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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Prostate-specific antigen: A surrogate endpoint for screening new agents against prostate cancer?

BACKGROUND: An endpoint for clinical trials of prostate cancer which simplifies traditional endpoints (response of measurable lesions, progression rates, and death) is urgently needed. This is especially true for hormone-unresponsive disease, for which many new drugs are presently in a development phase. This paper presents a rationale for the use of prostate-specific antigen ( PSA) in clinical trials of progressive prostate cancer under endocrine treatment. METHODS: The study is based on 84 patients who progressed after radical prostatectomy or node dissection, of whom 24 showed increasing PSA levels under subsequent endocrine treatment. An average linear relationship between (log-transformed) PSA and time and a subject-specific deviation from this average relationship were assessed. The predictive value of the subject-specific parameters of the linear fit with respect to time to prostate cancer-specific death was determined. The outcomes of the fitting procedure were used to calculate sample sizes for future studies (duration, 6 months) using PSA increase over time in hormone-unresponsive prostate cancer as a marker for treatment efficacy. RESULTS: The average PSA doubling time in this population was 4 months (corresponding time constant = 0.25). The assessed variance of the time constants equalled 0.04; the overall residual variance equalled 0.265. The subject-specific rate of change of the log-transformed PSA value in hormone-unresponsive prostate cancer was a highly significant predictor of prostate cancer-specific death. This suggests the potential usefulness of PSA as an endpoint in trials of hormone-unresponsive prostate cancer. Depending on conditions chosen (e.g, desired power and changes in log PSA slope), 18-70 participants per arm will be necessary in future phase III studies. A suggestion (algorithm) for the use of PSA in drug development is presented. CONCLUSIONS: Relatively small PSA-based trials in patients with hormone-unresponsive prostate cancer are possible if a similar patient population is utilized. As long as surrogacy is not established, such studies cannot be considered conclusive with respect to effectiveness of treatment, but are likely to be useful as a screening tool for new drugs. Experimental confirmation in human prostate cancer model systems of synergism between PSA decrease and tumor control by a given test treatment is likely to enhance the level of certainty of PSA-based drug evaluation.[1]


  1. Prostate-specific antigen: A surrogate endpoint for screening new agents against prostate cancer? Schröder, F.H., Kranse, R., Barbet, N., Hop, W.C., Kandra, A., Lassus, M. Prostate (2000) [Pubmed]
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