Presented at EAU on March 23, 2009

The drug Denosumab has shown itself both easy to tolerate by patients as well highly able to increases bone mineral density (BMD) when compared with placebo in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT).

The results of this multi-centre, randomized, double-blind, placebo-controlled, phase 3 study also showed that benefits reached significance usually within the first month of active treatment.

“Androgen deprivation therapy is the mainstay of treatment for recurrent and metastatic prostate cancer … [but] it has a variety of adverse effects, including accelerated bone loss and greater risk for fractures,” said principal investigator Matthew Smith, MD, Genitourinary Medical Oncology, The Clair and John Bertucci Center for Genitourinary Cancers, Massachusetts General Hospital, Boston, Massachusetts.

The researchers evaluated the effects of denosumab on BMD and fractures in men with nonmetastatic, hormone-sensitive prostate cancer receiving continuous ADT. Men aged younger than 70 years were required to have a history of osteoporotic fracture or low BMD (T score <-1.0 at the lumbar spine, total hip, or femoral neck).All men needed to be undergoing bilateral orchiectomy or to have initiated ADT with gonadotropin-releasing hormone agonists, to be expected to continue for 12 months or more, and to have an Eastern Cooperative Oncology Group performance status of 0 to 2.Exclusions included prostate-specific antigen (PSA) levels of more than 5 mg/mL after ADT of more than 1 month and a specific BMD T score <-4.0.In this study a total of 1,468 men were randomised to placebo (n = 734; mean age, 75.5 years) or denosumab 60 mg (n = 734; mean age, 75.3 years) every 6 months, as 6 doses over 36 months. All patients took daily supplements of calcium 100 mg and vitamin D 400 IU.Both groups had similar baseline clinical characteristics, including median ADT duration (23.8 vs 20.8 months), median PSA (0.15 vs 0.13 ng/mL), medium testosterone (8.00 vs 8.00 ng/dL), median serum C-telopeptide (0.61 vs 0.62 ng/mL), and mean BMD T scores for lumbar spine (-0.41 vs -0.31), femoral neck (-1.42 vs -1.41), and total hip (-0.88 vs -0.87).For the primary endpoint of change from baseline for lumbar spine BMD at 24 months, as measured by dual x-ray absorptiometry, denosumab showed significant benefit over placebo by 6.7% (P < .0001).Most of the secondary endpoints were also met for the denosumab benefits over control, including incidence of new vertebral fractures (relative risk, 0.38; P = .006), and changes from baseline for total hip (4.8%; P < .001) and femoral neck (3.9%; P < .001) BMD at 24 months, and for lumbar spine BMD at 36 months (P < .0001).There were also significant beneficial changes in total body BMD (4.0%; P < .0001); Dr. Smith stressed the benefit for distal 1/3 radius BMD (5.5%; P < .0001). "This is of particular interest because other antiresorptive agents, including bisphosphonates, do not increase BMD at cortical sites, such as distal radius," he said.With no changes in PSA levels during treatment, for the safety data "the rates of adverse events were similar between denosumab- and placebo-treated subjects, and those relating to discontinuation of treatment, serious adverse events, and deaths on study were also very similar," he added.There are two issues that need to be considered about this particular study. First, Amgen Inc., the drug manufacture, provided the funding for this study. Second, the trial did compare denosumab against the current standard of care drugs. So, its results need to greeted with some conservative caution.Joel T Nowak, MA, MSW