Bone Is One of the Most Common Sites for Metastases Affecting up to 75% of Patients with Advanced Prostate Canceri

Cambridge, UK, (April, 2011) – Amgen has announced the publication of results from a Phase 3 head-to-head trial that compared denosumab to Zometa® (zoledronic acid) in preventing bone complications called skeletal-related events (SREs) in 1,901 men with prostate cancer and bone metastases. The study, published in The Lancetii, met its primary and secondary endpoints and demonstrated denosumab's superiority compared to Zometa® in preventing SREs.

Denosumab was approved by the U.S. Food and Drug Administration (FDA) on Nov. 18, 2010 for the prevention of SREs in patients with bone metastases from solid tumours, including prostate cancer.iii Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma.iv Denosumab, the first and only FDA-approved RANK Ligand inhibitor, is a new treatment for advanced cancer patients with bone metastases in nearly a decade. Denosumab has not yet been approved in Europe.

Bone metastases, the spread of cancer to the bones, are a serious concern for patients with advanced cancer and present a considerable burden to the healthcare system.v vi Weakened bones due to metastases can lead to fractures and compression of the spinal cord and necessitate procedures including major surgery and radiation, designed to prevent or manage these bone complications.v The primary goal of treatment for bone metastases is to prevent the occurrence of debilitating and costly bone complications, which can disrupt a patient's life and cause disability, pain and hospitalisation.v

Denosumab is a fully human monoclonal antibody that binds to RANK Ligand, a protein essential for the formation, function and survival of osteoclasts (the cells that break down bone).vii Denosumab prevents RANK Ligand from activating its receptor, RANK on the surface of osteoclasts, thereby decreasing bone destruction.

This study is one of three pivotal phase 3 head-to-head trials comparing denosumab to Zometa®. In total, these studies, which formed the basis of the FDA’s approval, enrolled over 5,700 patients with advanced cancer.

An SRE consists of any of the following: fracture, radiation to bone, surgery to bone or spinal cord compression. All can be serious complications for advanced cancer patients. In this study, denosumab was superior to Zometa® in significantly delaying the time to first on-study SRE (hazard ratio 0.82, 95% CI: 0.71, 0.95; P = 0.008) with a median time to first on-study SRE of 20.7 months versus 17.1 months for Zometa®.ii Denosumab was also superior to Zometa® in significantly delaying the development of multiple SREs (time to first and subsequent on-study SRE) (hazard ratio 0.82, 95% CI: 0.71, 0.94; P = 0.008).

Overall rates of adverse events (AEs) and serious adverse events were generally similar between the two arms.ii Osteonecrosis of the jaw (ONJ) was infrequent, 22 patients receiving denosumab (2%), as compared with 12 patients receiving Zometa® (1%); the incidence of ONJ was not significantly different between treatment arms (P = 0.09). As with previous studies in advanced cancer patients, hypocalcaemia was more frequent in the denosumab arm. Overall survival and progression-free survival were similar between treatment arms. The most common AEs for denosumab were anaemia, back pain, and nausea, and the most common AEs for Zometa® were anaemia, back pain, and decreased appetite.

Study “103” is an international, phase 3, randomised, double-blind study comparing denosumab with Zometa® in the treatment of bone metastases in patients with advanced prostate cancer to prevent SREs.ii Patients enrolled in the study were randomised in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa® administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks adjusted for renal function as per the Zometa® label instructions. The study consisted of 1,901 patients with a median age of 71, who had bone metastases from castration resistant prostate cancer. The primary endpoint was time to first on-study SRE.

Denosumab can cause severe hypocalcaemia.iv Correct pre-existing hypocalcaemia prior to denosumab treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Advise patients to contact a healthcare professional for symptoms of hypocalcaemia.

Osteonecrosis of the jaw (ONJ) can occur in patients receiving denosumab. Patients who are suspected of having or who develop ONJ while on denosumab should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. The most common adverse reactions in patients receiving denosumab were fatigue/asthenia, hypophosphatemia, and nausea.

The most common serious adverse reaction in patients receiving denosumab was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcaemia.

Denosumab was approved by the FDA for the prevention of SREs in patients with bone metastases from solid tumours on Nov. 18, 2010. Denosumab is not indicated to prevent SREs in patients with multiple myeloma.

Amgen has also submitted marketing applications for denosumab in the European Union, Australia and Switzerland. In Japan, Amgen is working with its licensing partner, Daiichi-Sankyo Company, Limited and a marketing application was submitted.

Bone metastases occur in more than 1.5 millionviii patients with cancer worldwide and are commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75% of patients with metastatic disease.i

Approximately 50-70% of cancer patients with bone metastases will experience debilitating SREs.v ix x Events considered to be SREs include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation.xi Such events can profoundly disrupt a patient’s life and can cause disability and pain.xii xiii

The denosumab development programme demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumour types across the spectrum of cancer-related bone diseases. In addition, denosumab is approved by the FDA and EMA for the treatment of osteoporosis in postmenopausal women and marketed as Prolia® ▼. vii xiv

1. Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.
2. Fizazi, K., Carducci, M., et al Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study, Lancet 2011; 377:     813–22
3. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm234346.htm
4. Denosumab [prescribing information]. Thousand Oaks, Calif: Amgen; 2010.
5. Saad, F., Lipton, A. et al Pathologic Fractures Correlate With Reduced Survival in Patients With Malignant Bone Disease, Cancer 2007;110:1860–7.
6. Delea, T., Langer, C. The Cost of Treatment of Skeletal-Related Events in Patients with Bone Metastases from Lung Cancer, Oncology 2004;67:390-396
7. Prolia SmPC, EMA, 2010
8. R.E. Coleman and J.E. Brown in “Textbook of Bone Metastases”, John Wiley & Sons, 2005
9. Lipton A, Theriault RL, Hortobagyi GN. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 2000;88:1082-1090.
10. Rosen LS, Gordon D, Tchekmedyian NS, et al. Nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100:2613-2621.
11. Costa L, Badia X, Chow E, Lipton A, Wardley A. Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer. 2008; 16: 879-889.
12. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726–1733.
13. Saad F, Gleason DM, Murray R, et al. A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory Metastatic Prostate Carcinoma. Journal Ntl Cancer Inst 2002;19:1458-1468.
14. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm214150.htm