Enzalutamide

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Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is an androgen receptor antagonist drug developed by the pharmaceutical company Medivation for the treatment of metastatic castration-resistant prostate cancer.[1] Medivation has reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine.[2] Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth.[3][4] In August 2012, the U.S. Food and Drug Administration approved enzalutamide for the treatment of castration-resistant prostate cancer.[5][6]

Discovery

Enzalutamide was discovered by Charles Sawyers who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung at UCLA.[7][8]

Preclinical pharmacology

Enzalutamide has approximately fivefold higher binding affinity for the androgen receptor (AR) compared to the antiandrogen bicalutamide.[9] As opposed to bicalutamide, enzalutamide does not promote translocation of AR to the nucleus and in addition prevents binding of AR to DNA and AR to coactivator proteins.[9]

When LNCaP cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with enzalutamide, the expression of androgen dependent genes PSA and TMPRSS2 was down regulated in contrast to bicalutamide where the expression was upregulated.[9] In VCaP cells which over express androgen receptors, enzalutamide induced apoptosis whereas bicalutamide did not.[9] Furthermore enzalutamide behaves as an antagonist of the W741C mutant androgen receptor in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.[9]

Clinical studies

Enzalutamide is clinically active in metastatic castration-resistant prostate cancer.[10] PSA level decreased more than 50 percent in 40/65 chemo-naive patients and 38/75 chemotherapy-treated patients.[10] Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.[11]

Medivation conducted an international phase III trial that began in September 2009 known as AFFIRM. The aim of this trial was determine the safety and effectiveness of enzalutamide in patients who have previously failed chemotherapy treatment with docetaxel.[12] 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.[13] FDA approval was granted in August 2012.[5][14]

Another phase III trial known as PREVAIL is investigating the effectiveness of enzalutamide with patients who have not yet received chemotherapy.[15] On October 22, 2011, Medivation and Astellas announced that the PREVAIL trial met both co-primary endpoints of overall survival, with a 30% reduction in the risk of death compared with placebo (hazard ratio = 0.7; 95% confidence interval, range of 0.59-0.83), and radiographic progression-free survival, with an 81% reduction in risk of radiographic progression of death compared with placebo (hazard ratio = 0.19); 95% conficence interval, 0.15-0.23).[16] In addition, a phase II trial began in March 2011 comparing enzalutamide with a commonly used anti-androgen, bicalutamide, in prostate cancer patients who have progressed while on LHRH analogue therapy (e,g., leuprorelin) or surgical castration.[17][18]

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