Taxane Refractory Prostate Cancer

Purpose: Although docetaxel based therapy has become established as a front line therapy choice based on large, randomized studies, published studies of second line therapy for taxane refractory disease are limited. Material and Methods: The literature on the biology of taxane resistance and studies applied to prostate cancer were reviewed using a PubMed® search and proceedings from recent symposia. Results: Although taxane resistance invariably emerges in the treatment of prostate cancer, a consensus working definition or classification does not exist. Although there is a body of knowledge on the mechanisms of action of taxanes and resistance pathways, there are few clinical or translational studies in prostate cancer adequately assessing the modulation of these mechanisms. Results of additional clinical trials are needed to define and improve the standard of care in the second line setting for castration resistant prostate cancer after docetaxel failure. Conclusions: The validation of the microtubule as a target in prostate cancer implies that a finer understanding of specific mechanisms of efficacy and resistance may yield novel strategies. Taxane analogues that have greater antitumor activity and/or are less susceptible to drug resistance mechanisms than their prototypes are in development, as are nontaxane microtubule targeting agents and other agents directed against the mitotic spindle. Combinations of such agents may yield added efficacy but potentially added neurotoxicity. In contrast, combinations with drugs that inhibit cellular mechanisms of taxane resistance and vascular endothelial or tumor-stromal prosurvival interactions may have lower neurotoxic profiles. Although alternate classes of cytotoxic agents, eg satraplatin, are being studied, there is a strong imperative for translational studies in this setting.