Bisphosphonates and Overall Survival for Prostate Cancer Patients

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a late analysis of two trials conducted to test whether an oral bisphosphonate would influence outcomes in patients with prostate cancer, it is apparent that for those with metastatic disease, treatment resulted in improved overall survival. However, for those patients who did not have metastatic disease, bisphosphonate treatment had no effect on overall survival. The study supports the role of drugs in this class for patients with metastatic prostate cancer, but it remains to be determined whether oral agents, such as clodronate, will be as effective as the newer agents that have become available since the initiation of this trial, over 15 years ago.

Source: Dearnaley DP, et al. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: Long-term overall survival results from the MRC PRO4 and PRO5 randomized controlled trials. Lancet Oncol. 2009;10:872-876.

In the mid 1990s, the medical research council (MRC) sponsored two trials to determine the effectiveness of an oral, first-generation bisphosphonate (clodronate) for patients with prostate cancer. The first trial, PR04, evaluated patients with non-metastatic disease, whereas the second, PR05, evaluated those with metastatic disease. The primary reports for both trials have been published,1,2 and the purpose of the current report was to present the long-term data, particularly with regard to overall survival.

Men with metastatic disease (n = 311) were recruited to PR05 between 1994 and 1998 and those with non-metastatic disease (n = 508) to PR04 from 1994 to 1997. All men were treated according to the recruiting site's standard practice at the time: for metastatic disease, all men were either starting or responding to long-term hormone therapy; for non-metastatic disease, most men had radiotherapy, hormone therapy, or both. Men were randomly assigned to take four tablets per day of sodium clodronate (total daily dose, 2080 mg) or matching placebo for up to three years (metastatic disease) or five years (non-metastatic disease). Long-term overall survival was assessed on an intention-to-treat basis in all men at sites in England and Wales using data from the National Health Service Information Center, which held data for 278 of the 311 men in the PR05 trial and 471 of the 508 men in the PR04 trial. PR04- and PR05-enrolled subjects who lived in Scotland or New Zealand were not included in this final analysis because their records were not accessible through the National Health Service Information Center.

Of the 278 men with metastatic disease, 258 (93%) died. Evidence of a benefit for those with metastatic disease from use of sodium clodronate compared with placebo was seen in overall survival (hazard ratio [HR] 0.77, 95% CI 0.60-0.98; p = 0.032). Of the 471 men with non-metastatic disease, 281 (60%) were reported to have died and, in this cohort, there was no evidence of improvement in overall survival with clodronate compared with placebo (HR 1.12, 0.89-1.42; p = 0.94).

Commentary

These trials, first launched about 15 years ago, were among the first to look at the role of bisphosphonates in the management of prostate cancer. Since then, a number of studies have demonstrated the value of drugs in this class, particularly for patients with myeloma or breast cancer. For patients with multiple myeloma, it has long been known that intravenous pamidronate was a useful treatment for disease-associated hypercalcemia. However, reduced bone pain, improved quality of life, and possibly even slower tumor growth and improved survival have been reported, and the more general use of bisphosphonates in this disease is reflected by the recent American Society of Clinical Oncology guidelines.3 Similarly, for patients with breast cancer, the routine use of IV bisphosphonates has lessened the impact of skeletal complications and skeletal metastases, thereby decreasing the frequency of pathologic fractures, surgery for fracture or impending fracture, need for RT, spinal cord compression, and hypercalcemia. They have not been shown to have any survival impact in this disease, and the role of oral bisphosphonates remains unclear.4

The rationale for use in prostate cancer is less empiric, since metastatic disease is usually "blastic" and not "lytic." Nonetheless, fractures do occur and, as evidenced by the current report, bisphosphonates have been studied in men with prostate cancer for the purpose of delaying skeletal progression, protecting the bone from loss in density that can accompany treatment with androgen ablation therapy, and for palliation of bone pain. Furthermore, from the current report, it appears that overall survival is improved for patients with metastatic disease (but not for those treated for non-metastatic disease). It is also notable that an oral bisphosphonate was shown to be effective.

In more recent trials, zoledronic acid administered intravenously to patients with metastatic disease was shown to reduce skeletal fractures in patients with hormone-resistant prostate cancer5 but, once again, when used in those with early disease, there is not a clear indication of efficacy.6

In this context, the late analysis provided by this current report supports a role for bisphosphonate therapy in the management of patients with prostate cancer and bone metastases. Whether oral agents, such as clodronate (not available in the United States), will be comparable to the more powerful drugs in this class, such as zoledronate, remains to be determined. Furthermore, it remains an appealing concept that the early introduction of such drugs may be associated with reduced or delayed skeletal metastases when administered to patients with a high likelihood of developing metastases, but this has yet to be established by appropriate clinical trial.

References

1. Dearnaley DP, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst. 2003;95:1300-1311.

2. Mason MD, et al. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst. 2007;99:765-776.

3. Kyle RA, et al. American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Role of Bisphosphonates in Multiple Myeloma. J Clin Oncol. 2007;25:2464-2472.

4. Pavlakis N, et al. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005:CD003474.

5. Saad F, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.

6. Ross JR, et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ. 2003;327:469.