Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[ ] It is taken by mouth.
of enzalutamide when added to castration include asthenia, back pain, diarrhea, arthralgia, and .
Enzalutamide was first described in 2006, and was introduced for the treatment of prostate cancer in 2012.
Medical uses
Enzalutamide is
indicated for the treatment of people with castration-resistant prostate cancer; metastatic castration-sensitive prostate cancer; and non‑metastatic castration‑sensitive prostate cancer with biochemical recurrence at high risk for metastasis.
Prostate cancer
There is good evidence that enzalutamide is an effective treatment for increasing overall survival among people with high-risk non-metastatic castration-resistant prostate cancer, particularly those with a PSA doubling time ≤ 6 months.
Other uses
Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women.
Available forms
Enzalutamide is provided as a capsule or tablet.
Contraindications
Enzalutamide is
contraindication in women during
pregnancy.
It may cause
teratogen.
Side effects
Notable
of enzalutamide seen in
have included
gynecomastia,
mastodynia, fatigue,
diarrhea,
,
headache, sexual dysfunction, and, less commonly,
.
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 GABA
A receptor
in vitro ( = 3.6 μM)
and induces
in animals at high doses).
In addition to seizures, other potentially GABA
A 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
or
brain injury should be closely monitored during enzalutamide treatment.
NSAA-induced seizures are responsive to
benzodiazepine treatment, and it has been suggested that GABA
A receptor inhibition by enzalutamide could be treated with these drugs.
In dose-ranging studies, severe
fatigue was observed with enzalutamide at doses of 240 mg/day and above.
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 GABA
A receptor by enzalutamide.
Overdose
Enzalutamide may cause
in
overdose.
Interactions
Enzalutamide is a moderate to strong inducer of multiple cytochrome P450
including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant
.
Circulating concentrations of enzalutamide may be altered by
enzyme inhibitor and
enzyme inducer of CYP2C8 and CYP3A4, and should be avoided if possible.
In a clinical study of enzalutamide for -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.
Pharmacology
Pharmacodynamics
Enzalutamide acts as a selective silent antagonist of the androgen receptor (AR), the biological target of
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
.
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-fold lower affinity for the AR than 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.
Dose-ranging studies of enzalutamide in men with prostate cancer have been performed.
Changes in hormone levels
Enzalutamide monotherapy at a dosage of 160 mg/day has been found to increase circulating levels of
testosterone by 114.3%, dihydrotestosterone (DHT) by 51.7%,
estradiol by 71.7%, sex hormone-binding globulin (SHBG) by 100.6%, dehydroepiandrosterone (DHEA) by 9.6%,
androstenedione by 51.1%, luteinizing hormone (LH) by 184.7%, follicle-stimulating hormone (FSH) by 47.0%, and
prolactin by 16.8%.
These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy.
The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%.
Comparison with other antiandrogens
Enzalutamide has approximately 8-fold higher
binding affinity for the androgen receptor (AR) compared to
bicalutamide.
One study found an 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 IC
50 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:
-
AR mutations
-
AR
-
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
Cytochrome P450 modulation
Enzalutamide is reported to be a strong
enzyme 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.
Pharmacokinetics
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%.
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
metabolism in the
liver, mainly by the cytochrome P450
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.
Chemistry
Enzalutamide is a synthetic di
aryl 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.
History
Enzalutamide was discovered by
Charles Sawyers and Michael Jung at the University of California, Los Angeles.
They and their colleagues synthesized and evaluated nearly 200 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
in 2006 and described in 2007.
[
]
[1] Enzalutamide was developed and marketed by
Medivation for the treatment of prostate cancer.
It was approved by the US Food and Drug Administration (FDA) 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.
In July 2018, the FDA approved enzalutamide for the treatment of people with castration-resistant prostate cancer.[ ] The approval broadens the indication to include people with both non-metastatic castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.
In December 2019, the FDA approved enzalutamide for the treatment of people with metastatic castration-sensitive prostate cancer (mCSPC).
In June 2023, the FDA approved talazoparib, in combination with enzalutamide, for the treatment of people with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).[ ]
In November 2023, the FDA approved enzalutamide for the treatment of people with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis (high-risk BCR).[ ] Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled clinical trial of 1068 patients with nmCSPC with high-risk BCR.
Society and culture
Legal status
In June 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Enzalutamide Viatris, intended for the treatment of prostate cancer.
The applicant for this medicinal product is Viatris Limited.
[ Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] Enzalutamide Viatris is a generic of Xtandi.
Economics
Pfizer reported revenue of for Xtandi in 2023.
Research
Breast cancer
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.
Hirsutism
Enzalutamide has been suggested as a potential treatment for
hirsutism and
hyperandrogenism in women with polycystic ovary syndrome.
See also
