Combination Treatment Strategies with Docetaxel in Patients with Metastatic Prostate

Abstract

The combination of docetaxel with prednisone was the first treatment to demonstrate survival advantage in men with metastatic castration resistant prostate cancer (mCRPC) in 2004. Since then many investigators have attempted to establish more effective treatments by combining other drugs with this standard of care. The rationale for such combinations has included preclinical evidence of synergy, but also practical and commercial considerations. In all 9 docetaxel combination phase III trials have been performed, none of which has demonstrated significantly enhanced efficacy when compared to docetaxel plus prednisone alone. These trials can be broadly classified into combinations with anti-angiogenic therapies, combination with drugs which specifically enhance docetaxel cytotoxicity, combinations with the endothelin antagonists and combinations with immunotherapy. Each of these key trials is reviewed. With the recent results of trials demonstrating high efficacy for docetaxel when given to men with newly diagnosed advanced prostate cancer, this treatment has once again become a major focus for intervention and with it will come renewed interest in combination therapies. It is thus timely to consider the reasons for the failures of these earlier trials and how these may be avoided in the future.