Background: Bone-metastatic breast cancer (MBC) treatment (tx) is limited. In a phase 2a study of bone-dominant MBC patients (pts), Ra-223, a first-in-class α emitter with targeted cytotoxic effect on bone metastases (mets), reduced bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat 2014). This study evaluates efficacy and safety of Ra-223 v placebo (pbo), each + endocrine treatment (ET) in pts with HER2^- estrogen receptor (ER)⁺ bone-dominant MBC (NCT02258464). Methods: Eligible pts are pre- or postmenopausal with HER2^- ER⁺ bone-dominant MBC with ≥ 2 bone mets, soft tissue mets, and 1-2 prior symptomatic skeletal events (SSEs) (external beam radiotherapy, pathologic bone fracture, spinal cord compression, orthopedic surgery) who have received ≥ 1 line ET for MBC and are considered appropriate for further ET. Eligible pts must have evaluable disease (RECIST 1.1), be taking bisphosphonates or denosumab for ≥ 1 mo before study tx, have an ECOG score 0-1, and have adequate heme, renal, and liver function. Pts must not have had visceral or brain mets or leptomeningeal disease, or need chemotherapy for MBC and must not be suitable for everolimus for MBC. Pts are not eligible if they have prior Ra-223 tx or untreated spinal cord compression. Pts receive (1:1) Ra-223 50 kBq/kg IV or pbo q 4 wk (6 cycles) + ET + denosumab or bisphosphonates + best supportive care. Stratification is by geographic region, number of prior ET lines (1 v ≥ 2) for MBC, and number of prior skeletal events (1 v 2). Pts are assessed for efficacy and safety, and followed to SSE, radiologic progression, death, or withdrawal. The primary end point is SSE-free survival. Secondary end points are radiologic progression-free survival; overall survival; times to opioid use, pain progression, and chemotherapy; pain improvement rate; and safety. Assuming 1-sided α 0.1, power 90%, ~ 119 SSEs are needed for analysis. Time-to-event analysis will use a log-rank test, accounting for stratification. Kaplan-Meier estimates and survival curves will be given for each tx group. Safety analyses will be descriptive. Currently, 25 pts are randomized. Clinical trial information: NCT02258464