Is time to first skeletal-related event the best primary end point in the assessment of bisphosphonate efficacy in patients with castration-sensitive prostate cancer?

TO THE EDITOR: Zoledronic acid (Z) is known to be effective in reducing the risk of adverse skeletal-related events in patients with castration-resistant prostate cancer and metastatic bone disease. The results of the double-blind, phase III, multicenter, randomized clinical trial recently published in Journal of Clinical Oncology by Smith et al showed that Z treatment in patients with castration-sensitive disease was not associated with prolonged time to first skeletal-related event as compared with patients with castration-resistant disease. There are increasing data that show that bisphosphonates exhibit a variety of direct and indirect anticancer activities that affect both tumor cells and the surrounding bone microenvironment and can potentially modify the metastatic disease process. These mechanisms can lead to a survival improvement in patients with metastatic bone disease. A previous trial by the Medical Research Council (MRC) showed a survival improvement with clodronate administration versus placebo (that just failed to attain statistical significance) in men receiving primary androgen-deprivation therapy for metastatic prostate cancer. In the trial by Smith et al, no significant difference in overall survival was observed, but a hazard ratio (HR) of 0.88 favoring zoledronic acid administration was observed. We performed a pooled analysis of both trials (Fig 1) showing that early bisphosphonate administration was associated with a significant survival improvement with a cumulative HR of 0.84. No heterogeneity in the HRs between the two trials was observed in the interaction test. When we looked at the survival curves of both studies, we found that in the MRC study, the clodronate and placebo curves diverged early, whereas in the trial by Smith et al, they were initially similar and showed a divergent pattern only after 36 months. This different behavior may reflect the different designs of the two studies. In the study by Smith et al, Z was planned to be administered to all patients at the onset of castration-resistant disease, but this was not the case with clodronate in the MRC study. In the pivotal randomized clinical study in patients with castration-resistant prostate cancer and bone metastases, Z administration was associated with a nonsignificant survival improvement compared with placebo. So the exposure to Z during the castrationresistant phase of patients who were randomly assigned to the placebo arm in the study by Smith et al may have been responsible for the delayed divergent pattern of the survival curves. This suggests a survival advantage of early Z over the long term. In a subsequent report on the MRC study, with a longer follow-up period, the survival advantage of clodronate versus placebo attained statistical significance. It would be interesting to explore whether similar results will be obtained with more mature follow-up of the patients included in the study by Smith et al. In conclusion, we think that time to the onset of a skeletalrelated event may not be the best primary end point for testing the efficacy of antiresorptive agents in patients with castrationsensitive prostate cancer and bone metastases. The results of the two randomized trials in this setting provide the rationale for designing a prospective clinical trial that tests the efficacy of these drugs in terms of survival improvement.