The evolution of antiandrogens: MDV3100 comes of age

Since the Nobel Prize-winning discovery by Huggins and Hodges in 1941 [1] that reducing circulating testosterone levels by orchidectomy or exogenous estrogens has a beneficial effect on patients with prostate cancer, androgen-deprivation therapy (ADT) has become the mainstay of treatment for advanced disease. However, most patients will eventually progress on this treatment and develop what has previously been termed ‘hormone-refractory’ prostate cancer. This is a misnomer as several studies have shown that newer, more sophisticated antiandrogens and hormone biosynthesis inhibitors can continue to have significant activity in a proportion of patients, even at very advanced stages. Antiandrogens are oral compounds that compete with endogenous ligands for the androgen receptor (AR), and thereby block the biological effects of testosterone and dihydrotestosterone. When bound they induce a conformational change that impedes transcription. These drugs can be broadly split into two categories: steroidal and nonsteroidal. Steroidal antiandrogens, such as cyproterone acetate, were the first to emerge. These are broadacting drugs, however, and can be associated with a wide range of side effects. This led to the development in the 1970s of nonsteroidal agents, such as flutamide, nilutamide and bicalutamide, which are better tolerated. Bicalutamide has been extensively investigated in the Early Prostate Cancer program. This multicenter, prospective trial randomized 8113 men with nonmetastatic disease to bicalutamide 150 mg or placebo in addition to standard care. Standard care could be with surgery (radical prostatectomy), radical radiotherapy or watchful waiting where appropriate. The fourth and final ana lysis, with a minimum follow-up of 10 years, showed significant advantages for men with locally advanced disease in terms of progression-free survival [2]. There was also a highly significant improvement in overall survival in favor of bicalutamide when used as an adjuvant to radiotherapy for men with locally advanced prostate cancer.

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