baseline and post baseline physical functioning score available were analysed. This endpoint was not assessed in the China cohort as it was not prespecified in the SAP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort - SoC | Change From Baseline in Physical Functioning Score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients 30 (EORTC QLQ-C30) | -5.3 Score on a scale | Standard Error 1.03 |
| Global Cohort - SoC + Durvalumab | Change From Baseline in Physical Functioning Score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients 30 (EORTC QLQ-C30) | -3.6 Score on a scale | Standard Error 1.02 |
| Global Cohort - SoC + Durvalumab + Olaparib | Change From Baseline in Physical Functioning Score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients 30 (EORTC QLQ-C30) | -5.9 Score on a scale | Standard Error 0.98 |
95% CI: [-1.2, 4.5]Mixed model for repeated measures
95% CI: [-3.4, 2.2]Mixed model for repeated measures
Secondary
Duration of Response (DoR) Based on Investigator Assessment
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of DoR
Time frame: At baseline, every 9 wks up to 18 wks, then every 12 wks until objective radiological disease progression. Assessed until 12 Apr 2023 DCO, up to 35 months
Population: All participants with confirmed response were included in the analysis. FAS consisting of all patients randomised as part of global enrolment including patients from China who were randomised before the global recruitment was closed (up to and including 20 Apr 2022). This endpoint was not assessed in the China cohort as it was not prespecified in the statistical analysis plan (SAP).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Global Cohort - SoC | Duration of Response (DoR) Based on Investigator Assessment | 7.7 Months |
| Global Cohort - SoC + Durvalumab | Duration of Response (DoR) Based on Investigator Assessment | 13.1 Months |
| Global Cohort - SoC + Durvalumab + Olaparib | Duration of Response (DoR) Based on Investigator Assessment | 21.3 Months |
Secondary
Objective Response Rate (ORR) Based on Investigator Assessment
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of ORR
Time frame: At baseline, every 9 to 18 wks, then every 12 wks until objective radiological disease progression. Assessed until 12 Apr 2023 DCO (08 Jul 2024 DCO for China cohort), up to 50 months
Population: All participants with measurable disease at baseline were included in the analysis. FAS consisting of all patients randomised as part of global enrolment including patients from China who were randomised before the global recruitment was closed (up to and including 20 Apr 2022). China FAS includes all patients who were randomised at sites in China and Hong Kong. Odds ratio only calculated for Global cohort (per statistical analysis plan \[SAP\]).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Global Cohort - SoC | Objective Response Rate (ORR) Based on Investigator Assessment | 55.1 Percentage of participants |
| Global Cohort - SoC + Durvalumab | Objective Response Rate (ORR) Based on Investigator Assessment | 61.9 Percentage of participants |
| Global Cohort - SoC + Durvalumab + Olaparib | Objective Response Rate (ORR) Based on Investigator Assessment | 63.6 Percentage of participants |
| China Cohort - SoC | Objective Response Rate (ORR) Based on Investigator Assessment | 59.5 Percentage of participants |
| China Cohort - SoC + Durvalumab | Objective Response Rate (ORR) Based on Investigator Assessment | 59.4 Percentage of participants |
| China Cohort - SoC + Durvalumab + Olaparib | Objective Response Rate (ORR) Based on Investigator Assessment | 45.5 Percentage of participants |
95% CI: [0.89, 1.98]Regression, Logistic
95% CI: [0.95, 2.18]Regression, Logistic
Secondary
Overall Survival (OS) Analysis
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of OS
Time frame: Survival assessed every 2 months after RECIST defined radiological progression; assessed through study completion, up to 83 months
Secondary
Serum Concentration of Durvalumab
To characterise the pharmacokinetics (PK) of durvalumab and durvalumab in combination with olaparib
Time frame: PK sampling performed on Day 85 pre-dose, Day 183 pre-dose, and 3 months after study treatment discontinuation (up to 36 months)
Population: The Overall Number of Participants Analyzed reflects the total number of patients included in the PK Analysis Set, which comprises those treated with durvalumab per protocol and with valid PK data. However, PK concentrations were excluded at the sample level if they do not meet protocol-defined criteria. While some patients may not have any valid samples due to these exclusions, they remain part of the analysis population set by definition.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort - SoC | Serum Concentration of Durvalumab | Day 85, pre-dose (Trough concentration) | 203.133538 μg/mL | Geometric Coefficient of Variation 32.6 |
| Global Cohort - SoC | Serum Concentration of Durvalumab | Day 183, pre-dose (Trough concentration) | 265.575840 μg/mL | Geometric Coefficient of Variation 39.6 |
| Global Cohort - SoC | Serum Concentration of Durvalumab | Follow-up 3-months (Last valid dose + 3 months) | 27.977227 μg/mL | Geometric Coefficient of Variation 104.4 |
| Global Cohort - SoC + Durvalumab | Serum Concentration of Durvalumab | Day 183, pre-dose (Trough concentration) | 236.315365 μg/mL | Geometric Coefficient of Variation 38 |
| Global Cohort - SoC + Durvalumab | Serum Concentration of Durvalumab | Day 85, pre-dose (Trough concentration) | 196.218276 μg/mL | Geometric Coefficient of Variation 31.7 |
| Global Cohort - SoC + Durvalumab | Serum Concentration of Durvalumab | Follow-up 3-months (Last valid dose + 3 months) | 14.031316 μg/mL | Geometric Coefficient of Variation 206.8 |
| Global Cohort - SoC + Durvalumab + Olaparib | Serum Concentration of Durvalumab | Day 85, pre-dose (Trough concentration) | 183.414442 μg/mL | Geometric Coefficient of Variation 32.7 |
| Global Cohort - SoC + Durvalumab + Olaparib | Serum Concentration of Durvalumab | Follow-up 3-months (Last valid dose + 3 months) | 33.310921 μg/mL | Geometric Coefficient of Variation 43 |
| China Cohort - SoC | Serum Concentration of Durvalumab | Day 85, pre-dose (Trough concentration) | NA μg/mL | — |
| China Cohort - SoC | Serum Concentration of Durvalumab | Follow-up 3-months (Last valid dose + 3 months) | 11.252155 μg/mL | Geometric Coefficient of Variation 1429.7 |
| China Cohort - SoC | Serum Concentration of Durvalumab | Day 183, pre-dose (Trough concentration) | NA μg/mL | — |
Secondary
Time From Randomisation to Discontinuation of Treatment or Death (TDT)
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of TDT
Time frame: Time elapsed from randomisation to study treatment discontinuation or death. Assessed through study completion, up to 83 months
Secondary
Time From Randomisation to First Subsequent Therapy or Death (TFST)
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of TFST
Time frame: Time elapsed from randomisation to first subsequent therapy or death. Assessed every 12 wks following treatment discontinuation, through study completion (up to 83 months)
Secondary
Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of PFS2
Time frame: At baseline, every 9 to 18 wks, then every 12 wks until objective radiological disease progression. Assessments then per local practice every 12 wks until second progression. Assessed until 12Apr2023 DCO (08Jul2024 DCO for China cohort), up to 50 months
Population: FAS consisting of all patients randomised as part of global enrolment including patients from China who were randomised before the global recruitment was closed (up to and including 20 Apr 2022). China FAS includes all patients who were randomised at sites in China and Hong Kong.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Global Cohort - SoC | Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | 19.1 Months |
| Global Cohort - SoC + Durvalumab | Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | 22.2 Months |
| Global Cohort - SoC + Durvalumab + Olaparib | Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | NA Months |
| China Cohort - SoC | Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | 24.2 Months |
| China Cohort - SoC + Durvalumab | Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | 19.7 Months |
| China Cohort - SoC + Durvalumab + Olaparib | Time From Randomisation to Second Progression or Death (PFS2) Based on Local Standard Clinical Practice | 15.3 Months |
95% CI: [0.59, 1.07]Regression, Cox
95% CI: [0.4, 0.76]Regression, Cox
95% CI: [0.48, 2.21]Regression, Cox
95% CI: [0.68, 2.9]Regression, Cox
Secondary
Time From Randomisation to Second Subsequent Therapy or Death (TSST)
To determine the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy in newly diagnosed advanced or recurrent endometrial cancer patients by assessment of TSST
Time frame: Time elapsed from randomisation to second subsequent therapy or death. Assessed every 12 wks following treatment discontinuation, through study completion (up to 83 months)