Prostate cancer drug improves survival in men with metastases
12 August 2009
The results of a prostate cancer clinical trial have found that the drug oral sodium clodronate improves overall survival for men with advanced prostate cancer but not in men with localised disease. Findings showed a 23% relative decrease of death in the group allocated to clodronate*. The final results of the Medical Research Council’s PR04 and PR05 trials are published online in Lancet Oncology.
PR05 is the first clinical trial to show an overall survival benefit from using an oral bisphosphonate in addition to standard hormone therapy for men with cancer that has spread to bone (metastasised). Oral bisphosphonates like sodium clodronate can help to prevent the loss of bone mass. The men in the PR05 trial were starting, or already responding, to hormone therapy.
In contrast, the PR04 trial found no evidence that sodium clodronate is of any benefit when given to modify the effect of other treatment (usually hormone therapy, radiotherapy or both) for men with cancer that has not spread beyond the prostate.
Prostate cancer most commonly spreads to the bone and it has been suggested that bisphosphonates, such as sodium clodronate, a group of drugs that prevent the loss of bone mass, might improve the outcomes of patients with advanced prostate cancer.
Matthew Sydes Trial Statistician and Project Lead from the Medical Research Council Clinical Trials Unit said: “Most men diagnosed with localised prostate cancer today have an extremely good outlook, but prostate cancer still claims the lives of 10,000 men each year in the UK. Better treatments are still needed, and bisphosphonates may be an important weapon against prostate cancer spreading to bone. Sodium clodronate, as used in these trials, is not as potent as newer bisphosphonates, and the results suggest further research with such treatments.”
In 1994, two UK-led trials commenced to examine the effect of sodium clodronate in men with advanced or localised prostate cancer. In the first trial (PR05), 311 consenting men with advanced prostate cancer who were starting or responding to hormone therapy (standard care) for bone metastases were randomly allocated to take oral sodium clodronate or placebo for up to 3 years.
In the second trial (PR04), 508 consenting men with localised prostate cancer who were receiving standard care (usually treatment with radiotherapy, hormone therapy, or both) were randomly allocated to take oral sodium clodronate or placebo for up to 5 years. The primary results of the original trials, published 6 and 3 years previously, showed that men with advanced disease had a reduction in the development of symptomatic bone metastases and some improvement in overall survival, and that men with localised disease showed no improvement in overall survival or delay in the spread of cancer.
Matthew Sydes concluded: “This work highlights the importance of running clinical trials and we look forward to developing this work further with STAMPEDE, a follow-on trial that will assess a newer drug from the bisphosphonate class, zoledronic acid, which is many times more potent. Here, we have reported encouraging results.”
Original Research paper: Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials, will be published online in The Lancet, www.thelancet.com
STAMPEDE is a flagship trial for the MRC Clinical Trials Unit and the National Cancer Research Institute's Prostate Clinical Studies Group. It represents a major investment for Cancer Research UK and it is sponsored by the UK Medical Research Council. The trial is open in more than 50 centres all across the UK and more than 1000 men have joined the trial already. It will continue to recruit for another 3 years. The trial is also assessing the role of chemotherapy (with docetaxel) and a cox-2 inhibitor (celecoxib). Overall, there are 6 trial arms with all patients receiving hormone therapy: hormone therapy alone is the control arm. For more information see: www.stampedetrial.org
* (with a 95% confidence interval ranging between relative improvements of 2% and 40%). At 5 years, overall survival was 30% in the clodronate treated group and 21% in the placebo group and after 10 years, 17% vs 9% respectively. These were mature results: 93% of these men had now died. In men with localised disease, clodronate showed no benefit in overall survival—at 5 years, overall survival was 78% in patients given clodronate and 80% in patients given placebo, and after 10 years 48% vs 51% (this was a 12% relative worsening of risk, although a 95% confidence interval cannot rule out a true value that is an 11% relative improvement or a 42% relative worsening).
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