Antiandrogen therapies

Drugs that reduce circulating levels of androgens or that competitively inhibit the action of androgens remain central to the treatment of prostate cancer. The surgical or medical castration with orchiectomy or gonadotropin-releasing hormone (GnRH) agonists, respectively, suppresses testicular testosterone generation. However, the duration of response to castration is short [12-33 months) and, in almost all patients, is followed by the emergence of a castration-resistant phenotype [34]. The combination with antiandrogens to achieve the maximum androgen blockade (MAB) did not prove to prolong survival and 30% of the patients have a drop in PSA after discontinuing antiandrogens [3, 43]. For patients whose disease progresses after a MAB, antiandrogen can be discontinued [49], or can be switched to an alternative antiandrogen as showed in several reports [3, 43]. High-dose [150 mg daily) bicalutamide as second-line hormonal therapy resulted in >50% PSA reduction in 20%-45% of patients [12, 34].

• Oral Glucocorticoids (10mg/day) can result in temporary PSA responses for 25% of the patients, presumably due to adrenal androgen suppression [34, 50].

• Diethylstilboestrol (DES), a synthetic estrogen, as well as the other estrogens, suppresses the hypothalamic-pituitary-gonadal axis and it reduces >50% the total PSA in 26% to 66% of patients with CRPC. However, the important thromboembolic toxicity limited is use [50,51].

• Ketoconazol is an antifungal agent that can be given to CRPC patients after antiandrogen withdrawal because it inhibits cytochrome P-450 enzyme-mediated steroidogenesis in testes and adrenal glands and when given at high-dose (1200mg/day) or low dose (600

mg/day) it resulted in >50% PSA reduction in 27% to 63% and 27 to 46%, of patients, respectively [49]. However, the narrow therapeutic window of ketoconazole + hydrocortisone versus hydrocortisone alone must be kept in mind due to secondary effects of ketoconazole.

• Abiraterone acetate, a prodrug of abiraterone, is a potent and highly selective inhibitor of androgen biosynthesis that blocks cytochrome P450 c17 (CYP17] a critical enzyme in androgen synthesis in the testes, adrenals and in the tumor itself [52]. This enzyme catalyzes two sequential reactions: the conversion of pregnenolone and progesterone to their 17-a-hydroxy derivates and the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively. These two androgens are precursors of testosterone. As a result, plasma testosterone levels are significantly lower than those achieved with conventional hormone therapies; in addition, a reduction in intratumoral levels of andro-gens is obtained. The COU-AA-301, a phase III trial in post-docetaxel refractory CRPC, resulted in a significant improvement in overall survival in the abiraterone group [53]. Furthermore there is a second randomized phase III trial (COU-AA-302) targeting men with docetaxel and ketoconazole-naive CRPC showing positive results in the interim analysis in the Abiraterone group, achieving a delay in disease progression and fairly long expected survival. For this reason the study was recently unblinded before completion at the recommendation of the Independent Data Monitoring Committee.

• MDV3100 (Enzalutamide) is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. MDV 3100 was found clinically active for metastatic castration-resistant prostate cancer patients in ongoing phase I and II trials. The AFFIRM trial (a phase III trial) compared MDV3100 versus placebo in patients with docetaxel-refractory CRPC [34, 54]. The trial will determine the effectiveness of enzalutamide in patients who have previously failed chemotherapy treatment with docetaxel. In November 2011, this trial was halted after an interim analysis revealed that patients given the drug lived for approximately 5 months longer than those taking placebo, estimating a median survival of 18.4 months for men treated with MDV3100, compared with 13.6 months for men treated with placebo. This translates into a 37% reduction in the risk for death with MDV3100 (hazard ratio, 0.631]. As a result, the trial's Independent Data Monitoring Committee recommended that AFFIRM should be stopped earlier and that men who were receiving placebo should be offered MDV3100. The recommendation was based on the fact that the study's prespecified interim efficacy stopping criteria were successfully met. The committee also examined the safety profile to date and determined that MDV3100 demonstrated a risk/ benefit ratio that was favorable enough to stop the study. It is expected to file for FDA approval sometime in 2012. There is another phase III trial, known as PREVAIL, that is investigating the effectiveness of enzalutamide with patients who have not yet received chemotherapy [55].

• Orteronel (TAK-700]. Is an androgen synthesis inhibitor. It selectively inhibits the enzyme CYP17A1 which is expressed in testicular, adrenal, and prostatic tumor tissues. It is a very promising drug, but we still have to wait for results of two phase III clinical trials currently recruiting participants in CRPC patients and high risk patients [56].

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