Issues with the Use of Prostate-Specific Antigen as a Surrogate End Point in Hormone-Resistant Prostate Cancer

Context: High demand for new drugs in cancer therapy has resulted in a drive to reduce the length of clinical trials. One way to achieve this is to use surrogate end points for overall survival (OS). Measurement of prostate-specific antigen (PSA) levels is widely used in screening for prostate cancer and may be used as a biomarker of disease progression. However, although PSA may serve as a suitable prognostic biomarker, its utility as a valid surrogate end point for OS in hormone-resistant prostate cancer (HRPC) trials has been inconclusive. Evidence acquisition: The utility of PSA as a surrogate end point in HRPC is reviewed and alternative recommendations discussed. A nonsystematic review of the literature, including PubMed and congress abstracts, was performed in 2008. Evidence synthesis: Despite being widely available and easy to measure, reductions in PSA levels have not been validated as a surrogate end point for use in clinical trials of agents with novel mechanisms of action. Conflicting data from preliminary studies of cytotoxic and molecular-targeted agents in HRPC have shown that improvements in OS are not consistently reflected by reductions in PSA. There are a number of potential reasons for this inconsistency, including heterogeneity of PSA expression with disease progression and the influence of comorbidities, including age. Although changes in PSA levels may be a suitable surrogate end point for studies of cytotoxic agents, it may have less utility in studies of targeted agents with antiproliferative or anti-invasive mechanisms of action. As questions have emerged about the utility of PSA levels as a surrogate end point, the Prostate Cancer Clinical Trials Working Group has reviewed the criteria for outcome measures in clinical trials that evaluate systemic treatment for patients with progressive prostate cancer. Recommendations note that PSA responses may be delayed in trials of non-cytotoxic agents, and rising PSA levels in the absence of other signs of progression should not lead to discontinuation of trials. Conclusions: OS remains the most accurate end point for clinical trials, and changes in PSA levels may not reflect a patient's response to therapy. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.