HR (95% CI) / RRR (%)

0.82 (0.70, 0.95) / 18

0.83 (0.71, 0.97) / 17

0.83 (0.72, 0.96) / 17

0.83 (0.76, 0.90) / 17

Superiority p-value

0.0074

0.0215

0.0134

< 0.0001

First radiation to bone

Median time (months)

NR

NR

NR

NR

NR

28.6

NR

33.2

HR (95% CI) / RRR (%)

0.74 (0.59, 0.94) / 26

0.78 (0.63, 0.97) / 22

0.78 (0.66, 0.94) / 22

0.77 (0.69, 0.87) / 23

Superiority p-value

0.0121

0.0256

0.0071

< 0.0001

NR = not reached; NA = not available; HCM = hypercalcaemia of malignancy; SMR = skeletal morbidity rate; HR = Hazard Ratio; RRR = Relative Risk Reduction †Adjusted p-values are presented for Studies 1, 2 and 3 (first SRE and first and subsequent SRE endpoints); *Accounts for all skeletal events over time; only events occurring  21 days after the previous event are counted.

** Including NSCLC, renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, GI/genitourinary cancer and others, excluding breast and prostate cancer

Figure 1. Kaplan-Meier plots of time to first on-study SRE

Disease progression and overall survival

Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three-studies combined.

In all three studies overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and 95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91, 1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). A post-hoc analysis in study 2 (patients with other solid tumours or multiple myeloma) examined overall survival for the 3 tumour types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between XGEVA and zoledronic acid in other tumour types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n = 894). This study did not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]) (see section 4.4).

Effect on pain

The time to pain improvement (i.e.,  2 point decrease from baseline in BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and the integrated analyses. In a post-hoc analysis of the combined dataset, the median time to worsening pain (> 4-point worst pain score) in patients with mild or no pain at baseline was delayed for XGEVA compared to zoledronic acid (198 versus 143 days) (p = 0.0002).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with XGEVA in one or more subsets of the paediatric population in bone metastases (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Following SC administration, bioavailability was 62% and denosumab displayed non-linear pharmacokine