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