The evidence supporting this protocol is provided by a phase 3 multicentre international randomised trial involving 1904 patients comparing denosumab with zoledronic acid alone in patients with castrate resistant prostate cancer.r
Between May 2006 and October 2009, 950 patients were randomised to receive 120 mg denosumab and 951 patients were randomised to receive 4 mg zoledronic acid (or equivalent creatinine-adjusted dose of zoledronic acid in patients with a baseline creatinine clearance of 60 mL/min) every 4 weeks.r
The primary end point was time to first on-study skeletal-related event (noninferiority analysis), and secondary end points were time to first on-study skeletal-related event (superiority analysis) overall survival, investigator-assessed overall disease progression, prostate-specific antigen concentration during the study, and change in bone turnover markers from baseline. Safety endpoints included frequency of treatment-emergent adverse events, changes in routine chemistry and haematology laboratory values, and presence of neutralising anti- denosumab antibodies.r
Efficacy
After a median time on study of 12.2 months for the denosumab group and 11.2 months for the zoledronic acid group, the median time to first on-study skeletal-related event was 20.7 months (95% CI 18.8–24.9) with denosumab compared with 17.1 months (15.0–19.4) with zoledronic acid (hazard ratio 0.82, 95% CI 0.71–0.95; p=0.0002 for non- inferiority; p=0.008 for superiority).r
Kaplan-Meier estimates of time to first on-study skeletal-related eventr
© Lancet 2011
Kaplan-Meier estimates (A) overall survival (B) time to disease progressionr
© Lancet 2011
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Toxicity
Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0.0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0.09).r
Toxicityr
© Lancet 2011