Advanced Ovarian Cancer
Conditions
Keywords
Advanced Ovarian Cancer, Ovarian neoplasms
Brief summary
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.
Detailed description
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.
Interventions
DRUGBevacizumab
Bevacizumab by intravenous infusion. In tBRCAm cohort bevacizumab is optional according to local practice.
DRUGDurvalumab
Durvalumab by intravenous infusion
DRUGOlaparib
Olaparib tablets
DRUGPlacebo olaparib
Placebo tablets to match olaparib
Matching placebo for intravenous infusion
Standard of care chemotherapy
Sponsors
AstraZeneca
European Network of Gynaecological Oncological Trial Groups (ENGOT)
GOG Foundation
Myriad Genetic Laboratories, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
The study consists of 2 independent cohorts: 3 double-blind treatment arms cohort for patients with no tBRCA mutation, and a single open label arm cohort for patients with tBRCA mutation
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Female patients with newly diagnosed, histologically confirmed, advanced (Stage III-IV) high grade epithelial ovarian cancer including high grade serious, high grade endometriod, clear cell ovarian cancer or carcinosarcoma, primary peritoneal cancer and / or fallopian-tube cancer * Patients must be aged ≥18 years of age. For patients enrolled in Japan that are aged \<20 year * All patients should be candidates for cytoreductive surgery either: upfront primary surgery OR plan to undergo chemotherapy with interval debulking surgery * Evidence of presence or absence of BRCA1/2 mutation in tumour tissue * Mandatory provision of tumour sample for centralised tBRCA testing * ECOG performance status 0-1 * Patients must have preserved organ and bone marrow function * Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test Key
Exclusion criteria
Non-epithelial ovarian cancer, borderline tumors, low grade epithelial tumors or mucinous histology * Prior systemic anti-cancer therapy for ovarian cancer * Inability to determine the presence or absence of a deleterious or suspected deleterious BRCA mutation * Prior treatment with PARP inhibitor or immune mediated therapy * Planned intraperitoneal cytotoxic chemotherapy * Active or prior documented autoimmune or inflammatory disorders * Patients considered a poor medical risk due to a serious, uncontrolled intercurrent illness * Clinically significant cardiovascular disease * Patients with known brain metastases * History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study treatment and of low potential risk for recurrence (patients who have received prior adjuvant chemotherapy for early stage breast cancer may be eligible, provided that it was completed ≥3 years prior to registration, and that the patient remains free of recurrent or metastatic disease) * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Endometrial cancer FIGO Stage IA, Grade 1 or Grade 2 * Persistent toxicities CTCAE Grade \>2 caused by previous cancer therapy * Patients with a known hypersensitivity to olaparib, durvalumab or any of the excipients of these products and to the combination/comparator agents * Breast feeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) by Investigator Assessment Using Modified RECIST 1.1 - Full Analysis Set | 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 | 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. |
| Progression-free Survival (PFS) by Investigator Assessment Using Modified RECIST 1.1 - (Full Analysis Set, HRD Positive) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Subsequent Therapy (TFST) - (Full Analysis Set, HRD-positive) | 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. | 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 to Second Subsequent Therapy (TSST) - Full Analysis Set | 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. | 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 to Second Subsequent Therapy (TSST) - (Full Analysis Set, HRD-positive) | 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. | 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 to Treatment Discontinuation (TDT) - Full Analysis Set | Assessed through study completion, up to 73 months for global non-tBRCAm (DCO3 17MAR2025) and up to 46 months for and China (DCO1 17MAR2025) | 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 to Treatment Discontinuation (TDT) - (Full Analysis Set, HRD-positive) | Assessed through study completion, up to 73 months for global non-tBRCAm (DCO3 17MAR2025) and up to 46 months for and China (DCO1 17MAR2025) | 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. |
| Change From Baseline in Physical Function Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - Full Analysis Set | Assessed at week 96. | 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. |
| Change From Baseline in Physical Function Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - (Full Analysis Set, HRD Positive) | Assessed at week 96. | 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. |
| Change From Baseline in Global Health Status/QoL Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - Full Analysis Set | Assessed at week 96. | 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. |
| Change From Baseline in Global Health Status/QoL Score of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 Questionnaires - (Full Analysis Set, HRD Positive) | Assessed at week 96 | 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. |
| Summary of Serum Concentrations (μg/mL) of Durvalumab for Each Treatment - Non-tBRCAm Cohort With Primary Cytoreductive Surgery (Pharmacokinetic Analysis Set) | Assessed at Day 85 pre-dose, Day 183 pre-dose and 3 months after last dose of durvalumab. | To characterize the PK of durvalumab in combination with bevacizumab and olaparib. This was prespecified to be assessed only in Global Non-tBRCAm patients. |
| Summary of Plasma Concentrations (μg/mL) of Olaparib - Non-tBRCAm Cohort With Primary Cytoreductive Surgery (Pharmacokinetic Analysis Set) | Assessed on Day 148 post-dose (1-3 hours, 3-6 hours and 6-12 hours) | To determine olaparib plasma concentrations via sparse sampling for population PK analyses. This was prespecified to be assessed only in Global Non-tBRCAm patients. |
| Summary of ADA Responses During the Study for Durvalumab - Non-tBRCAm Cohort With Primary Cytoreductive Surgery (ADA Analysis Set) | 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 | To characterize the immunogenicity of durvalumab in combination with bevacizumab and olaparib. This was prespecified to be assessed only in Global Non-tBRCAm patients. |
| Progression-free Survival (PFS) by Investigator Assessment Using Modified RECIST 1.1 - Full Analysis Set | 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. | 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. |
| Overall Survival - Full Analysis Set | 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. | 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. |
| Overall Survival - (Full Analysis Set, HRD-positive) | 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. | 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 to Second Progression or Death Based on Local Standard Clinical Practice (PFS2) - Full Analysis Set | 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. | 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 to Second Progression or Death Based on Local Standard Clinical Practice (PFS2) - (Full Analysis Set, HRD-positive) | 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. | 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. |
| Objective Response Rate Based on Investigator Assessment (Full Analysis Set) | 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) | 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. |
| Objective Response Rate Based on Investigator Assessment (Full Analysis Set, HRD-positive) | 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) | 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. |
| Duration of Objective Response Based on Investigator Assessments (Full Analysis Set, HRD-positive) | 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). | 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. |
| Duration of Objective Response Based on Investigator Assessments (Full Analysis Set) | 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) | 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 to First Subsequent Therapy (TFST) - Full Analysis Set | 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. | 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. |
Countries
Austria, Belgium, Brazil, Bulgaria, Canada, China, Denmark, Finland, France, Germany, Hungary, Italy, Japan, Peru, Poland, Romania, South Korea, Spain, Turkey (Türkiye), United States
Contacts
PRINCIPAL_INVESTIGATORPhilipp Harter
European Network of Gynaecological Oncological Trial Groups (ENGOT)
PRINCIPAL_INVESTIGATORCarol Aghajanian
GOG
Participant flow
Recruitment details
Overall, 1407 patients were randomised into the study. Global Cohort: 1502 patients screened across 179 sites in 20 countries. 1130 were randomised in the Non-tBRCAm cohort and 154 allocated to the tBRCAm cohort. China Cohort: 134 patients screened across 29 sites; 124 were randomized. 1 patient in the China cohort was randomised prior to Global recruitment closure and hence included in both the Global and China cohort summaries. No patients in the tBRCAm cohort were enrolled from China
Pre-assignment details
This study planned to allocate/randomise approximately 1254 patients with newly-diagnosed advanced ovarian cancer patients. In addition, a China cohort of approximately 120 non-tBRCAm patients with newly-diagnosed advanced ovarian cancer patients was planned to be randomised.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 53.9 Years STANDARD_DEVIATION 9.4 |
| Age, Customized <65 | 981 Participants |
| Age, Customized >=65 | 427 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 10 Participants |
| Race/Ethnicity, Customized ASIAN | 52 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 0 Participants |
| Race/Ethnicity, Customized MISSING | 8 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants |
| Race/Ethnicity, Customized OTHER | 16 Participants |
| Race/Ethnicity, Customized WHITE | 997 Participants |
| Sex/Gender, Customized Female | 374 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 205 / 378 | 200 / 374 | 193 / 378 | 47 / 154 | 14 / 40 | 11 / 43 | 7 / 41 |
| other Total, other adverse events | 369 / 376 | 367 / 373 | 372 / 378 | 151 / 153 | 40 / 40 | 43 / 43 | 41 / 41 |
| serious Total, serious adverse events | 132 / 376 | 165 / 373 | 152 / 378 | 74 / 153 | 19 / 40 | 17 / 43 | 22 / 41 |
Outcome results
None listed