ER-positive and HER2-negative metastatic or locally advanced breast cancer with either a germline or somatic BRCA mutation, or a deleterious alteration of other genes involved in homologous recombination repair (HRR) or in MSI status. MedDRA version: 20.0 Level: LLT Classification code 10072740 Term: Locally advanced breast cancer System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864 MedDRA
Conditions
Sponsors
UNICANCER
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed ER-positive (=10%), HER2-negative (0, 1+, 2+, and no HER2 gene amplification by ISH), metastatic or locally advanced breast cancer that is not amenable to resection or radiation with curative intent. 2. Patients aged =18 years old (post-menopausal or pre-menopausal women and men). 3. Documented personal germline alteration in BRCA1 or BRCA2 that is predicted to be deleterious. Testing may be performed at any time prior to inclusion. OR Deleterious germline or somatic alterations implicated in the HRR pathway (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes (AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor next generation DNA sequencing performed at screening visit. A tumor biopsy sample must be available: if obtaining an adequate metastatic tumor biopsy is impossible (including bone metastasis), analyses will be done on a biopsy from the primary breast tumor. 4. Patients with a life expectancy =16 weeks. 5. ECOG performance status 0-1. 6. At least one evaluable lesion, either measurable or non-measurable that can be accurately assessed at baseline by CT-scan or MRI by RECIST v1.1. 7. Patients could have received 1 line of endocrine therapy (including CDK4/6 inhibitor, but excluding fulvestrant or mTOR inhibitor) and/or 1 line of chemotherapy in the metastatic setting. 8. Within 28 days prior to administration of study treatment, patients must have adequate organ and bone marrow functions: - Hemoglobin =10 g/dL with no blood transfusion in the past 28 days. - Absolute neutrophil count (ANC) =1.5 x 109/L. - Platelet count =100 x 109/L. - Total bilirubin =1.5 x institutional upper limit of normal (ULN). - AST/ALT =2.5 x institutional ULN unless liver metastases are present in which case AST/ALT levels must be =5 x ULN. - Estimated creatinine clearance = 51 mL/min according to the Cockcroft-Gault equation or based on a 24-hour urine test. 9. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. 10. Woman of childbearing potential patients must agree to use adequate contraception for the duration of trial participation and up to 3 months after the last dose of olaparib. Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception. 11. Patients having provided written informed consent prior to any study-related procedures. 12. Patient is willing and able to comply with the protocol for the duration of the study. 13. Patients must have national social insurance coverage (applicable only in France). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 58 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: 1. Patients without olaparib targetable genomic anomaly identified during the screening phase. 2. Gene variants (class 1, 2, and 3) of unknown significant prognostic for olaparib sensitivity. 3. Patients with history of other malignancy except non-melanoma skin cancer, in-situ cancer of the cervix, or solid tumors including lymphomas (without bone marrow involvement) curatively treated and with no evidence of disease for =5 years prior to study entry. 4. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia. 5. Patients with symptomatic uncontrolled brain metastases. In addition, treatment of the central nervous system disease must have finished (whole brain radiation, radiosurgery) at least 2 weeks before Cycle 1 Day 1. Patients must not require >10 mg of prednisone per day or an equivalent dose of other corticosteroids. 6. Prior treatment with a PARP inhibitor (including olaparib) and/or PD-1 or PD-L1 inhibitor (including durvalumab). 7. Patients having received anticancer chemotherapy or any other investigational therapy within 3 weeks prior of the study. Endocrine therapy must have been discontinued 7 or more days before Cycle 1 Day 1. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1. Biphosphonates and denosumab are allowed. 8. Major surgery within 2 weeks prior to registration. Patients must have recovered from earlier major surgery before registration. 9. Persistent toxicities (NCI-CTCAE grade =2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy (grade =2). 10. Patients with known history of bleeding diathesis or hemorrhage. 11. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 12. Patients considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, and active bleeding diatheses. Recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, or any psychiatric disorder that prohibits obtaining informed consent. 13. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. 14. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal or inhaled corticosteroids or systemic corticosteroids at ph
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of the combination of olaparib, durvalumab, and fulvestrant for the treatment of patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with BRCA gene alterations or alterations of genes involved in HRR or MSI status, in terms of the progression-free survival rate (PFSR) at 24 weeks.;Secondary Objective: Efficacy objective in the overall study population 1. To determine the efficacy in term of overall survival (OS). 2. To determine the efficacy in term of objective response rate (ORR). 3. To determine the efficacy in term of duration of response (DoR). 4. To determine the efficacy in term of progression-free survival (PFS). Efficacy objective in the germline BRCA mutated population 1. To determine the efficacy in term of OS. 2. To evaluate the efficacy in term of PFSR at 24 weeks. 3. To evaluate the efficacy in term of ORR. 4. To evaluate the efficacy in term of DoR. 5. To evaluate the efficacy in term of PFS. Safety objective in overall and germline BRCA mutated populations 1. To determine the safety of the combination of olaparib, durvalumab, and fulvestrant. Exploratory analysis to evaluate efficacy and safety of the combination will be performed in patients: 1. Previously treated with CDK4/6 inhibitors. 2. With different PD-L1 expression status.;Primary end point(s): The progression-free survival rate at 24 weeks defined as the percentage of patients alive without disease progression at 24 weeks after inclusion. PFSR will be evaluated by local investigator using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). The death of a patient for any cause within 24 weeks will be considered as failure. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy endpoint in the overall study population 1. OS is defined as the interval between the date of inclusion and the date of death from any cause. A patient alive will be censored at the last date of follow-up. The RECIST v1.1 will be used to determine: 2. The ORR defined as the percent of patients with a complete response (CR) or a partial response (PR). 3. The DoR defined as the duration between the time measurement criteria are first met for CR or PR until the first date that recurrent disease is objectively documented 4. PFS defined as the interval between the date of inclusion and the date of progression or death. A patient alive and without progression will be censored at the last date of follow-up. Efficacy endpoint in the germline BRCA mutated population will be evaluated in terms of OS, PFS, PFSR at 24 weeks, ORR and DoR. Safety endpoint in overall and germline BRCA mutated populations will be evaluated according to the NCI-CTCAE v5.0. Exploratory analysis to evaluate efficacy in terms of OS, PFS, ORR, and DoR and safety will be also performed in patients with: 1) prior CDK4/6 inhibitors ; 2) different PD-L1 expression status. ANCILLARY ENDPOINT(S): 1. Investigation of the association of the RAD51 assay with alterations of BRCA1/2 and other HRR genes in one hand, and with clinical response in another hand. 2. Investigation of the correlation between biomarkers (biochemical, genomic) of the immune cell population and ORR that will be evaluated according the irRECIST criteria. 3 ctDNA sequencing will be performed on plasma samples to assess pre/post treatment ctDNA mutational status. | — |
Countries
Belgium, France
Contacts
Public ContactProject Manager
UNICANCER
Outcome results
None listed