Durvalumab, With Olaparib and Fulvestrant in Advanced ER+, HER2- Breast Cancer Patients.

NCT04053322 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: UC-0140/18122018-003832-57
• Study Type: interventional
• Target: 172
• Locations: 1 country
• Sites: 2

Brief Summary

This study evaluates 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 homologous recombination repair (HRR) or microsatellite instability (MSI) status.

Conditions

ER-positive and HER2-negative Metastatic or Locally Advanced Breast Cancer; a Germline or Somatic BRCA Mutation, or a Deleterious Alteration of Other Genes Involved in Homologous Recombination Repair (HRR) or in MSI Status

Outcome Measures

Primary Outcomes (1)

• Progression-free survival rate (PFSR)

  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

  24 weeks

Secondary Outcomes (5)

• The incidence of adverse events (Safety)

  6 years

• Overall Survival (OS)

  6 years

• Objective response rate (ORR)

  3 years

• Duration of response (DoR).

  3 years

• Progression-free survival (PFS)

  6 years

Study Arms (1)

Study Arm

EXPERIMENTAL

Drug: Durvalumab; Drug: Olaparib; Drug: Fulvestrant

Interventions

Durvalumab DRUG

Durvalumab will start 4 weeks after the first dose of olaparib (Cycle 2, Day 1) at 1500 mg intravenous (IV) every 4 weeks.

Study Arm

Olaparib DRUG

2 x 150 mg tablets taken in the morning and in the evening orally (2 X 300 mg daily)

Study Arm

Fulvestrant DRUG

Two intramuscular injections of 250 mg each on Cycle 1 Days 1 and 15, and then Day 1 of each subsequent 28-day cycle.

Study Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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 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.
• 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.
• 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.
• 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).
• Aspartate aminotransferase (AST)/Alanine aminotransferase (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.

You may not qualify if:

• 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. 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 (HBV; 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 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.
• 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.

Sponsors & Collaborators

• UNICANCER: lead
• ARCAGY/ GINECO GROUP: collaborator
• SOLTI Breast Cancer Research Group: collaborator

Study Sites (2)

Institut de Cancerologie de Montpellier

Montpellier, 34000, France

Location

Centre Henri-Becquerel

Rouen, 76000, France

Location

Related Publications (1)

• Guiu S, Balmana J, Lemercier P, Follana P, Goncalves A, Bigot F, Frenel JS, Brain E, Mailliez A, Chakiba Brugere C, Curtit E, Derbel O, Dalenc F, Derquin F, Duhoux F, Canon JL, Pimentel I, Chevalier LM, Buisson A, Guyonneau C, Lemonnier J, Delaloge S, Bachelot T. Combination of Olaparib, Durvalumab, and Fulvestrant in Patients with Advanced ER+/HER2- Breast Cancer and Selected Genomic Alterations: Results of the DOLAF Trial. Clin Cancer Res. 2025 Nov 14;31(22):4633-4643. doi: 10.1158/1078-0432.CCR-24-4221.

  PMID: 40986529 DERIVED

MeSH Terms

Interventions

durvalumab; olaparib; Fulvestrant

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Severine GUIU

  INSTITUT DE CANCEROLOGIE DE MONTPELLIER

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2019
• First Posted: August 12, 2019
• Study Start: August 26, 2019
• Primary Completion: November 15, 2023
• Study Completion (Estimated): August 1, 2027
• Last Updated: March 12, 2025

Record last verified: 2025-02

Locations

FR (2)