DIAGNOSIS AND 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/per-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
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
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
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).
NON INCLUSION CRITERIA:
1. Patients without olaparib targetable genomic anomaly identified during the screening
2. Gene variants (class 1, 2, and 3) of unknown significant prognostic for olaparib
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
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 >470 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 physiological doses, not exceeding 10 mg/day of
prednisone, or an equivalent corticosteroid.
15. 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
16. Active or prior documented inflammatory bowel disease (Crohn's disease, ulcerative
17. History of allogeneic organ transplant, including previous allogenic bone marrow
transplant or double umbilical cord blood transplantation.
18. Received live attenuated vaccination within 30 days prior to study entry.
19. 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).
20. Pregnant or breast feeding women.
21. Known hypersensitivity to durvalumab, olaparib, and/or fulvestrant or any of the
excipients of these products.
22. 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
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.
23. 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
24. Persons deprived of their liberty or under protective custody or guardianship.
25. Patients enrolled in another therapeutic study within 30 days prior inclusion.
26. Involvement in the planning and/or conduct of the study.