Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
OBJECTIVE
This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases.


METHODS
Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression).


RESULTS
Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39).


CONCLUSIONS
Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.
University of Arizona, Arizona Cancer Center, Tucson, AZ, USA. astopeck@azcc.arizona.edu
Alison T
AT
Stopeck
Allan
A
Lipton
Jean-Jacques
JJ
Body
Guenther G
GG
Steger
Katia
K
Tonkin
Richard H
RH
de Boer
Mikhail
M
Lichinitser
Yasuhiro
Y
Fujiwara
Denise A
DA
Yardley
María
M
Viniegra
Michelle
M
Fan
Qi
Q
Jiang
Roger
R
Dansey
Susie
S
Jun
Ada
A
Braun
D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001847:Bone Diseases / Q000209:etiology / Q000517:prevention & control*; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D000069448:Denosumab; D004164:Diphosphonates / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008875:Middle Aged; D053245:RANK Ligand / Q000627:therapeutic use*; D000077211:Zoledronic Acid
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053245:RANK Ligand; D000069448:Denosumab; D000077211:Zoledronic Acid