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
Authors: Coleman Robert E. , Fried Georgeta , Kim Sung-Bae , Kuchuk Iryna , Kiesl David , Ramos Manuel , Sohn Joohyuk , Siegel Jonathan , Li Rui , Uema Deise , Wagner Volker , Rugo Hope S. 
Published: February 2021

Abstract
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.
Efficacy endpoints with Ra-223 vs placebo in women with mBC on background hormone monotherapyRadium-223 (n=49)Placebo (n=50)Difference between treatment armsSSE-FS,* median (80% CI), months30.1 (21.8; 43.0)18.4 (9.1; 28.2)HR 0.745 95% CI 0.409, 1.356, P=0.3339†SSE, n (%)Overall13 (26.5)18 (36.0)External-beam radiotherapy13 (26.5)15 (30.0)Spinal-cord compression1 (2.0)1 (2.0)Symptomatic pathologic bone fracture5 (10.2)8 (16.0)Tumor-related orthopedic surgical intervention2 (4.1)4 (8.0)OS, median (80% CI), months43.0 (22.9; NE)32.4 (23.7; NE)HR 0.888 95% CI 0.458, 1.724, P=0.7259†rPFS, median (80% CI), months8.1 (5.7; 10.6)5.8 (5.1; 7.9)HR 1.02395% CI 0.640, 1.637, P=0.9227†Time to opiate use for cancer pain, median (80% CI), months21.3 (8.3; NE)20.2 (8.8; NE)HR 0.932 95% CI 0.374, 2.323, P=0.8785†Time to pain progression, median (80% CI), months14.8 (5.9; 21.3)8.8 (3.7; 14.3)HR 0.824 95% CI 0.452, 1.502, P=0.5240†Pain improvement rate, % (n/N evaluable)¶37.5 (12/32)25.7 (9/35)P=0.345‡Time to cytotoxic chemotherapy, median (80% CI), months16.0 (14.1; 22.4)17.3 (10.9; 27.6)HR 0.968 95% CI 0.535, 1.750, P=0.9128†*Primary endpoint. †Two-sided P-value, log-rank test, stratified by geographic region, prior lines of hormone therapy in the metastatic setting, and prior skeletal-related events). ‡Cochran–Mantel–Haenszel test (same strata). ¶Confirmed pain improvement was defined as a 2-point decrease in worst pain score from baseline over two consecutive assessment periods conducted at least 4 weeks apart, without an increase in pain management in patients with a worst pain score ≥2 at baseline.CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival; rPFS, radiologic progression-free survival; SSE, symptomatic skeletal events, SSE-FS, symptomatic skeletal event-free survival.
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.