Randomized, double-blind study of denosumab versus zoledronic acid in the
treatment of bone metastases in patients with advanced cancer (excluding breast
and prostate cancer) or multiple myeloma.
Author(s): Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV,
Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J,
Jiang Q, Jun S, Dansey R, Yeh H.
Affiliation(s): Joan Karnell Cancer Center, Philadelphia, PA 19106, USA.
davidhenry@pennoncology.com
Publication date & source: 2011, J Clin Oncol. , 29(9):1125-32
PURPOSE: This study compared denosumab, a fully human monoclonal anti-receptor
activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA)
for delaying or preventing skeletal-related events (SRE) in patients with
advanced cancer and bone metastases (excluding breast and prostate) or myeloma.
PATIENTS AND METHODS: Eligible patients were randomly assigned in a double-blind,
double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or
intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily
supplemental calcium and vitamin D were strongly recommended. The primary end
point was time to first on-study SRE (pathologic fracture, radiation or surgery
to bone, or spinal cord compression).
RESULTS: Denosumab was noninferior to ZA in delaying time to first on-study SRE
(hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally
favorable, denosumab was not statistically superior to ZA in delaying time to
first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or
time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to
1.04; P = .14). Overall survival and disease progression were similar between
groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of
the jaw occurred at similarly low rates in both groups. Acute-phase reactions
after the first dose occurred more frequently with ZA, as did renal adverse
events and elevations in serum creatinine based on National Cancer Institute
Common Toxicity Criteria for Adverse Events grading.
CONCLUSION: Denosumab was noninferior (trending to superiority) to ZA in
preventing or delaying first on-study SRE in patients with advanced cancer
metastatic to bone or myeloma. Denosumab represents a potential novel treatment
option with the convenience of subcutaneous administration and no requirement for
renal monitoring or dose adjustment.
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