Reply to M.R. Smith et al

Abstract

Smith and Kantoff raise a question regarding the evaluation of changes in prostate-specific antigen (PSA) kinetics in our recent report of a phase I clinical trial of a DNA vaccine encoding prostatic acid phosphatase. They cite previous phase II clinical trials showing changes in PSA doubling time (PSA DT) in patients enrolled onto placebo control arms. They conclude that “post-treatment changes in PSA DT following vaccine treatment do not provide evidence of biologic activity. Additional studies are necessary to assess the relationship between PSA kinetics and clinical outcomes and to evaluate the utility of post-treatment PSA DT or PSA velocity in the development of new drugs.” We agree that the use of changes in PSA DT is not validated as an end point associated with known impact on clinical outcomes. We acknowledged this issue in the article, wherein we stated that “it should be highlighted that the clinical significance of changes in PSA DT from any treatment remains unknown and awaits the results of prospective randomized trials to determine whether changes are associated with changes in radiographic disease progression.” We would further highlight that our study was a phase I trial in which the primary end points were safety and immunologic effect in eliciting prostatic acid phosphatase– specific CD8 T cells. Consequently, our specified measure of biologic effect was an immunologic end point and not a change in PSA kinetics. We believe that our immunologic analyses do provide evidence of biologic activity. However, because PSA is the only measure of disease in the setting of biochemical recurrence of prostate cancer, it is important to collect and report these data, as has been recommended by a consensus panel on this topic. As such, our plan moving forward is to conduct a randomized phase II clinical trial with this DNA vaccine, using time to radiographic progression as the primary clinical end point.