Olaparib and Radiotherapy in Inoperable Breast Cancer

Inclusion criteria

• ≥18 years of age
• Histological proven breast cancer or local recurrence of breast cancer which is inoperable or/and metastatic, including inflammatory breast cancer
• No participation in trial with neoadjuvant systemic treatment, except for previous contralateral breast cancer
• Tumor in breast accessible for biopsy
• WHO performance 0-2
• Life expectancy of at least 6 months
• Adequate hematological, renal and hepatic functions
• Hemoglobin 6.2 mmol/l
• Leucocytes 3.0 x 10E9/l

• Absolute neutrophil count 1.5x10E9/l
• Platelet count 100 x 10E9/l
• Total bilirubin ≤ 1.5 x ULN
• ASAT/ALAT ≤ 2.5 x ULN; or in the presence of liver metastases ≤ 5 x ULN
• Creatinine clearance 50 ml/min; measured or calculated
• Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 21 days of study treatment. Non-childbearing potential or postmenopausal is defined as:

• Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
• LH and FSH levels in post menopausal range for women under 50 years of age
• Radiation-induced oophorectomy with last menses > 1 year ago
• Chemotherapy-induced menopause with > 1 year interval since last menses
• Surgical sterilisation (bilateral oophorectomy or hysterectomy)
• Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards
• Signed written informed consent

Exclusion criteria

• Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within 3 weeks prior to start of therapy (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin ornitrosourea). Patient may continue the use of tamoxifen, aromatase inhibitor and LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids. The use of denosumab for bone disease is not allowed.
• Major surgery within two weeks of starting study treatment.
• Participation in other trial with investigational drug or treatment modality
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required.
• Prior ipsilateral radiotherapy to the chest or breast.
• Blood transfusion in the four weeks prior to study entry
• Persistent toxicities (CTC ≥ grade 2) with the exception of alopecia, caused by previous cancer therapy
• QT-interval > 470 msec
• Significant cardiovascular disease as defined by

• History of congestive heart failure defined as NYHA class III
• History of unstable angina pectoris or myocardial infarction up to 3 months prior to trial entry;
• Presence of severe valvular heart disease
• Presence of a ventricular arrhythmia requiring treatment;
• Uncontrolled hypertension
• Patients considered a poor medical risk due to:

• non-malignant systemic disease
• active, uncontrolled infection requiring parenteral antibiotics
• a serious, uncontrolled medical disorder; examples include, but are not limited to:

• uncontrolled major seizure disorder
• unstable spinal cord compression
• superior vena cava syndrome
• extensive bilateral lung disease on HRCT scan
• any psychiatric disorder that prohibits obtaining informed consent.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
• Patients with known active hepatic disease (i.e. Hepatitis B or C)
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear.
• Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication
• Concomitant medications:

• Any previous treatment with a PARP inhibitor, including Olaparib
• Patients receiving the following classes of inhibitors of CYP3A4 (see Section 6.4.2 for guidelines and wash out periods)

• Azole antifungals
• Macrolide antibiotics
• Protease inhibitors
• Patients with a known hypersensitivity to olaparib or any of the excipients of the product
• Breast-feeding women