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Background
Skeletal-related events (SREs) cause significant morbidity in patients with solid
tumours and bone metastases (BMs). An ad hoc analysis was undertaken to compare the effect of denosumab with zoledronic acid (ZA)
in the prevention of SREs in patients with BMs secondary to solid tumours who participated
in the denosumab pivotal phase 3 studies.
Methods
Patients with breast cancer (N = 2046), prostate cancer (N = 1901), or other solid tumours (N = 1597) and BMs were randomly assigned in a 1:1 ratio to receive subcutaneous denosumab
120 mg or IV ZA 4 mg (adjusted for renal function) every 4 weeks. Patient-level data from three identically
designed, double-blind, double-dummy studies were combined. Time to first on-study
SRE and time to first and subsequent SREs were analysed using the Cox proportional
hazards model and Anderson–Gill method, respectively.
Findings
Patients received denosumab (N = 2776) or ZA (N = 2768). Denosumab was superior to ZA in delaying time to first on-study SRE and time
to first and subsequent SREs. Denosumab reduced the risk of a first SRE by 18% compared
with ZA (HR 0.82 [95% confidence interval (CI): 0.75, 0.89], p < 0.0001), reflecting a delay in median time to first SRE of 8.2 months. Denosumab also
reduced the risk of first and subsequent SREs by 19% (HR 0.81 [95% CI: 0.74, 0.88],
p < 0.0001) compared with ZA. Disease progression and survival were similar between groups.
Incidence of adverse events (96.2% of denosumab group and 96.7% of ZA group), serious
adverse events (56.2% of denosumab group and 57.3% of ZA group), and osteonecrosis
of the jaw (1.7% of denosumab and 1.3% of ZA; p = 0.18) were similar in both groups. Hypocalcaemia was more frequent with denosumab
(9.5% versus 4.8% for ZA) and acute phase reactions (first 3 days) were more common
with ZA (20.4% versus 8.7% for denosumab).
Interpretation
This integrated analysis confirmed results from the individual studies; denosumab
was superior to ZA in reducing the risk of both first and multiple SREs among patients
with solid tumours and BMs.
Funding
Amgen Inc.
A.T. Stopeck is a consultant for Amgen and Novartis; G. Richardson has received honoraria
and research funding from Amgen; S. Siena has no conflicts of interest to declare;
A. Lipton is a member of the speakers’ bureau, is a consultant, has received research
support from Amgen and Novartis, and has provided expert testimony for Novartis; J.
Brown has received consultancy fees from Amgen and Novartis, and payment for lectures
from Amgen, Novartis, and Bayer; K. Fizazi has participated in Advisory Boards for
Amgen and Novartis; D. Henry is a member of the speakers’ bureau, has participated
in research and advisory boards for Amgen and Johnson and Johnson; F. Saad is a consultant
and has carried out research for Amgen and Novartis; C. Ke and A. Braun are employed
by Amgen and own stock.
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Identification
Copyright
© 2012 Published by Elsevier Inc.
