Adjuvant Denosumab in Early Breast Cancer (D-CARE): An International Multicentre Randomised Controlled Phase 3 Trial

Q: What was the goal of the D-CARE trial?

To determine whether denosumab combined with standard adjuvant or neoadjuvant systemic therapy and locoregional treatments increases bone metastasis-free survival in women with early breast cancer.

Q: How were patients treated in the denosumab vs placebo groups?

Patients received denosumab 120 mg or matching placebo subcutaneously every 3–4 weeks initially, then every 12 weeks, with treatment continuing to a total duration of 5 years.

Q: Did denosumab improve the primary endpoint of bone metastasis-free survival?

No. Bone metastasis-free survival did not differ significantly between groups (hazard ratio 0·97, 95% CI 0·82–1·14; p=0·70).

Q: What were the main safety concerns observed?

Grade 3 or worse events included neutropenia, febrile neutropenia, and leucopenia. Positively adjudicated osteonecrosis of the jaw occurred more often with denosumab, and treatment-emergent hypocalcaemia was also more frequent.

Jul 10, 2026

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Denosumab, a fully human monoclonal antibody targeting RANKL, was evaluated for whether adding it to standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments improves bone metastasis-free survival in women with stage II–III early breast cancer. In the double-blind, placebo-controlled D-CARE phase 3 trial, 4509 patients were randomized across 389 centers in 39 countries. Results showed no significant benefit for the primary endpoint and identified key adverse effects including osteonecrosis of the jaw and hypocalcaemia.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

Background

Methods

Study design and randomisation

Treatment regimen and endpoints

Findings

Interpretation

Funding

Articles Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial Robert Coleman, Dianne M Finkelstein, Carlos Barrios, Miguel Martin, Hiroji Iwata, Roberto Hegg, John Glaspy, Alvaro Montaño Periañez, Katia Tonkin, Ines Deleu, Joohyuk Sohn, John Crown, Suzette Delaloge, Tian Dai, Ying Zhou, Danielle Jandial, Arlene Chan Summary Background Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. Method: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3–4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with [ClinicalTrials.gov](ClinicalTrials.gov), NCT01077154 . Findings Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82–1·14; p=0·70) . The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%) . Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. Interpretation Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. Funding Amgen. Copyright © 2019 Elsevier Ltd. All rights reserved. Introduction Breast cancer is the most common cancer and the second leading cause of cancer-related death in women worldwide.1 Because of the osteotropic nature of disseminated cells from breast cancer, bone is the most frequent site of distant relapse, occurring in approximately 40% of all first distant recurrences.2 Up to 80% of patients with metastatic breast cancer will develop bone metastases during their disease course2 with substantial associated long-term morbidity and adverse effects on patients’ quality of

FAQs

What was the goal of the D-CARE trial?

To determine whether denosumab combined with standard adjuvant or neoadjuvant systemic therapy and locoregional treatments increases bone metastasis-free survival in women with early breast cancer.

How were patients treated in the denosumab vs placebo groups?

Patients received denosumab 120 mg or matching placebo subcutaneously every 3–4 weeks initially, then every 12 weeks, with treatment continuing to a total duration of 5 years.

Did denosumab improve the primary endpoint of bone metastasis-free survival?

No. Bone metastasis-free survival did not differ significantly between groups (hazard ratio 0·97, 95% CI 0·82–1·14; p=0·70).

What were the main safety concerns observed?

Grade 3 or worse events included neutropenia, febrile neutropenia, and leucopenia. Positively adjudicated osteonecrosis of the jaw occurred more often with denosumab, and treatment-emergent hypocalcaemia was also more frequent.

Jul 10, 2026

Upload by Logic