Phase II Trial of Durvalumab, Olaparib, and Fulvestrant in ER-Positive, HER2-Negative Metastatic Breast Cancer with BRCA or HRR Gene Alterations

Trial ID: 2024-516847-23-00
Protocol: UC-0140/1812
Sponsor: Unicancer

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Diseases & Conditions

Breast cancer Breast cancer metastatic Hormone receptor positive breast cancer

Objectives

The primary objective of this study is to evaluate the **efficacy** of the combination of olaparib, durvalumab, and fulvestrant in patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with BRCA gene alterations or alterations in genes involved in homologous recombination repair (HRR) or microsatellite instability (MSI) status. The evaluation will focus on the progression-free survival rate (PFSR) at 24 weeks. This is clinically relevant as it aims to determine the potential of this combination therapy to improve outcomes in a specific subset of breast cancer patients, potentially offering a targeted treatment option.

Secondary objectives include:

Determining the safety of the combination in overall and germline BRCA mutated populations.
Assessing efficacy in terms of overall survival (OS), objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in both the overall study population and the germline BRCA mutated population.
Evaluating the efficacy in terms of PFSR at 24 weeks in the germline BRCA mutated population.
Conducting exploratory analyses to evaluate efficacy and safety in patients previously treated with CDK4/6 inhibitors and with different PD-L1 expression statuses.

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on various clinical outcomes and patient subgroups, further informing its potential clinical application.

Participants

The clinical trial involves participants diagnosed with **ER-positive** and **HER2-negative** metastatic or locally advanced breast cancer, characterized by either a germline or somatic BRCA mutation or a deleterious alteration of other genes involved in homologous recombination repair (HRR) or in MSI status. The study population includes both male and female subjects aged 18 years and older, encompassing post-menopausal, pre-menopausal, and perimenopausal women, as well as men. Participants are required to have a life expectancy of at least 16 weeks and an ECOG performance status of 0-1. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include histologically confirmed ER-positive, HER2-negative breast cancer that is not amenable to resection or radiation with curative intent, and participants must have received prior endocrine therapy with a CDK4/6 inhibitor in the metastatic setting. Adequate organ and bone marrow function are necessary, and participants must agree to use effective contraception during and after the trial. The trial population was selected based on these criteria, ensuring that participants have the necessary genetic alterations and health status to evaluate the efficacy of the combination treatment of olaparib, durvalumab, and fulvestrant.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of a combination therapy involving **olaparib**, **durvalumab**, and **fulvestrant** in patients with ER-positive, HER2-negative metastatic or locally advanced breast cancer. This trial is a phase II, randomized, double-blind, controlled study, with an estimated duration from August 2019 to February 2027. The primary objective is to assess the progression-free survival rate at 24 weeks, with secondary endpoints including overall survival, objective response rate, and duration of response. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed cancer type, BRCA gene alterations, and adequate organ function. Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments conducted using RECIST v1.1 criteria. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.

Participants are expected to be involved in the study for a maximum treatment period of 28 days per cycle, with the possibility of multiple cycles depending on individual response and tolerance. The trial includes specific conditions for early termination, such as disease progression, unacceptable toxicity, or withdrawal of consent. The study aims to provide comprehensive data on the safety and efficacy of the treatment regimen, contributing to the understanding of therapeutic options for this patient population. The trial is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

Treatment

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Faslodex** (fulvestrant) is provided as a 250 mg **solution for injection**. It is administered via **intramuscular use** with a maximum daily dose of 500 mg and a total dose of 1000 mg over a treatment period of 28 days. The active substance, fulvestrant, is of chemical origin and is manufactured by AstraZeneca AB.

**Lynparza** (olaparib) is available in two formulations: 100 mg and 150 mg **film-coated tablets**. Both formulations are administered orally. The maximum daily dose for each formulation is 600 mg, with a total dose of 16800 mg over 28 days. Olaparib is a chemical substance, also produced by AstraZeneca AB, and is used in the trial to evaluate its efficacy in combination with other treatments.

**IMFINZI** (durvalumab) is provided as a 50 mg/mL **concentrate for solution for infusion**. It is administered via **intravenous use** with a maximum daily and total dose of 1500 mg over the 28-day treatment period. Durvalumab is a protein-based substance, specifically categorized as "Protein - Other," and is manufactured by AstraZeneca AB. This medication is included in the trial to assess its potential benefits in combination therapy.

**Zoladex** (goserelin acetate) is administered as a 3.6 mg **implant** for **subcutaneous use**. The maximum daily and total dose is 3.6 mg, with a treatment period of 28 days. Goserelin acetate is a chemical substance produced by AstraZeneca AB. This medication is used in the trial to explore its effects in conjunction with other investigational drugs.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy of these medications, particularly in combination, for the treatment of ER-positive, HER2-negative breast cancer with specific genetic alterations. The study does not include any non-experimental treatments such as standard-of-care therapy or placebo. All medications are subject to changes in labelling and secondary packaging as part of the investigational medicinal product (IMP) requirements.

Efficacy

The efficacy of the combination of **olaparib**, **durvalumab**, and **fulvestrant** in the treatment of patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer will be assessed primarily through the **progression-free survival rate (PFSR)** at 24 weeks. This primary endpoint is defined as the percentage of patients alive without disease progression at 24 weeks after inclusion. The evaluation will be conducted by local investigators using the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). Any patient death within 24 weeks will be considered a failure.

Secondary efficacy endpoints include overall survival (OS), defined as the interval between the date of inclusion and the date of death from any cause, with patients alive being censored at the last date of follow-up. The objective response rate (ORR) will be determined as the percentage of patients achieving a complete response (CR) or partial response (PR) according to RECIST v1.1. The duration of response (DoR) will be measured from the time CR or PR criteria are first met until the first date of documented recurrent disease. Progression-free survival (PFS) will be calculated as the interval between the date of inclusion and the date of progression or death, with patients alive and without progression censored at the last follow-up date.

Exploratory analyses will evaluate efficacy in terms of OS, PFS, ORR, and DoR, as well as safety, in patients previously treated with CDK4/6 inhibitors and those with different PD-L1 expression statuses. Safety will be assessed according to the NCI-CTCAE v5.0 in both the overall and germline BRCA mutated populations.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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
Patients aged ≥18 years old (post-menopausal or pre/per-menopausal women and men).
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 Documented 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. Testing may be performed at any time prior to inclusion. Local NGS can be used but reports will have to be sent to central NGS platforms for validation. 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
Patients with a life expectancy ≥16 weeks
ECOG performance status 0-1.
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
In the metastatic setting: patients must have received 1 line of endocrine therapy with CDK4/6 inhibitor and could have received 1 line of chemotherapy. Note 1: Patient may have received tamoxifen in first intent (the patient will have received a maximum of 2 lines of ET) Note 2: Fulvestrant and mTOR inhibitor are not allowed
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.
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.
Woman of childbearing potential patients must agree to use adequate contraception for the duration of trial participation and up to 6 months after the last dose of olaparib. Male patients must use a condom during treatment and for 6 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.
Patients having provided written informed consent prior to any study-related procedures
Patient is willing and able to comply with the protocol for the duration of the study
Patients must have national social insurance coverage (applicable only in France)

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Exclusion Criteria

Patients without olaparib targetable genomic anomaly identified during the screening phase.
Gene variants (class 1, 2, and 3) of unknown significant prognostic for olaparib sensitivity.
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
Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia
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
Prior treatment with a PARP inhibitor (including olaparib) and/or PD-1 or PD-L1 inhibitor (including durvalumab).
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 and CDK4/6 inhibitor must have been discontinued 14 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.
Major surgery within 2 weeks prior to registration. Patients must have recovered from earlier major surgery before registration.
Persistent toxicities (NCI-CTCAE grade ≥2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy (grade ≤2).
Patients with known history of bleeding diathesis or hemorrhage.
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.
Patients considered at poor medical condition due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection, symptomaticcongestive 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.
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
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 physiological doses, not exceeding 10 mg/day of prednisone, or an equivalent corticosteroid.
Active or prior documented autoimmune disease within the past 2 years except for patients with vitiligo or psoriasis without systemic treatment during the past 2 years
Active or prior documented inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
History of allogeneic organ transplant, including previous allogenic bone marrow transplant or double umbilical cord blood transplantation
Received live attenuated vaccination within 30 days prior to study entry
Patients unable to swallow orally administered medication, patients with gastrointestinal disorders likely to interfere with the absorption of olaparib, and patients with long-term oral anticoagulant therapy (excluding Warfarin).
Pregnant or breast feeding women
Known hypersensitivity to durvalumab, olaparib, and/or fulvestrant or any of the excipients of these products
Concomitant use of a known :  Strong or moderate CYP3A inhibitors. The required washout period prior to starting olaparib is 2 weeks.  Strong or moderate CYP3A inducers. The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Warning: For men and pre/per-menopausal women who will receive goserelin (Zoladex®) in combination with study drugs, the use of concomitant drugs which can prolong the QT interval or induce Torsades de pointes should be evaluated with caution
Whole blood transfusions in the 120 days prior to study enrolment (packed red blood cells and platelet transfusions are acceptable, if outside of 28 days prior to treatment).
Persons deprived of their liberty or under protective custody or guardianship
Patients enrolled in another therapeutic study within 30 days prior inclusion
Involvement in the planning and/or conduct of the study.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	27 Aug 2019	7
France	Not Recruiting	27 Aug 2019	142
Spain	Not Recruiting	27 Aug 2019	23

Sites & Investigators

Research sites

Hospital Universitari General De Catalunya Hospital Vall d’Hebron Polyclinique De Limoges L'Hopital Prive Du Confluent

Investigators

Rafael L.Isabelle D.Frederic B.florence D.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
Lynparza 100 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	600	28	PRD6163465
IMFINZI 50 mg/mL concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS USE	1500	28	PRD6651398
Faslodex 250 mg solution for injection.	Test	SOLUTION FOR INJECTION	INTRAMUSCULAR USE	500	28	PRD3545745
Lynparza 150 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	600	28	PRD6152224
Zoladex 3.6 mg Implant	Test	IMPLANT	SUBCUTANEOUS USE	3.6	28	PRD395489