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In Reply

Department of Medicine, Oregon Health and Science University Cancer Institute, Portland, OR

The androgen-independent prostate cancer study of calcitriol-enchancing taxotere (ASCENT) was not designed to determine whether prostate-specific antigen (PSA) response rate can be a surrogate for docetaxel activity or whether the effect of calcitriol on survival is independent of docetaxel activity. It is important to note, however, that while the PSA response rate was not statistically different between the two arms of the ASCENT study (at 63% v 52%; P = .07), the observed point estimates favored the experimental (calcitriol) arm. The absolute difference of 11% in the point estimates is not dissimilar from the 13% absolute difference observed in the pivotal docetaxel prostate cancer study (TAX 327). It is certainly possible that the much larger sample size of TAX 327 (n = 672) contributed to the trial's ability to detect statistically significant differences in the PSA response rate where the smaller ASCENT study (n = 250) fell short. Recent analyses of the two phase III studies of docetaxel-containing chemotherapy highlight the limitation of PSA decline as a surrogate for survival. Analyses of both Southwest Oncology Group trial 9916 and TAX 327 demonstrate that while correlated with survival, the difference in the fraction of patients experiencing a 50% or greater PSA decline explained only about half of the observed survival differences.^1,2 We have no reason to suspect that PSA decline would have been a more robust surrogate in ASCENT than it was in these two larger studies.

We agree that both vitamin D status and measures of parathyroid axis could be of interest. However, these measures were not collected as part of the ASCENT study and are not available for analysis.

The exploratory analyses of skeletal-related events (SREs) should be interpreted with great caution and used solely for hypothesis generation. These analyses were not planned in advance and the sample size did not provide adequate statistical power or adjustments for multiple hypothesis testing. Further, the decision to treat patients with zoledronic acid was neither random nor controlled by the study.

In the manuscript, we reported SRE-free survival, an end point that combines SREs with death. This is a clinically meaningful end point. Remaining free of an SRE is only of interest if the patient is still alive. However, this end point does not isolate SREs, which could be useful for hypothesis-generating analyses of the kind the correspondents suggest.

To complement the SRE incidence results reported in our manuscript, we carried out the time-to-SRE analyses suggested by the correspondents. Again, these analyses lacked statistical power and it is difficult to make any interpretations (eg, fewer than 50% of patients experienced an SRE and the median time-to-SRE was not reached in any of the arms examined). Nonetheless, these analyses, as shown in Figure 1, did not reveal statistically significant differences in time-to-SRE by treatment assignment in the overall study or when stratified by zoledronic acid use.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time to first skeletal related event in (A) all patients enrolled in the ASCENT study; (B) patients enrolled in the ASCENT study who were also receiving zoledronic acid; and (C) patients enrolled in the ASCENT study who were not receiving zoledronic acid. DN-101, a new high-dose oral formulation of calcitriol; NE, not evaluated.

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Tomasz M. Beer, Novacea (C) Stock Ownership: Tomasz M. Beer, Novacea Honoraria: Tomasz M. Beer, Novacea, Sanofi-aventis Research Funding: Tomasz M. Beer, Novacea, Sanofi-aventis Expert Testimony: None Other Remuneration: None

REFERENCES

1. Petrylak DP, Ankerst DP, Jiang CS, et al: Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 98:516-521, 2006[Abstract/Free Full Text]

2. Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 25:3965-3970, 2007[Abstract/Free Full Text]

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