Enzalutamide was first described in 2006, and was introduced for the treatment of prostate cancer in 2012. It was the first second-generation NSAA to be introduced. The medication is available widely throughout the world.
Enzalutamide is clinically effective in the treatment of mCRPC. An up to 89% decrease in serum prostate specific antigen (PSA) levels have been reported after a month of taking the drug. PSA level decreased more than 50% in 40 of 65 chemo-naive patients and 38 of 75 chemotherapy-treated patients. Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.
Medivation, the developer of enzalutamide, conducted an international phase IIItrial 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. In November 2011, this trial was stopped early after an interim analysis revealed that patients given the drug lived for approximately 5 months longer than those taking placebo. FDA approval was granted in August 2012.
Another phase III trial known as PREVAIL is investigating the effectiveness of enzalutamide with patients who have not yet received chemotherapy. On October 22, 2013, 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 or death compared with placebo (hazard ratio = 0.19); 95% confidence interval, 0.15-0.23). In addition, a phase II trial began in March 2011 comparing enzalutamide with bicalutamide in prostate cancer patients who have progressed while on gonadotropin-releasing hormone (GnRH) analogue therapy (e.g., leuprorelin) or surgical castration. Addition of Enzalutamide with testosterone suppression in men with castration-resistant prostate cancer showed better survival compared to standard nonsteroidal antiandrogen therapy.
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. In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not. Furthermore, enzalutamide behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.
Enzalutamide has approximately 5- to 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide. One study found an IC50 of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in the LNCaP cell line (7.6-fold difference), while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference). In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide. Also, unlike with the first-generation NSAAs, there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.
Resistance mechanisms in prostate cancer
Enzalutamide is only effective for a certain period of time, after that the growth of the cancer is not inhibited by this antiandrogen. The mechanisms of resistance to Enzalutamide are being intensively studied. Currently, several mechanisms have been found:
Enzalutamide is reported to be a strong inducer of the enzymeCYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes.
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^ abSaad F, Heinrich D (2013). "New Therapeutic Options for Castration-resistant Prostate Cancer". The Journal of Oncopathology. 1 (4): 23–32. [...] enzalutamide was the first second-generation AR antagonist to be approved by the FDA in 2012 and by the EMA and Health Canada in 2013 [...]
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^Davis, Ian D.; Martin, Andrew J.; Stockler, Martin R.; Begbie, Stephen; Chi, Kim N.; Chowdhury, Simon; Coskinas, Xanthi; Frydenberg, Mark; Hague, Wendy E.; Horvath, Lisa G.; Joshua, Anthony M.; Lawrence, Nicola J.; Marx, Gavin; McCaffrey, John; McDermott, Ray; McJannett, Margaret; North, Scott A.; Parnis, Francis; Parulekar, Wendy; Pook, David W.; Reaume, M. Neil; Sandhu, Shahneen K.; Tan, Alvin; Tan, T. Hsiang; Thomson, Alastair; Tu, Emily; Vera-Badillo, Francisco; Williams, Scott G.; Yip, Sonia; Zhang, Alison Y.; Zielinski, Robert R.; Sweeney, Christopher J. (11 July 2019). "Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer". New England Journal of Medicine. 381 (2): 121–131. doi:10.1056/NEJMoa1903835.
^Fishman, Sarah L.; Paliou, Maria; Poretsky, Leonid; Hembree, Wylie C. (2019). "Endocrine Care of Transgender Adults": 143–163. doi:10.1007/978-3-030-05683-4_8. ISSN2523-3785. Non-steroidal selective androgen receptor antagonists, developed as a treatment for androgen-sensitive prostate cancer, are occasionally used in transgender females who do not achieve their desired results or do not tolerate alternative drugs . There are isolated reports of successful outcomes with flutamide (Eulexin), though reportedly not as effective as cyproterone acetate in reducing testosterone levels . Both flutamide and bicalutamide (Casodex), in conjunction with oral contraceptive pills, have shown significant improvements in hirsutism in natal females with polycystic ovarian syndrome (PCOS) [53, 54, 55, 56, 57]. The use of these agents as antiandrogens in transgender patients has been limited by concerns of hepatotoxicity. However, at low doses, these agents have shown to be both well tolerated and effective when used for the treatment of hirsutism . [...] Table 8.2: Antiandrogens: [...] Androgen receptor blocker: [...] Type: Enzalutamide. Route: Oral. Dose: 160 mg/day.Cite journal requires |journal= (help)
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