Background: Treatment of bone-metastatic breast cancer (MBC) is limited. Multimodality therapy may improve symptom control and survival. In a phase 2a study of advanced breast cancer pts with bone-dominant and no visceral disease, Ra-223, a first-in-class α-emitter selectively targeting bone mets, reduced baseline bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat 2014). This study (NCT02258464) evaluates Ra-223 efficacy and safety vs placebo (pbo) in HER2^- hormone receptor⁺ breast cancer pts with bone mets receiving single-agent HT. Methods: Pts receive (1:1) Ra-223 50 kBq/kg IV or pbo q 4 wk (6 cycles) + concurrent single-agent HT + best supportive care. Stratification is by geographic region, prior lines of HT for MBC, and number of prior skeletal events. Pts are assessed for efficacy and safety, and followed to symptomatic skeletal event (SSE), radiologic progression, death, or withdrawal. Primary endpoint is SSE-free survival. Eligible pts are pre- or postmenopausal with estrogen receptor⁺, HER2^-, bone-dominant MBC with ≥ 2 bone mets and ≥ 1 or 2 prior SSEs (external beam radiotherapy for bone pain, pathologic bone fracture, spinal cord compression, orthopedic surgery). Pts had ≥ 1 line of HT for MBC; are taking bisphosphonates or denosumab for ≥ 1 month before study; are eligible for endocrine treatment; and have evaluable disease (RECIST 1.1), asymptomatic or mildly symptomatic bone disease (Brief Pain Inventory), ECOG score 0-1, and adequate hematologic, renal, and liver function. Pts may not have had visceral or brain mets or leptomeningeal disease, need for chemotherapy for mets, and untreated spinal cord compression. Assuming a 1-sided α of 0.1, power of 90%, ~ 119 SSEs are required for the analysis. Time-to-event variable analysis will use a log-rank test, accounting for stratification. Kaplan-Meier estimates and survival curves will be given for each treatment group. Safety analyses will be descriptive. Target enrollment is 227 pts. First pt first visit is expected in early 2015. Clinical trial information: NCT02258464