Metastatic castration-resistant prostate cancer

Abiraterone acetate 117 is an androgen biosynthesis inhibitor, which was developed by the Institute of Cancer Research in the UK and further developed by Janssen for the oral treatment of patients with metastatic castration-resistant prostate cancer [75]. Its synthesis is relatively easy through a Suzuki coupling between the 17-enol triflate derived from the 3-acetate of dehydro-epiandrosterone (115) and 3-pyridyl-diethylborane (116) (Scheme 27) [76]. The reaction is catalysed by PdCl2(PPh3)2 and proceeds in good yield (84%). A similar Suzuki-based route in which the ketone starting material was converted into an alkenyliodide has also been published [77]. 

Enzalutamide (1, marketed as Xtandi and formerly known as MDV3100) was developed by the pharmaceutical company Medivation and was approved by the US FDA on August 31, 2012, for men with docetaxel-pretreated, metastatic castration-resistant prostate cancer (CRPC). The current market price for enzalutamide treatment is approximately 7000/month with treatments lasting 5-8 months. 

Yang LP (2011) Abiraterone acetate in metastatic castration-resistant prostate cancer. Drugs 71 2067-2077... 

Keizman D, Huang P, Carducci MA, Eisenberger MA. Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer clinical factors associated with PSA response and disease progression. Prostate 2012 72(4) 461-7. 

Enzalutamide is an oral inhibitor of AR signalling that blocks AR interaction, inhibits translocation of the AR to the nucleus, impairs AR binding to DNA and inhibits co-activator recruitment and receptor-mediated DNA transcription. In the United Kingdom, enzalutamide is licensed for the treatment of men wi metastatic, castrate-resistant prostate cancer whose disease has progressed on or after docetaxel-based chemotherapy. 

Chi KN, Hotte SJ, Yu EY et al (2010) Randomized phase II study of docetaxel and prednisone with ot without OGX-OII in patients with metastatic castration-resistant prostate cancer. J Qin Oncol 28 4247-4254... 

Ishteiwy RA, Ward TM, Dykxhoom DM, Bumstein KL. The microRNA-23b/-27b cluster suppresses the metastatic phenotype of castration-resistant prostate cancer cell. PLoS One. 2012 7(12)e52106. doi 10.1371/joumal.pone.0052106. 

Provenge Sipuleucel-T Treatment of men with asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer 125197/0 Dendreon Corp 3005 First Ave Seattle, WA 98121, USA License 1749 4/29/2010... 

Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhom TF, Higano CS, True LD, Nelson PS (2008) Maintenance of intratumoral androgens in metastatic prostate cancer a mechanism for castration-resistant tumor growth. Cancer Res 68 4447-4454... 

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