Management of high risk metastatic prostate cancer: The case for novel therapies

Purpose: We reviewed the results of preliminary studies of select novel agents for metastatic prostate cancer and discuss the potential benefit of these agents for earlier stage disease, eg biochemically recurrent prostate cancer with high risk features. Materials and Methods: Available data on select investigational immunotherapies as well as endothelin-A receptor antagonists and survivin inhibitors were obtained and reviewed through PubMed searches, conference proceedings and unpublished proprietary information, when available. Results: A large number of promising agents are in varying stages of development. Phase III results have been reported for the endothelin-A receptor antagonist atrasentan. Several immunotherapies are currently in phase II/III trials, namely the GM-CSF transduced tumor cell vaccine GVAX (R), the prostatic acid phosphatase loaded dendritic cell vaccine Provenge (R) and the prostate specific antigen expressing poxvirus vaccine PROSTVAC (R)-VF. Another immunotherapy, the prostate specific membrane antigen immunoconjugate MLN2704 (Millennium Pharmaceuticals, Cambridge, Massachusetts), is in phase I/II study. The first clinical inhibitors of survivin are in early phase I studies. Several of these agents, including atrasentan, have shown statistically significant but modest effects in the advanced disease setting in which they have been studied. Conclusions: Clinical trial design with these novel therapies presents particular challenges since most of these agents may induce disease stabilization rather than disease regression. There is a risk of false-negative results and failure to recognize a potentially efficacious agent if these cytostatic agents are studied only in men with advanced, heavily pretreated disease in whom life expectancy is measured in months. We advocate the early referral and enrollment of men with high risk prostate cancer in clinical trials.