This is a Phase III randomised, double-blind, multi-centre study to evaluate the efficacy and safety of durvalumab in combination with standard of care platinum based chemotherapy and bevacizumab followed by maintenance durvalumab and bevacizumab or durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer.
Eligible patients will be those patients with newly diagnosed, histologically confirmed advanced (Fédération Internationale de Gynécologie et d'Obstétrique \[FIGO\] Stage III-IV) ovarian, primary peritoneal cancer and/or fallopian-tube cancer. All patients should be candidates for cytoreductive surgery which could be conducted as immediate upfront primary surgery following diagnosis or can be conducted after initiation of platinum based neoadjuvant chemotherapy. All patients should be eligible to start first line platinum based chemotherapy in combination with bevacizumab. The study aims to evaluate the efficacy and safety of standard of care (SoC) platinum-based chemotherapy and bevacizumab followed by maintenance bevacizumab either as monotherapy, or in combination with durvalumab, or in combination with durvalumab and olaparib. Therefore, this study aims to see which combination allows patients to live longer without the cancer coming back or getting worse. The study is also looking to see which combination makes patients live longer and how the treatment and the cancer affects their quality of life.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1,407
Bevacizumab by intravenous infusion. In tBRCAm cohort bevacizumab is optional according to local practice.
Durvalumab by intravenous infusion
Olaparib tablets
Progression-free Survival (PFS) by Investigator Assessment Using Modified RECIST 1.1 - Full Analysis Set
To determine the efficacy of durvalumab in combination with platinum based chemotherapy and bevacizumab and continued as maintenance in combination with bevacizumab and olaparib versus SoC platinum based chemotherapy in combination with bevacizumab by assessment of PFS (using investigator assessment according to Response Evaluation Criteria in Solid Tumours version 1.1 \[RECIST 1.1\]) in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Per MTP, the comparison of SoC+D+O v SoC in the Non-tbRCAm patients is a primary endpoint. SoC+D v SoC is reported separately as a secondary endpoint. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. Assessed until primary analysis - (05DEC2022 for Global cohort, 17MAR2025 for China cohort) - upto 46 months
Progression-free Survival (PFS) by Investigator Assessment Using Modified RECIST 1.1 - (Full Analysis Set, HRD Positive)
To determine the efficacy of durvalumab and olaparib assessed by PFS in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Per MTP, the comparison of SoC+D+O v SoC in the Non-tBRCAm HRD positve population is a primary endpoint. SoC+D v SoC is reported separately as a secondary endpoint. Results for tBRCAm SoC+D+O are not presented as as this was prespecified to be assessed only in the Non-tBRCAm patients.
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. Assessed until DCO1 - (05DEC2022 for Global cohort, 17MAR2025 for China cohort) - upto 46 months
Progression-free Survival (PFS) by Investigator Assessment Using Modified RECIST 1.1 - Full Analysis Set
To determine the efficacy of durvalumab assessed by PFS in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Per MTP, the comparison of SoC+D v SoC is a secondary endpoint. SoC+D+O v SoC is reported separately as a primary endpoint. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
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Placebo tablets to match olaparib
Matching placebo for intravenous infusion
Standard of care chemotherapy
Research Site
Foothill Ranch, California, United States
Research Site
Los Angeles, California, United States
Research Site
Orange, California, United States
Research Site
San Francisco, California, United States
Research Site
Tampa, Florida, United States
Research Site
Augusta, Georgia, United States
Research Site
Hinsdale, Illinois, United States
Research Site
Indianapolis, Indiana, United States
Research Site
Towson, Maryland, United States
Research Site
Detroit, Michigan, United States
...and 204 more locations
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. For global cohort, assessed until DCO2 (18SEP2023) - up to 55 months. For China cohort assessed until DCO1 (17MAR2025) - 46 months.
Overall Survival - Full Analysis Set
To determine the efficacy of durvalumab and olaparib assessed by OS in the first line treatment patients with newly diagnosed advanced ovarian cancer. Overall survival (OS) is defined as the time from randomisation/allocation to death due to any cause regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
Time frame: Survival assessed every 12 weeks after RECIST 1.1 defined progression. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - up to 46 months.
Overall Survival - (Full Analysis Set, HRD-positive)
To determine the efficacy of durvalumab and olaparib assessed by OS in the first line treatment patients with newly diagnosed advanced ovarian cancer. Overall survival (OS) is defined as the time from randomisation/allocation to death due to any cause regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
Time frame: Survival assessed every 12 weeks after RECIST 1.1 defined progression. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - up to 46 months.
Time to Second Progression or Death Based on Local Standard Clinical Practice (PFS2) - Full Analysis Set
To assess the efficacy of durvalumab and olaparib in terms of PFS2 in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to second progression or death (PFS2) is defined as the time from the date of randomisation/allocation to the earliest of the progression event subsequent to first subsequent therapy or death. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
Time frame: Assessed every 12 weeks after RECIST 1.1 defined progression. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - 46 months.
Time to Second Progression or Death Based on Local Standard Clinical Practice (PFS2) - (Full Analysis Set, HRD-positive)
To assess the efficacy of durvalumab and olaparib in terms of PFS2 in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to second progression or death (PFS2) is defined as the time from the date of randomisation/allocation to the earliest of the progression event subsequent to first subsequent therapy or death. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
Time frame: Assessed every 12 weeks after RECIST 1.1 defined progression. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - 46 months.
Objective Response Rate Based on Investigator Assessment (Full Analysis Set)
To assess the efficacy of durvalumab and olaparib in terms of ORR (Complete Response + Partial Response) by investigator assessment by modified RECIST 1.1: 1. in all patients with evaluable disease at baseline 2. prior to surgery in those patients planned to have IDS with evaluable disease at baseline. Objective response rate (ORR) is defined similarly for the non-tBRCAm and tBRCAm cohorts as the number (percentage) of patients with at least one investigator-assessed visit response of CR or PR and will be based on a subset of all randomised/allocated patients who have evaluable disease at baseline per the site investigator.
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. Up to 55 months for global non-tBRCAm (DCO2 18SEP2023). Up to 46 for Global tBRCAm (DCO1 05DEC2022) and China (DCO1 17MAR2025)
Objective Response Rate Based on Investigator Assessment (Full Analysis Set, HRD-positive)
To assess the efficacy of durvalumab and olaparib in terms of ORR (Complete Response + Partial Response) by investigator assessment by modified RECIST 1.1 1. in all patients with evaluable disease at baseline 2. prior to surgery in those patients planned to have IDS with evaluable disease at baseline. Objective response rate (ORR) is defined similarly for the non-tBRCAm and tBRCAm cohorts as the number (percentage) of patients with at least one investigator-assessed visit response of CR or PR and will be based on a subset of all randomised/allocated patients who have evaluable disease at baseline per the site investigator. This was prespecified to be assessed only in the non-tBRCAm cohort.
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. Up to 55 months for global non-tBRCAm (DCO2 18SEP2023). Up to 46 for China (DCO1 17MAR2025)
Duration of Objective Response Based on Investigator Assessments (Full Analysis Set)
To assess the efficacy of durvalumab and olaparib in terms of duration of response (DoR) in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Duration of response (DoR) is defined similarly for the non-tBRCAm and tBRCAm cohorts using the corresponding FAS among patients with a response (CR or PR), as the time from the date of first documented response (i.e., the first time at which the visit response is PR or CR) according to modified RECIST v1.1 as assessed by the investigator until date of documented progression or death in the absence of disease progression. This was prespecified to be assessed only in the Global patients.
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. Up to 55 months for global non-tBRCAm (DCO2 18SEP2023). Up to 46 for Global tBRCAm (DCO1 05DEC2022)
Duration of Objective Response Based on Investigator Assessments (Full Analysis Set, HRD-positive)
To assess the efficacy of durvalumab and olaparib in terms of duration of response (DoR) in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Duration of response (DoR) is defined similarly for the non-tBRCAm and tBRCAm cohorts using the corresponding FAS among patients with a response (CR or PR), as the time from the date of first documented response (i.e., the first time at which the visit response is PR or CR) according to modified RECIST v1.1 as assessed by the investigator until date of documented progression or death in the absence of disease progression. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: At baseline, within 3 weeks of last dose of chemotherapy, then every 12 weeks for 3 years and thereafter every 24 weeks. Up to 55 months for global non-tBRCAm (DCO2 18SEP2023).
Time to First Subsequent Therapy (TFST) - Full Analysis Set
To assess the efficacy of durvalumab and olaparib in terms of TFST in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to start of first subsequent therapy or death (TFST) is defined as the time from randomisation/allocation to the earlier of first subsequent therapy start date following study treatment discontinuation, or death. This was prespecified to be assessed only in Non-tBRCAm patients.
Time frame: Assessed every 12 weeks following treatment discontinuation. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - up to 46 months.
Time to First Subsequent Therapy (TFST) - (Full Analysis Set, HRD-positive)
To assess the efficacy of durvalumab and olaparib in terms of TFST in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to start of first subsequent therapy or death (TFST) is defined as the time from randomisation/allocation to the earlier of first subsequent therapy start date following study treatment discontinuation, or death. This was prespecified to be assessed only in Non-tBRCAm patients.
Time frame: Assessed every 12 weeks following treatment discontinuation. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - up to 46 months.
Time to Second Subsequent Therapy (TSST) - Full Analysis Set
To assess the efficacy of durvalumab and olaparib in terms of TSST in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to second subsequent therapy or death (TSST) is defined as the time from randomisation/allocation to the earlier of the second subsequent anti-cancer therapy start date following study treatment discontinuation, or death. This was prespecified to be assessed only in Non-tBRCAm patients.
Time frame: Assessed every 12 weeks following treatment discontinuation. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - up to 46 months.
Time to Second Subsequent Therapy (TSST) - (Full Analysis Set, HRD-positive)
To assess the efficacy of durvalumab and olaparib in terms of TSST in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to second subsequent therapy or death (TSST) is defined as the time from randomisation to the earlier of the second subsequent anti-cancer therapy start date following study treatment discontinuation, or death. This was prespecified to be assessed only in Non-tBRCAm patients.
Time frame: Assessed every 12 weeks following treatment discontinuation. For global cohort, assessed until DCO3 (17MAR2025) - up to 73 months. For China cohort assessed until DCO1 (17MAR2025) - up to 46 months.
Time to Treatment Discontinuation (TDT) - Full Analysis Set
To assess the efficacy of durvalumab and olaparib in terms of TDT in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to permanent study treatment discontinuation or death (TDT) is defined as the time from randomisation/allocation to the earlier of the date of permanent study treatment discontinuation or death. This was prespecified to be assessed only in Non-tBRCAm patients.
Time frame: Assessed through study completion, up to 73 months for global non-tBRCAm (DCO3 17MAR2025) and up to 46 months for and China (DCO1 17MAR2025)
Time to Treatment Discontinuation (TDT) - (Full Analysis Set, HRD-positive)
To assess the efficacy of durvalumab and olaparib in terms of TDT in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Time to permanent study treatment discontinuation or death (TDT) is defined as the time from randomisation/allocation to the earlier of the date of permanent study treatment discontinuation or death. This was prespecified to be assessed only in Non-tBRCAm patients.
Time frame: Assessed through study completion, up to 73 months for global non-tBRCAm (DCO3 17MAR2025) and up to 46 months for and China (DCO1 17MAR2025)
Change From Baseline in Physical Function Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - Full Analysis Set
To determine the effects on HRQoL, global health status and ovarian cancer symptoms of the combination of durvalumab and olaparib in the first line treatment of non-tBRCAm patients with newly diagnosed advanced ovarian cancer. The physical functioning score is a score from 0 to 100. Higher scores on the physical functioning score indicate better health status/function. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed at week 96.
Change From Baseline in Physical Function Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - (Full Analysis Set, HRD Positive)
To determine the effects on HRQoL, global health status and ovarian cancer symptoms of the combination of durvalumab and olaparib in the first line treatment of non-tBRCAm patients with newly diagnosed advanced ovarian cancer. The physical functioning score is a score from 0 to 100. Higher scores on the physical functioning score indicate better health status/function. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed at week 96.
Change From Baseline in Global Health Status/QoL Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - Full Analysis Set
To determine the effects on HRQoL, global health status and ovarian cancer symptoms of the combination of durvalumab and olaparib in the first line treatment of non-tBRCAm patients with newly diagnosed advanced ovarian cancer. 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. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed at week 96.
Change From Baseline in Global Health Status/QoL Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - (Full Analysis Set, HRD Positive)
To determine the effects on HRQoL, global health status and ovarian cancer symptoms of the combination of durvalumab and olaparib in the first line treatment of non-tBRCAm patients with newly diagnosed advanced ovarian cancer. 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. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed at week 96
Summary of Serum Concentrations (μg/mL) of Durvalumab for Each Treatment - Non-tBRCAm Cohort With Primary Cytoreductive Surgery (Pharmacokinetic Analysis Set)
To characterize the PK of durvalumab in combination with bevacizumab and olaparib. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed at Day 85 pre-dose, Day 183 pre-dose and 3 months after last dose of durvalumab.
Summary of Plasma Concentrations (μg/mL) of Olaparib - Non-tBRCAm Cohort With Primary Cytoreductive Surgery (Pharmacokinetic Analysis Set)
To determine olaparib plasma concentrations via sparse sampling for population PK analyses. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed on Day 148 post-dose (1-3 hours, 3-6 hours and 6-12 hours)
Summary of ADA Responses During the Study for Durvalumab - Non-tBRCAm Cohort With Primary Cytoreductive Surgery (ADA Analysis Set)
To characterize the immunogenicity of durvalumab in combination with bevacizumab and olaparib. This was prespecified to be assessed only in Global Non-tBRCAm patients.
Time frame: Assessed pre-infusion at Cycle 2, Cycle 4, Cycle 6 and the third cycle of the maintenance phase as well as 3 months after last dose of durvalumab