Bisphosphonate associated with increased OS in metastatic prostate cancer

According to long-term survival data from the Medical Research Council PR05 and PR04 trials, sodium clodronate improved OS in men with metastatic prostate cancer. However, there was no evidence of benefit among men with non-metastatic disease.

“PR05 is the first trial, to our knowledge, to show an overall survival benefit conferred by an oral bisphosphonate when given in addition to standard hormone therapy to men with bone metastases who are starting or responding to hormone therapy for prostate cancer,” the researchers wrote.

In 2003 and 2007, similar results were published from the primary analyses of both studies: clodronate was associated with improved OS in men with metastatic disease (HR=0.80; 95% CI, 0.62-1.03) but not in men with non-metastatic disease (HR=1.02; 95% CI, 0.80-1.30).

PR05 included 311 men with metastatic disease who were starting or responding to long-term hormone therapy. The men were randomly assigned to four sodium clodronate tablets per day or matching placebo for up to three years.

The PR04 study included 508 men with non-metastatic disease who had radiotherapy, hormone therapy or both. These men were also randomly assigned to sodium clodronate or placebo for up to five years.

The long-term OS analysis was conducted five years after the preliminary data were published. The researchers obtained data from the National Health Service Information Center, which included information for 278 patients from PR05 and 471 from PR04.

Ninety-three-percent of men from PR05 and 60% from PR04 had died. Compared with placebo, sodium clodronate was associated with improved OS in men with metastatic disease (HR=0.77; 95% CI, 0.60-0.98), but not among those with non-metastatic disease (HR=1.12; 95% CI, 0.89-1.42).

Dearnaley DP. Lancet. 2009;doi:10.1016/S1470-2045(09)70201-3

In this paper, for the first time, the use of clodronate has been shown to improve survival in men with metastatic prostate cancer treated with hormone therapy. The five-year survival was 21% with placebo and 30% with clodronate (HR=0.77, 95% CI 0.60-0.98) in men with metastatic prostate cancer treated with clodronate; this survival advantage was not seen in men without metastases.

Although another bisphosphonate, zolendronic acid, has shown improvements in skeletal related events when given in men with castrate resistant metastatic prostate cancer, this article is the first to show potential activity of these agents on metastases that might affect survival. However, the study is limited by the rather small numbers (278 men), the lack of information of secondary treatments given to men in each arm (chemotherapy, etc), and most importantly, lack information on the number of patients receiving bisphosphonates in each arm after the treatment was completed (three years for the metastatic group).

– Alan So, MD

Assistant Professor in the Department of Urologic Sciences at the University of British Columbia,

Research Scientist at the Prostate Centre at Vancouver General Hospital