Abstract Background: Radium-223 dichloride (Ra-223), a first-in-class α-emitter with a potent, targeted antitumor effect on bone metastases (mets), was well tolerated and reduced baseline bone biomarker levels in a phase 2 study in metastatic breast cancer (MBC) patients (pts) with bone-dominant disease (Coleman et al. Breast Cancer Res Treat 2014). Adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) versus EXE alone in human epidermal growth factor receptor 2–negative (HER2-), hormone receptor–positive (HR+) MBC pts with advanced disease. This trial will evaluate efficacy and safety of Ra-223 with EXE and EVE in pts with HER2-, HR+ breast cancer and bone mets (NCT02258451). Trial design: Pts scheduled to receive EXE (25 mg PO once daily) and EVE (10 mg PO once daily) will be randomized 1:1 to Ra-223 (50 kBq/kg IV) or placebo × 6 cycles q4wk. EXE and EVE treatment (tx) will continue until disease progression, unacceptable toxicity, or the pt can no longer travel to the clinic to receive study medication. Stratification will be by geographic region, previous lines of hormone therapy, and presence of visceral disease. Safety and efficacy will be assessed at each 4-week clinic visit during tx. Long-term safety will be assessed until study termination (ie, pt death, pt loss to follow-up, or pt reaching required number of events). Main eligibility criteria: Eligible pts are pre- or postmenopausal with estrogen receptor–positive and HER2- bone lesion–related asymptomatic or mildly symptomatic MBC not amenable to cure by surgery or radiotherapy, and with ≥2 bone mets visible on bone scan. Pts must have measurable disease per RECIST v1.1, ≥1 prior line of hormonal therapy in the metastatic setting, and 1-2 skeletal related events before study entry; be on bisphosphonates or denosumab for ≥1 mo before study entry; and have ECOG performance status of 0-1, adequate hematologic, renal, and liver function, and life expectancy ≥6 mo. Pts may not have prior or current need for chemotherapy in the metastatic setting, unresolved spinal cord compression, and prior or current EVE tx. Specific aims: The primary endpoint is symptomatic skeletal event (SSE)–free survival. Secondary endpoints are overall survival, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, radiologic PFS (rPFS), and acute and long-term safety. Exploratory endpoints include time to first on-study SSE, time to bone alkaline phosphatase (bALP) progression, bALP response at wk 12 and end of tx, bone-specific rPFS, resource utilization, biomarker assessments, and time to visceral mets onset. Statistical methods: Assuming a one-sided α of 0.1, power of 90%, ∼160 SSEs will be required at the time of analysis. A stratified log-rank test will be used to analyze efficacy (intent-to-treat population). Safety analysis will be descriptive. Present and target accrual: This trial is now enrolling pts. Target accrual is 311. Citation Format: Rugo HS, Huang L, Petrenciuc O, Zaccarini P, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-11.