A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2–negative hormone receptor–positive breast cancer and bone metastases

Abstract

Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223 (Ra-223), a first-in-class a emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat 2014). In patients with HER2- estrogen receptor∗ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) vs EXE alone. Ra-223 plus EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of Ra-223 vs placebo in these patients (NCT02258451 ). Methods: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and ≥ 2 bone or soft tissue mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment. Patients are randomized to receive (1:1) Ra-223 (50 kBq/kg IV) or placebo x 6 cycles q 4 wk plus EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N Amer v Asia), prior hormone therapy (1 v ≥ 2), and presence of visceral disease (yes v no). Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination.The primary end point is symptomatic skeletal event (SSE)-free survival. Secondary end points are overall survival; times to opiate use, pain progression, and chemotherapy; radiologic PFS; and safety. Assuming a 1-sided a of 0.1, 90% power, ∼ 160 SSEs will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive. Estimated enrollment is ∼ 311 patients. Currently, 29 patients are randomized.