Oral clodronate extends prostate cancer survival …


… by 23 percent, but only in combination with hormone therapy in men with metastatic disease, and in a relatively small trial.

It has been well understood for some time that the bisphosphonates (drugs like clodronate, zoledronate/Zometa, and alendronate/Fosamax) might affect the development of symptomatic bone metastases in men with prostate cancer. So between 1994 and 1998, in the UK, the Medical Research Council (MRC) enrolled patients to two randomised, controlled trials (PR05 and PR04) designed to investigate the impact on sodium clodronate (an oral, first-generation bisphosphonate) on progression of disease. The article by Dearnaley et al., published yesterday in Lancet Oncology, provides the final results of long-term survival data with additional follow-up in both trials.

The structure of these two trials was as follows:

  • 311 men with metastatic disease were recruited to PR05 between 1994 and 1998.
  • 508 men with non-metastatic disease were recruited to PR04 from 1994 to 1997.
  • In PR05, all men had metastatic disease and were either starting or already responding to long-term hormone therapy.
  • In PR04, all men had non-metastatic disease, and most men had been or were being treated with radiotherapy, hormone therapy, or both.
  • In each trial, the patients were randomized to receive either four tablets of sodium clodronate (2,080 mg) per day or a matching placebo for up to 3 years (metastatic disease) or 5 years (non-metastatic disease).

So what did the results of these two trials show?

Let’s look first at the results of PR05, the trial in men with metastatic disease:

  • Data was available for 278/311 patients with metastatic disease who originally entered the trial.
  • 258/278 patients (93 percent) were reported to have died after a median follow-up of 11.5 years.
  • The patients who received clodronate showed a 23 percent overall survival benefit  (hazard ratio 0.77; p=0.032) compared with those who received placebo.
By contrast, in PR04, the trial in men with non-metastatic disease:
  • Data was available for 471/508 patients with non-metastatic disease who originally entered the trial.
  • 281/471 patients (60 percent) were reported to have died after a median follow-up of 12 years.
  • The patients who received clodronate showed no evidence of overall survival benefit (hazard ratio 1.12; p=0.94) compared with those who received placebo.
The authors of the study conclude that, “Long-term data from these trials show that … sodium clodronate, improves overall survival in men with metastatic prostate cancer who are starting hormone therapy, but there is no evidence of an effect in men with non-metastatic prostate cancer.”
There is little doubt that the resulst of this study will set off a series of further attempts to clearly demonstrate whether other, newer bisphosphonates (as well as yet-to-be approved drugs like denosumab), when given in combination with hormone therapy, can show better prostate cancer-specific and overall survival data when used in combination with hormone therapy in men with metastatic prostate cancer.

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