Novel Therapeutic Strategies for Castration Resistant Prostate Cancer: Inhibition of Persistent Androgen Production and Androgen Receptor Mediated Signaling

Purpose: Androgen receptor signaling remains essential for many prostate cancers that have progressed despite androgen deprivation therapy. After medical or surgical castration persistent though not insignificant low levels of androgens are produced from nongonadal sources, such as the adrenal glands. Some castration resistant prostate cancers acquire the ability to convert adrenal steroids to androgens, maintaining levels sufficient to activate androgen receptor. Inhibition of persistent androgen production and androgen receptor mediated signaling are relevant therapeutic strategies for castration resistant prostate cancer. Materials and Methods: The scientific foundation of and clinical experience with secondary hormonal therapy as well as the development of new investigational agents for castration resistant prostate cancer, specifically selective cytochrome p450 17 inhibitors and second generation antiandrogens, are discussed. Results: Selective inhibition of cytochrome p450 17 has emerged as an important therapeutic pathway for castration resistant prostate cancer. The selective cytochrome p450 17 inhibitor abiraterone acetate showed promising activity and tolerability in phase I-II trials. Phase III studies are underway in men with chemotherapy naive castration resistant prostate cancer as well as those with progression after docetaxel based chemotherapy. TAK-700 and TOK-001 (formerly VN124-1) are novel selective cytochrome p450 17 inhibitors that recently entered phase I/II evaluation. MDV3100 is a second generation antiandrogen that blocks androgen receptor signaling by inhibiting nuclear translocation of the ligand-receptor complex. Clinical data on MDV3100 are encouraging and support continued phase III study. Conclusions: Novel therapies for castration resistant prostate cancer that target persistent androgen production and androgen receptor mediated signaling have demonstrated promising activity in many men with castration resistant prostate cancer and may redefine the clinical management of these patients.