Evidence in advanced disease: The challenge for new therapies

Prostate cancer mortality rates have recently begun to decline, however, the large number of people with advanced prostate cancer continues to make this disease an important healthcare problem. A range of new agents are in development, resulting in the need for new methods of rapid evaluation. The use of surrogate markers for survival has been proposed as a means of gaining an early indication of the effectiveness of treatment. Prostate-specific antigen (PSA) is a strong candidate for a marker of activity in advanced prostate cancer. However, PSA alone has not yet complied with the strict criteria for surrogacy, which requires evidence that a significant difference between treatments in a randomised trial correlates with a significant difference in the potential surrogate marker. Despite preclinical studies showing that PSA response is not always associated with a reduction in tumour size, and reports that a proportion of men with prostate cancer will progress clinically without a rise in PSA level, emerging evidence indicates that changes in PSA levels predict survival in advanced disease. An algorithm has been developed involving confirmation of activity in an experimental animal model in parallel with clinical studies, in order to gain a full picture of the potential of new treatments for prostate cancer. This algorithm is currently being used in a Phase II study of the orally active, selective, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) ZD1839 ('Iressa')1 in patients with prostate cancer experiencing rising PSA levels while undergoing endocrine treatment. Results from this and other PSA-based trials are awaited with interest, as they may clarify the role of PSA change as a surrogate marker for survival in patients with advanced prostate cancer.

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