Xgeva is used in men with advanced and metastatic prostate cancer with bone metastases for the prevention of developing additional skeletal-related events (not to be confused with bone mineral density).
In a phase 3 trial, the 147 Study, evaluating denosumab (Xgeva) versus placebo 1,432 men with castrate-resistant prostate cancer demonstrated that Xgeva improved median bone metastasis-free survival by 4.2 months (HR=0.85, 95 percent CI 0.73-0.98, p=0.03) compared to the placebo group (primary endpoint), and significantly improved time to first occurrence of bone metastases (secondary endpoint). The overall survival was similar between the Xgeva and placebo groups (secondary endpoint). Despite this, the FDA did not approve Xgeva for use with men who have not yet developed an initial bone metastases!
Xgeva’s main competition is from the old stand by drug zoledronic acid (Zometa). In a phase 3 head-to-head trial involving 1.901 men with prostate cancer and existing bone metastases directly comparing Xgeva to Zometa in preventing additional bone complications (called skeletal-related events or SREs) demonstrated Xgeva to be superior compared to Zometa in preventing SREs. Based on this trial, like Zometa, the FDA has approved Xgeva for the prevention additional SREs.
Xgeva is a powerful drug and is contraindicated in men with pre-existing hypocalcaemia, which is the presence of low serum calcium levels in the blood. Blood calcium levels are tightly regulated within a narrow range for proper cellular processes and Xgeva can make existing low calcium levels worse, even fatal. Also some men are allergic to Xgeva and should not be taken by anyone who is sensitive to the drug itself.
As mentioned, Xgeva can cause severe symptomatic hypocalcaemia, which has proven to be fatal, so constant monitoring of serum (blood) calcium levels is vital.
Other significant adverse side effects seen with the use of Xgeva are osteonecrosis of the jaw (ONJ) and serious atypical femoral fractures.
Additionally, less significant, but common side effects include pyrexia (fever), fatigue, bone pain, arthralgia (joint pain), and chills.
Using Xgeva can delay the development of new SREs, but it is a powerful drug with the potential of serious side effects.
1. XGEVA® (denosumab) prescribing information, Amgen.
2. Data on file, Amgen.
3. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48(16):3082-3092.
4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066.
5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653.
6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507.
7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development.BioDrugs. 2010;24:23-39.
8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-
Joel T. Nowak, M.A., M.S.W.