A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride versus placebo when administered to metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases treated with hormonal treatment background therapy

1. Have provided written informed consent.
2. Documentation of histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative adenocarcinoma of the breast must be available.
3. Tumors (from either primary or metastatic sites) must be ER+ defined as *10% positive tumor nuclei in the analyzed sample.
ER+/progesterone receptor positive (PR+) and ER+/ progesterone receptor negative (PR-)
4. Women (*18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy.
5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are eligible.
6. Subjects with bone dominant disease (with or without metastases in soft tissue including lymph nodes) with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by computed tomography (CT)/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes) and/or visceral metastases is allowed.
7. Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors v1.1 criteria.
8. Subjects must have received at least one line of hormonal therapy in the metastatic setting.
9. Subjects who are eligible for further standard of care endocrine treatment with any of the following administered as in second line or greater of hormone therapy in metastatic setting:
Selective estrogen receptors modulators such as tamoxifen and toremifene
Non-steroidal aromatase inhibitors such as anastrozole and letrozole
Steroidal aromatase inhibitors such as exemestane
Estrogen receptor down-regulators such as fulvestrant
10. Subjects must have experienced no more than 2 skeletal-related events (SREs)
11. Subjects must be on therapy with bisphosphonate or denosumab and are required to have been on such therapy for at least a months before the start of study treatment.
12. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
13. Life expectancy >/<= 6 months
14. Laboratory requirements:
o Absolute neutrophil count *1.5 x 109/L
o Platelet count *100 x 10_9/L without platelet transfusion within 4 weeks1 prior to randomization
o Hemoglobin *9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or erythropoietin within 4 weeks1 prior to randomization
o Total bilirubin *1.5 x institutional upper limit of normal (ULN) (except for subjects with documented Gilbert*s disease)
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) *2.5 x institutional ULN. AST and ALT values above the ULN must not be related to liver metastases
o Creatinine *1.5 x ULN
o Estimated glomerular filtration rate*30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease abbreviated formula
o International normalized ratio of prothrombin time (INR) and partial thromboplastin time (PTT) or activated PTT *1.5 x ULN at study entry. Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban, or aspirin (e.g. *100 mg daily) will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be required until stability is achieved for anticoagulants that require their monitoring as per local label.
o Serum albumin >30 g/L
o Pulse oximetry O2 saturation >92% if lung metastases are present
15. Able to swallow oral medication

1. HER2-positive breast cancer (IHC=3+, positive FISH, or positive CISH/other ISH validated assey); equivocal or unknown HER2 status
2. Subjects eligible for treatment with everolimus
3. Subjects with any of the following cancers:
Inflammatory breast cancer
Bilateral breast cancer or a history of 2 distinct breast cancers
4. History and/or presence of confirmed visceral metastases
5. Subjects who have either received chemotherapy for metastatic disease or are considered by the treating Investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/neoadjuvant disease is acceptable.
6. Subjects with any previous untreated or concurrent cancer that is distinct in primary site or histology from the cancer under study, except treated basal cell carcinoma or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before enrollment are allowed. All cancer treatments must be completed at least 3 years prior to study entry.
7. Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis.
8. Imminent or established untreated spinal cord compression based on clinical findings and/or MRI.
9. Prior treatment with radium-223 dichloride
10. Prior hemibody external radiotherapy.
11. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188
12. ECOG Performance Status > or = 2
13. Blood transfusions, platelet transfustion or use of erythropoietin within 4 weeks prior to randomization.
14. Use of biologic response modifiers, such as granulocyte macrophage colony-stimulating factor or granulocyte colony-stimulating factor, within 4 weeks prior to randomization
15. Treatment with an investigational drug or with any anti cancer treatments not permitted by the protocol, within 4 weeks prior to randomization
16. Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget*s disease of bone)
17. Any other serious illness or medical condition such as, but not limited to:
Any uncontrolled infection
Cardiac failure New York Heart Association Class III or IV
Crohn*s disease or ulcerative colitis
Bone marrow dysplasia
18. Previous assignment to treatment in this study
19. Brestfeeding women
20. Known hypersensitivity to the active substance or to any of the excipients of radium-223 dichloride
21. Known presence of osteonecrosis of the jaw
22. Patients with immediate life-threatening visceral disease, for whom chemotherapy is the preferred treatment option.
23. Lymphatic carcinomatosis.
24. Patients with ascites requiring paracentesis within 2 weeks prior to study entry.