An analysis of patients with advanced solid tumours (excluding breast and prostate) and bone metastases included in a randomised, double-blind, phase 3 study found that denosumab reduced the occurrence of bone complications (SREs; pathological fracture, surgery or radiation to bone, or spinal cord compression) versus zoledronic acid (Henry D, et al. Support Care Cancer 2014;322:679–87). An alternative clinically relevant composite endpoint of SSEs (symptomatic fracture, surgery or radiation to bone, or spinal cord compression) has recently been introduced to also measure skeletal morbidity.
Adult patients with solid tumours, evidence of ≥1 bone metastasis and no prior intravenous (IV) bisphosphonates were randomised to receive either subcutaneous (SC) denosumab 120mg/IV placebo or IV zoledronic acid 4mg (adjusted for creatinine clearance)/SC placebo every 4 weeks. Patients were recommended to take daily oral calcium and vitamin D supplementation. This post-hoc SSE analysis includes symptomatic pathologic fractures (investigator decision), spinal cord compressions and the requirement for palliative or corrective surgery or radiation to bone.
Fewer patients who received denosumab than zoledronic acid had confirmed first and subsequent SREs, this was also the case when the definition of SSE was applied (Table). The median (95% CI) estimate of time to first SSE for denosumab was not reached (not estimable [NE], NE) and for zoledronic acid it was 21.8 (19.0, NE) months (HR = 0.81 [0.66, 0.99]; P = 0.04).
|Number of Confirmed Events||Denosumab (N = 800)||ZA (N = 797)||Hazard or Rate Ratio (95% CI)|
|First SSE, n (%)*||181 (22.7)||211 (26.5)||HR = 0.81 (0.66, 0.99) P = 0.04|
|First SRE, n (%)||236 (29.5)||277 (34.8)||HR = 0.81 (0.68, 0.96) P = 0.02|
|First and subsequent SSEs*||234||264||RR = 0.86 (0.71, 1.04) P = 0.11|
|First and subsequent SREs||328||374||RR = 0.85 (0.72, 1.00) P = 0.05|
*SSE analysis is based on actual stratum versus SRE analysis based on randomised stratum thus for SSE analysis N = 799
Skeletal morbidity improved with denosumab versus zoledronic acid, regardless of whether the endpoint was defined as SRE or SSE. The risk of developing first and multiple SSEs was reduced by up to 14% when comparing denosumab with zoledronic acid.
Clinical trial identification
Legal entity responsible for the study
R. von Moos: Advisory Boards: Amgen, Bayer, GSK, Novartis, Roche, Research Grant: Bayer. G. Scagliotti: Consultant for Eli Lilly; Received honoraria from AstraZeneca, Roche, Pfizer, Eli Lilly and Clovis Oncology. V. Hirsh: Honoraria for Advisory Boards: Amgen, Novartis, Roche, Pfizer, Astra Zeneca, Merck, Eli Lilly, BMS. H-S. Radcliffe: Employee of Amgen and holds Amgen stock. D. Niepel: Amgen employee and holds Amgen stock. D.H. Henry: Research grant from Amgen Inc. and was a consultant to and/or participated in an advisory board for Amgen Inc. All other authors have declared no conflicts of interest.