|ATC code||L02BB04 (WHO)|
|Metabolism||Hepatic (primarily CYP2C8 and CYP3A4)|
|Biological half-life||8–9 days|
|Excretion||Renal (71%), biliary (14%)|
|Chemical and physical data|
|Molar mass||464.44 g·mol−1|
|3D model (Jmol)||Interactive image|
Enzalutamide (brand name Xtandi) is a synthetic non-steroidal antiandrogen (NSAA) which was developed by the pharmaceutical company Medivation for the treatment of metastatic castration-resistant prostate cancer. Medivation has reported up to an 89% decrease in serum prostate specific antigen (PSA) levels after a month of taking the drug. Research suggests that enzalutamide may also be effective in the treatment of certain types of breast cancer. In August 2012, the United States (U.S.) Food and Drug Administration (FDA) approved enzalutamide for the treatment of castration-resistant prostate cancer.
Enzalutamide is clinically active in metastatic castration-resistant prostate cancer. 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 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. 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% conficence 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.
Notable side effects of enzalutamide seen in clinical trials have included gynecomastia, breast pain/tenderness, fatigue, diarrhea, hot flashes, headache, sexual dysfunction, and, less commonly, seizures. Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching).
Central side effects
Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials. This is thought to be due to enzalutamide crossing the blood-brain-barrier and exerting off-target binding to and inhibition of the GABAA receptor in the central nervous system (it has been found to inhibit the GABAA receptor in vitro (IC50 = 3.6 μM) and induces seizures in animals at high doses). In addition to seizures, other potentially GABAA receptor-related side effects observed with enzalutamide treatment in clinical trials have included anxiety, insomnia, vertigo, paresthesia, and headache. Due to its ability to lower the seizure threshold, patients with known seizure disorders or brain injury should be closely monitored during enzalutamide treatment. NSAA-induced seizures are responsive to benzodiazepine treatment, and it has been suggested that GABAA receptor inhibition by enzalutamide could be treated with these drugs.
There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment. The mechanism of action of the side effect is unknown, but it was proposed to a consequence of inhibition of the GABAA receptor by enzalutamide.
Comparison with other antiandrogens
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, enzalutamide, at a dosage of 160 mg/day, has been found to produce similar increases in testosterone, estradiol, and luteinizing hormone (LH) levels relative to high-dosage bicalutamide (300 mg/day), and an almost two-fold higher increase in testosterone levels relative to 150 mg/day bicalutamide (114% versus 66%). These findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison. Also, unlike with the first-generation NSAAs (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.
Unlike the first-generation NSAA bicalutamide, enzalutamide does not promote translocation of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator proteins. As such, it has been described as an AR signaling inhibitor in addition to antagonist.
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 only 2- to 3-fold lower affinity for the AR relative to the endogenous ligand dihydrotestosterone (DHT).
Cytochrome P450 modulator
Enzalutamide is reported to be a strong inducer of the enzyme CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes.
Enzalutamide has a very long half-life of 8–9 days. Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation. The drug is metabolized hepatically by CYP2C8 and CYP3A4, with CYP2C8 primarily responsible for the formation of an active metabolite, N-desmethylenzalutamide. Circulating concentrations of enzalutamide may be altered by inhibitors and inducers of CYP2C8 and CYP3A4, and should be avoided if possible.
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:
- AR mutations
- AR splice variants
- Glucocorticoid receptor bypass
- Increase in flux of glycolysis
- Autophagy mediated resistance
- Wnt signaling activation
- Increase in intra-tumoral androgen biosynthesis mediated by AKR1C3 enzyme
- Interleukin 6 signaling mediated resistance
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