Abstract PS14-01: Radium-223 in women with HR-positive bone-metastatic breast cancer receiving endocrine therapy: International phase 2, randomized, double-blind, placebo-controlled trial

Background: Approximately 65-75% of women with metastatic breast cancer (mBC) have skeletal involvement, which can result in bone pain, pathologic fractures, and spinal-cord compression (SCC), impairing quality of life and function. Radium-223 dichloride (Ra-223) is a targeted alpha-emitting radionucleotide therapy that is approved for treatment of bone metastases from castration-resistant prostate cancer, but has been little studied in mBC. Objective: To assess the efficacy and safety of Ra-223 in women with bone-metastatic hormone receptor (HR)-positive breast cancer receiving endocrine monotherapy. Methods: This international, phase 2, randomized, double-blind, placebo-controlled trial (NCT02258464) involved women ≥18 years with HER2-negative, HR-positive, bone-dominant (≥2 skeletal lesions) mBC. Women with 1-2 skeletal-related events before study entry, treated with ≥1 line of hormonal therapy in the metastatic setting and bone-supportive agents, were randomized 1:1 to receive Ra-223 55 kBq/kg or placebo intravenously every 4 weeks for up to 6 cycles, combined with local standard of practice endocrine monotherapy and bone-targeted therapy with denosumab or a bisphosphonate. The primary endpoint was symptomatic skeletal event-free survival (SSE-FS). SSE was defined as external beam radiotherapy to relieve skeletal symptoms, symptomatic pathologic fractures, SCC, cancer-related orthopedic surgery, or death from any cause. Secondary endpoints included overall survival (OS), radiologic progression-free survival (rPFS), pain measurements, and safety. Results: Considering the evolving treatment landscape and slow recruitment, enrollment was closed early, and patients who completed treatment were permitted to roll over early to a follow-up study. Of the planned 227 women, 99 were randomized (Ra-223 n=49, placebo n=50; median age 57 years, range 28-85 years; 89% postmenopausal). The median number of injections received was 6 (range 1-6) in both arms. Median SSE-FS was 30 months (80% confidence interval [CI] 22, 43) in the Ra-223 arm vs 18 months (80% CI 9, 28) in the placebo arm; hazard ratio 0.75 (95% CI 0.41, 1.36; P=0.334). Trends in favor of Ra-223 over placebo were found for OS and pain measurements (Table). Treatment-emergent adverse events (TEAEs) occurred in 96% of patients in the Ra-223 arm and 94% in the placebo arm; drug-related TEAEs occurred in 44% and 33% of patients, respectively, and grade 3/4 TEAEs in 31% and 39%, respectively. In the Ra-223 vs placebo arms, there were fewer serious TEAEs (6% vs 25%, respectively, most commonly bone pain), bone-associated TEAEs (21% vs 27%, respectively; fracture 4% vs 12%, respectively), and TEAEs leading to treatment discontinuation (2% vs 6%, respectively). Conclusion: Although the primary endpoint was not met, possibly because of the small sample size, early discontinuation of follow-up, and lower than anticipated event rates, numerical trends consistently favored Ra-223 over placebo for SSE-FS, OS, and bone pain measurements. The overall TEAE rate was similar in both arms, but fewer serious or severe TEAEs were observed with Ra-223 than placebo. Citation Format: Robert E. Coleman, Georgeta Fried, Sung-Bae Kim, Iryna Kuchuk, David Kiesl, Manuel Ramos, Joohyuk Sohn, Jonathan Siegel, Rui Li, Deise Uema, Volker Wagner, Hope S. Rugo. Radium-223 in women with HR-positive bone-metastatic breast cancer receiving endocrine therapy: International phase 2, randomized, double-blind, placebo-controlled trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-01.