The US Food and Drug Administration (FDA) has approved the use of denosumab, developed by Amgen Inc. and marketed as Prolia, for the treatment of bone loss and consequent fracture risk following hormone-based treatments for breast and prostate cancer. Specifically, denosumab, which is a monoclonal antibody that binds to RANKL, a protein involved in bone resorption, has now been approved for men receiving androgen deprivation therapy for non-metastatic prostate cancer and for women treated with aromatase inhibitors for breast cancer. The drug has already been licensed for the prevention of fraction in post-menopausal women with osteoporosis and in patients with bone metastases from solid tumours.

Approval of denosumab for these two further indications is based on the results of two pivotal Phase III clinical trials, one in prostate and the other in breast cancer. The prostate cancer trial was led by Matthew Smith from the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA, for the international Denosumab HALT Prostate Cancer Study Group; the breast cancer trial was led by Georgina Ellis from Seattle Cancer Care Alliance, Seattle, Washington, USA. The primary end point for each trial was the change in bone mineral density measured at the lumbar spine between the baseline and the end of the study period.

Smith and his co-workers enrolled 1,468 men treated with androgen deprivation therapy for non-metastatic prostate cancer who were either over 70 years of age or considered at risk of developing fractures from bone density measurements or medical history.

The patients were randomized to receive six six-monthly injections of either denosumab or placebo by subcutaneous injection. A little over sixty percent of participants (63.6% in the denosmab group and 60.6% in the placebo group) completed the three-year study. Bone mineral density measurements were significantly higher in the denosumab group at all four of the skeletal points assessed and at all times from one to 36 months from study entry; lumbar spine values increased by a mean of 5.6% in the denosumab group compared to a decrease of 1.0% in the controls.

Furthermore, significantly fewer fractures were observed in patients receiving denosumab: 3.9% in the placebo group versus 1.5% in the denosumab group at 36 months, giving a relative risk of 0.38 (95% confidence interval 0.19 to 0.78, P = 0.006).

Similar results were observed by Ellis and her co-workers in a two-year trial of denosumab in post-menopausal women with low bone mass who were taking aromatase inhibitors for hormone receptor positive, non-metastatic breast cancer. A total of 252 women were randomized to receive four six-monthly subcutaneous injections of either denosumab or placebo, with randomization stratified by the length of time they had been taking hormone therapy prior to trial entry.

Bone mineral density at the lumbar spine changed over the study period by +4.8% in the denosumab group, compared to -0.7% in the control group. Subgroup analysis showed that women in the denosumab arm had higher bone mineral density measurements after 12 and 24 months regardless of age, body mass index, prior tamoxifen use or time since menopause, and most differences were statistically significant.

Both trials noted a higher incidence of arthralgia and back pain in the denosumab arm than in the placebo arm, but this was not severe, and no severe adverse events that could be definitely linked to denosumab use in either trial. The FDA concluded that there was enough evidence from both trials to license denosumab for both these important indications in oncology.

References

 Smith, M.R., Egerdie, B, Toriz, N.H. and 9 others, for the Denosumab HALT Prostate Cancer Study Group (2009). Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer. NEJM 361(8), 745-755. doi: 10.1056/NEJMoa0809003

 Ellis, G.K., Bone, H.G., Chlebowski, R., Paul, D., Spadafora, S., Fan, M. and Kim, D. (2009). Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res. Treat. 118(1), 81-7, doi: 10.1007/s10549-009-0352-y