Denosumab better than current gold standard of zoledronic acid for preventing bone events in men with hormone-resistant prostate cancer

February 24, 2011

Prostate cancer in men usually becomes resistant to initial hormone treatment within a few years of diagnosis (and is thereafter called castration-resistant prostate cancer) and tumours begin to grow again and spread to other parts of the body (metastasis), including bones. This increases the risk of bone breakages and other bone events that cause significant disability and quality of life issues. An Article published Online First by The Lancet shows that a new drug denosumab is better than the current standard treatment of zoledronic acid for delaying and preventing bone events in men with castration-resistant prostate cancer. The Article is by Professor Karim Fizazi, Department of Cancer Medicine, University of Paris Sud, France, and colleagues.

Denosumab works by inhibiting the RANKL gene, which then lowers activity of the body's osteoclast cells responsible for re-absorbing (and therefore weakening) bone; zoledronic acid also inhibits osteoclasts but using a different mechanism.

In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate drugs (such as zoledronic acid) were enrolled from 342 centres in 39 countries. Patients were assigned 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks. Patients were organized so that previous skeletal-related events, prostate-specific antigen concentration, and chemotherapy within 6 weeks before randomisation for prostate cancer did not have an effect on the drug comparison. Supplemental calcium and vitamin D were strongly recommended for bone strengthening, and were taken by 90% of 950 patients in the denosumab group and 87% of 951 assigned to zoledronic acid. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression).

Median time to first on-study skeletal-related event was 20•7 months with denosumab compared with 17•1 months with zoledronic acid. Overall, 36% of patients had bone events in the denosumab group compared with 41% in the zoledronic acid group. Adverse events were recorded in almost all patients in both groups, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. Of the adverse events most likely related to the treatments, more events of hypocalcaemia (very low calcium concentrations) occurred in the denosumab group (13%) than in the zoledronic acid group (6%). Osteonecrosis of the jaw occurred infrequently (2% denosumab vs 1% zoledronic acid)

The authors say: "Therapeutic intervention targeting the RANKL pathway is a recent strategy in the management of skeletal complications of metastatic disease: denosumab is the first monoclonal antibody to be investigated for this purpose."

They say their study is one of three that have all confirmed the better performance of denosumab compared with zoledronic acid (one published, one in press) and conclude: "Denosumab represents a novel potential treatment option for the prevention of skeletal complications in patients with metastatic castration-resistant prostate cancer"

In a linked Comment, Dr Jeanny B Aragon-Ching, George Washington University Medical Center, Washington, DC, USA says that denosumab is a welcome addition to the options available for treatment of metastatic prostate cancer. She adds that since pain and fatigue were commonly reported in both groups, reports on how each drug affects quality of life would be informative. She concludes: "As with other agents that have been successful in the metastatic setting, moving this drug towards early stages of disease is the logical next step in identification of its other potential uses. Denosumab has already been shown to reduce skeletal fractures in men who are undergoing androgen-deprivation therapy without overt clinical metastasis. Clinical trials assessing the use of denosumab in the delay of onset of metastasis have been promising and will help further define its role in prostate cancer."
-end-
Professor Karim Fizazi, Department of Cancer Medicine, University of Paris Sud, France. T) + 33 1 42 11 43 17 E) fizazi@igr.fr / acrouan@igr.fr / aline.bailly@igr.fr / chloe.louys@igr.fr

Dr Jeanny B Aragon-Ching, George Washington University Medical Center, Washington, DC, USA. T) +1 202-741-2478 E) jaragonching@mfa.gwu.edu

For full Article and Comment, see: http://press.thelancet.com/prostatebone.pdf

NOTE: THE ABOVE LINK IS FOR JOURNALISTS ONLY; IF YOU WISH TO PROVIDE A LINK TO THE FREE ABSTRACT OF THIS PAPER FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62344-6/abstract

Lancet

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