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Clinical Trial
. 2024 Apr;204(2):249-259.
doi: 10.1007/s10549-023-07147-z. Epub 2023 Dec 20.

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials

Hope S Rugo #  1   2 , Catherine H Van Poznak  3 , Patrick Neven  4 , Iwona Danielewicz  5 , Soo Chin Lee  6 , Mario Campone  7 , Jeannie Y K Chik  8 , Estela Vega Alonso  9 , Bjørn Naume  10 , Etienne Brain  11 , Jonathan M Siegel  12 , Rui Li  12 , Deise Uema  12 , Volker J Wagner  13 , Robert E Coleman #  14   15
Affiliations
Clinical Trial

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials

Hope S Rugo et al. Breast Cancer Res Treat. 2024 Apr.

Abstract

Background: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases.

Methods: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory).

Results: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%.

Conclusions: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Keywords: Bone metastasis; Breast cancer; Endocrine therapy; Hormone receptor positive; Radium-223; Symptomatic skeletal event-free survival.

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Conflict of interest statement

HSR: Grants to institution from Astellas, AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi, Gilead, Lilly, Macrogenics, Merck, Novartis, Pfizer, Polyphor, Roche, Seattle Genetics, and Sermonix; honoraria from Mylan, NAPO, Puma, and Samsung. CVP: Research grant from Bayer for a study outside of the one associated with this manuscript; royalties from UpToDate; board member (unpaid) of Cancer and Bone Society, an independent organization that promotes international collaborations within the cancer and bone field in both clinical and basic research. PN: Research funding from Kom op Tegen Kanker; consulting fees from AstraZeneca, Lilly, Novartis, Pfizer, and Roche; consulting or advisory roles for Lilly, Novartis, Pfizer, and Roche. ID, YKC, EVA, BN: No conflicts to disclose. SCL: Research grants from ACT Genomics, Eisai, Pfizer, and Taiho; consulting/advisory roles for, and payment/honoraria from, AstraZeneca, Daiichi-Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche; travel/meeting attendance support from Pfizer and Roche. MC: Payment and/or honoraria from Amgen, Gilead, GSK, Merck Sharp & Dohme, Novartis, Pfizer, and Seagen (to institution) and from Lilly, Pierre Fabre, and Sanofi (to self). EB: Consulting fees from Daiichi-Sankyo, Pfizer, and Sandoz; payment and/or honoraria from Eli Lilly, Pfizer, and Seagen; travel/meeting attendance support from Pfizer and Sandoz; consultancy/advisory role for Daiichi-Sankyo. JMS: Employee of Bayer; stock ownership in Bayer AG; leadership and/or committee roles in Pharmaceutical Industry Working Group on Estimands in Oncology, Society for Clinical Biostatistics Subcommittee for Statistics in Regulatory Affairs, and American Statistical Association. RL, DU, VW: Employee of Bayer. REC: Consulting fees from Sanofi; payment/honoraria from Amgen and Beigene; patent for MAF gene test and stock options with Inbiomotion; consultancy/advisory role for AstraZeneca.

Figures

Fig. 1
Fig. 1
Kaplan–Meier estimates of efficacy endpoints a Symptomatic skeletal event-free survival (SSE-FS) (primary endpoint), b radiographic progression-free survival (rPFS) (secondary endpoint), c overall survival (OS) (secondary endpoint), and d time to bone alkaline phosphatase (ALP) progression (exploratory endpoint): intention-to-treat population. Missing bone ALP measurements resulted in high patient censoring. CI confidence interval, HR hazard ratio
See this image and copyright information in PMC

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