|By mouth (capsules)|
|Drug class||Nonsteroidal antiandrogen|
Humans: unknown (but at least 84.6% based on recovery from excretion)
Enzalutamide: 97–98% (primarily to albumin)|
|Metabolism||Liver (primarily CYP2C8 and CYP3A4)|
• NDME (active)|
• Carboxylic acid derivative metabolite (inactive)
Enzalutamide: 5.8 days (range 2.8–10.2 days)|
NDME: 7.8–8.6 days
|Chemical and physical data|
|Molar mass||464.44 g·mol−1|
|3D model (JSmol)|
Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic castration-resistant prostate cancer. It is taken by mouth.
Side effects of enzalutamide when added to castration include asthenia, back pain, diarrhea, arthralgia, and hot flashes. Rarely, it can cause seizures. It has a high potential for drug interactions. Enzalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body.
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 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% 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.
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). Enzalutamide monotherapy is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogues but similar to that of other NSAAs such as bicalutamide.
Central adverse 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 convulsions 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.
Rare adverse reactions
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.
Enzalutamide is a moderate to strong inducer of multiple cytochrome P450 enzymes including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant drug interactions. Circulating concentrations of enzalutamide may be altered by inhibitors and inducers of CYP2C8 and CYP3A4, and should be avoided if possible.
In a clinical study of enzalutamide for ER-positive breast cancer in women, enzalutamide was found to decrease serum concentrations of the aromatase inhibitors anastrozole and exemestane by 90% and 50%, respectively, which could reduce their effectiveness.
Enzalutamide acts as a selective silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). 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. The drug is described as a "second-generation" NSAA because it has greatly increased efficacy as an antiandrogen relative to so-called "first-generation" NSAAs like flutamide and bicalutamide. The drug has only 2- to 3-fold lower affinity for the AR relative to DHT, the endogenous ligand of the AR in the prostate gland.
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.
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.
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:
Cytochrome P450 modulation
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.
The bioavailability of enzalutamide in humans is unknown, but is at least 84.6% based on the amount recovered from urine and bile in excretion studies. Similarly, the bioavailability of enzalutamide in rats is 89.7%. Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation. The plasma protein binding of enzalutamide is 97 to 98%, while that of N-desmethylenzalutamide (NDME), its major metabolite, is 95%. Enzalutamide is primarily bound to albumin. The medication is metabolized in the liver, mainly by the cytochrome P450 enzymes CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of NDME. Enzalutamide has a long elimination half-life of 5.8 days on average, with a range of 2.8 to 10.2 days. The elimination half-life of NDME is even longer, at about 7.8 to 8.6 days. Enzalutamide is eliminated 71.0% in urine, 13.6% in bile, and 0.39% in feces.
Enzalutamide is a synthetic diarylthiohydantoin derivative and is structurally related to the earlier first-generation NSAAs such as flutamide, nilutamide, and bicalutamide as well as to newer second-generation NSAAs like apalutamide and proxalutamide.
Enzalutamide was discovered by Charles Sawyers who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung at the University of California, Los Angeles. They and their colleagues synthesized and evaluated nearly 200 thiohydantoin derivatives of RU-59063, an analogue of nilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide and RD-162 as lead compounds. These compounds were patented in 2006 and described in 2007. Enzalutamide was developed and marketed by Medivation for the treatment of prostate cancer. It was approved by the Food and Drug Administration for the treatment of mCRPC in the United States in August 2012 and for the treatment of nonmetastatic castration-resistant prostate cancer in July 2018. Enzalutamide was the first new AR antagonist to be approved for the treatment of prostate cancer in over 15 years, following the introduction of the first-generation NSAA bicalutamide in 1995. It was the first second-generation NSAA to be introduced.
Society and culture
Enzalutamide is available widely in the Western world, including in the United States, Canada, the United Kingdom, Ireland, and widely elsewhere throughout Europe. Outside of the Western world, it is available South Korea and Chile.
Research suggests that enzalutamide may be effective in the treatment of certain types of breast cancer in women. It has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.
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