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.[2]
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.[16]
Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials.[19][21] This is thought to be due to enzalutamide crossing the
blood–brain barrier[25][26] 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 (
IC50Tooltip half-maximal inhibitory concentration = 3.6 μM)[26][27][28] and induces
convulsions in animals at high doses).[19][21] 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.[29] Due to its ability to lower the
seizure threshold, patients with known
seizure disorders or
brain injury should be closely monitored during enzalutamide treatment.[30] 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.[27] In
dose-ranging studies, severe
fatigue was observed with enzalutamide at doses of 240 mg/day and above.[31][32]
In a clinical study of enzalutamide for
ERTooltip estrogen receptor-positive
breast cancer in women, enzalutamide was found to decrease serum concentrations of the
aromatase inhibitorsanastrozole and
exemestane by 90% and 50%, respectively, which could reduce their effectiveness.[35]
Pharmacology
Pharmacodynamics
Enzalutamide acts as a
selectivesilentantagonist 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
coactivatorproteins.[36] As such, it has been described as an AR signaling inhibitor in addition to antagonist.[19] 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.[37]
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.[36] In VCaP cells which over-express the AR, enzalutamide induced
apoptosis whereas bicalutamide did not.[36] 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.[36]
Enzalutamide has approximately 8-fold higher
binding affinity for the
androgen receptor (AR) compared to
bicalutamide.[36][39] One study found an
IC50Tooltip half-maximal inhibitory concentration of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in the
LNCaP cell line (7.6-fold difference),[40] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference).[41] 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.[24][38] 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.[42][43]
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.[44] 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.[54][34]
Enzalutamide was discovered by
Charles Sawyers and
Michael Jung at the
University of California, Los Angeles.[56][57][58] They and their colleagues
synthesized and evaluated nearly 200
thiohydantoinderivatives of
RU-59063, an
analogue of
nilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide and
RD-162 as lead compounds.[36][58] These compounds were
patented in 2006 and described in 2007.[11] Enzalutamide was developed and marketed by
Medivation for the treatment of prostate cancer.[59] 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.[19][60] 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.[61] It was the first second-generation NSAA to be introduced.[14]
In July 2018, the FDA approved enzalutamide for the treatment of people with castration-resistant prostate cancer.[62] The approval broadens the indication to include people with both non-metastatic castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.[62] Enzalutamide was previously approved for the treatment of people with metastatic castration-resistant prostate cancer.[62]
In December 2019, the FDA approved enzalutamide for the treatment of people with metastatic castration-sensitive prostate cancer (mCSPC).[10] Enzalutamide was previously approved for the treatment of people with castration-resistant prostate cancer.[10]
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).[63]
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).[64] Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled clinical trial of 1068 patients with nmCSPC with high-risk BCR.[64] All patients had prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent, had PSA doubling time ≤ 9 months, and were not candidates for salvage radiotherapy at enrollment.[64] Patients were randomized 1:1:1 to receive blinded enzalutamide 160 mg once daily plus leuprolide, open-label single- agent enzalutamide 160 mg once daily, or blinded placebo once daily plus leuprolide.[64] The application was granted
priority review and
fast track designations.[64]
Research
Breast cancer
Research suggests that enzalutamide may be effective in the treatment of certain types of
breast cancer in women.[65][66] It has been tested for the treatment of triple-negative, AR-positive breast cancer in a
phase IIclinical trial.[67][68]
^
abKim TH, Jeong JW, Song JH, Lee KR, Ahn S, Ahn SH, et al. (November 2015). "Pharmacokinetics of enzalutamide, an anti-prostate cancer drug, in rats". Archives of Pharmacal Research. 38 (11): 2076–82.
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^World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization.
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^Fishman SL, Paliou M, Poretsky L, Hembree WC (2019). "Endocrine Care of Transgender Adults". Transgender Medicine. Contemporary Endocrinology. pp. 143–163.
doi:
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S2CID86772102. 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 [52]. There are isolated reports of successful outcomes with flutamide (Eulexin), though reportedly not as effective as cyproterone acetate in reducing testosterone levels [12]. 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 [57]. [...] Table 8.2: Antiandrogens: [...] Androgen receptor blocker: [...] Type: Enzalutamide. Route: Oral. Dose: 160 mg/day.
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^Labrie F (January 2015). "Combined blockade of testicular and locally made androgens in prostate cancer: a highly significant medical progress based upon intracrinology". J. Steroid Biochem. Mol. Biol. 145: 144–56.
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^Traina TA, O'Shaughnessy J, Nanda R, Schwartzberg L, Abramson V, Cortes J, et al. (2015). "Abstract P5-19-09: Preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)". Cancer Research. 75 (9 Supplement): P5-19-09.
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