Denosumab delays bone metastases in prostate cancer trial

Most men with advanced prostate cancer are at high risk for developing bone metastases, the process by which cancer spreads to and weakens the bones. A serious health and financial concern, bone metastases can lead to fractures, spinal cord compression, pain and a need for radiation therapy or bone surgery. These complications are referred to collectively by clinicians as “skeletal-related events.”

Denosumab is an FDA approved drug for treating bone metastases in men with prostate cancer. It works by acting as an inhibitor of RANK ligand (RANKL), a protein associated with progression of prostate cancer in bone. Studies show that men with metastatic prostate cancer who took Denosumab lived longer without skeletal-related events than men who take a placebo or other medicines for bone health.

Given the evidence for preventing skeletal-related events, some doctors  have theorized that Denosumab may also be able to prevent metastases in men whose cancer has not yet spread. A new study published in Lancet last month offers insight into this important question.

A multinational group of researchers recruited 1400 men from 30 countries with nonmetastatic castrate resistant prostate cancer (CRPC) to participate in a two year trial. The men were free of bone metastases at the start of the study but were all determined to be at high risk. The purpose of the trial, which was sponsored by the pharmaceutical company that manufactures and markets the product, was to determine if denosumab impacted the rate of bone metastasis as well as the overall survival rate of the participants.

At the start of the study, researchers randomly assigned the men to one of two groups. Every four weeks for two years, one group received injections of denosumab while the other group received a placebo. Periodic bone scans and skeletal surveys were used to measure bone metastases during the study.

At the end of the study, the researchers found that bone metastasis was significantly delayed in men who took denosumab compared to those who were given a placebo. The men who received the drug developed bone metastasis over four months later than their counterparts. The researchers also found, however, that while denosumab impacted bone metastasis, it did not impact survival rate in either group.

Although these results suggest denosumab may slightly delay metastases in some men with nonmetastatic prostate cancer, temporarily reducing the risk of skeletal-related events, the drug’s benefits may be outweighed by its costs.  The decision to prescribe this medicine will require careful consideration between the doctor and patient.

Denosumab is an expensive drug, costing nearly twice as much as traditional treatment for bone metastases.  It is also associated with risky side effects,  such as osteonecrosisof the jaw –bone death that causes pain, limited range of motion, and increased risk of severe arthritis —  and hypocalcemia— a calcium deficiency that damages bones and can be life-threatening if left untreated. With the possibility of only a slight delay in the development of metastases and no impact on survival rate, there is no clear cut recommendation that will be applicable to all patients.

Evidence to date does not support the use of denosumab as a preventive agent for bone metastases in men with prostate cancer. This trial, however, resulted in important knowledge about the role of RANKL inhibitors in bone metastases, and a better understanding of prostate cancer progression in general. Future research will build on this knowledge to clarify the role of denosumab as well as other bone modifying agents that affect bone health in prostate cancer patients.

More information on denosumab and the latest prostate cancer research can be found in the 2011 Annual Report on Prostate Diseases.