As reported in The Lancet Oncology by Robert Coleman, MD, FRCP, and colleagues, the phase III D-CARE trial has shown no benefit of adjuvant therapy with the RANKL inhibitor denosumab vs placebo in improving bone metastasis–free survival in women with moderate- to high-risk early breast cancer.
Robert Coleman, MD, FRCP
Study Details
The double-blind trial included 4,509 women with stage II or III breast cancer at moderate to high risk of recurrence from 389 sites in 39 countries. Patients were randomly assigned between June 2010 and August 2012 to receive subcutaneous denosumab at 120 mg (n = 2,256) or placebo (n = 2,253). Treatment was given every 3 or 4 weeks concomitantly with standard neoadjuvant or adjuvant chemotherapy for approximately 6 months and then every 12 weeks for a total of 5 years.
The primary endpoint was bone metastasis–free survival.
KEY POINTS
- Denosumab did not significantly improve bone metastasis–free survival vs placebo.
- No difference in disease-free survival was observed.
Bone Metastasis-Free Survival
The median follow-up was 67.2 months in the denosumab group and 67.3 months in the placebo group. Median bone metastasis–free survival was not reached in either group (hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.82–1.14, P = .70). Bone metastasis–free survival events occurred in 13% of the denosumab group vs 14% of the placebo group, including bone events in 7% vs 8%. Median disease-free survival was not reached in either group (HR = 1.04, P = .57). Disease-free survival events occurred in 20% vs 19% of patients.
Adverse Events
The most common grade ≥ 3 adverse events were neutropenia (15% vs 15%), febrile neutropenia (5% vs 6%), and leukopenia (3% vs 3%). Positively adjudicated osteonecrosis of the jaw occurred in 5% vs < 1% of patients. Atypical femur fracture occurred in nine patients (< 1%) vs no patients. Hypocalcemia of any grade occurred in 7% vs 4%.
The investigators concluded, “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.”
Dr. Coleman, of the Department of Oncology and Metabolism, University of Sheffield, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Amgen. For full disclosures of the study authors, visit thelancet.com.
