by 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
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, 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 (<1 152="" 2218="" 82="" acute="" and="" consciousness.="" deaths="" depressed="" due="" group="" hypocalcaemia="" in="" leukaemia="" level="" myeloid="" o:p="" occurred="" of="" patients="" placebo="" the="" to="" treated="" treatment-emergent="" treatment-related="" two="" versus="" with="">
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.
