Enzalutamide isindicated 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]
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 aPSA doubling time ≤ 6 months.[17]
Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials.[20][22] This is thought to be due to enzalutamide crossing theblood–brain barrier[26][27] and exerting off-target binding to and inhibition of theGABAA receptor in thecentral nervous system (it has been found to inhibit the GABAA receptorin vitro (IC50Tooltip half-maximal inhibitory concentration = 3.6 μM)[27][28][29] and inducesconvulsions in animals at high doses).[20][22] In addition to seizures, other potentially GABAA receptor-related side effects observed with enzalutamide treatment in clinical trials have includedanxiety,insomnia,vertigo,paresthesia, and headache.[30] Due to its ability to lower theseizure threshold, patients with knownseizure disorders orbrain injury should be closely monitored during enzalutamide treatment.[31] NSAA-induced seizures are responsive tobenzodiazepine treatment, and it has been suggested that GABAA receptor inhibition by enzalutamide could be treated with these drugs.[28] Indose-ranging studies, severefatigue was observed with enzalutamide at doses of 240 mg/day and above.[32][33]
In a clinical study of enzalutamide forERTooltip estrogen receptor-positivebreast cancer in women, enzalutamide was found to decrease serum concentrations of thearomatase inhibitorsanastrozole andexemestane by 90% and 50%, respectively, which could reduce their effectiveness.[36]
WhenLNCaP 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 andTMPRSS2 was down regulated in contrast to bicalutamide where the expression was upregulated.[37] In VCaP cells which over-express the AR, enzalutamide inducedapoptosis whereas bicalutamide did not.[37] Furthermore, enzalutamide behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pureagonist when bound to the W741C mutant.[37]
Enzalutamide has approximately 8-fold higherbinding affinity for theandrogen receptor (AR) compared tobicalutamide.[37][40] One study found anIC50Tooltip half-maximal inhibitory concentration of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in theLNCaP cell line (7.6-fold difference),[41] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference).[42] 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.[25][39] Also, unlike with the first-generation NSAAs, there has been no evidence ofhepatotoxicity orelevated liver enzymes in association with enzalutamide treatment in clinical trials.[43][44]
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.[45] Currently, several mechanisms have been found:
Enzalutamide is reported to be a stronginducer of theenzymeCYP3A4 and a moderate inducer ofCYP2C9 andCYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes.[55][35]
Enzalutamide was discovered byCharles Sawyers andMichael Jung at theUniversity of California, Los Angeles.[57][58][59] They and their colleaguessynthesized and evaluated nearly 200thiohydantoinderivatives ofRU-59063, ananalogue ofnilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide andRD-162 as lead compounds.[37][59] These compounds werepatented in 2006 and described in 2007.[12] Enzalutamide was developed and marketed byMedivation for the treatment of prostate cancer.[60] It was approved by the USFood 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.[20][61] 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 NSAAbicalutamide in 1995.[62] It was the first second-generation NSAA to be introduced.[15]
In July 2018, the FDA approved enzalutamide for the treatment of people with castration-resistant prostate cancer.[63] The approval broadens the indication to include people with both non-metastatic castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.[63] Enzalutamide was previously approved for the treatment of people with metastatic castration-resistant prostate cancer.[63]
In December 2019, the FDA approved enzalutamide for the treatment of people with metastatic castration-sensitive prostate cancer (mCSPC).[11] Enzalutamide was previously approved for the treatment of people with castration-resistant prostate cancer.[11]
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).[64]
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).[65] Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled clinical trial of 1068 patients with nmCSPC with high-risk BCR.[65] 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.[65] 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.[65] The application was grantedpriority review andfast track designations.[65]
In June 2024, theCommittee for Medicinal Products for Human Use of theEuropean 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.[66][67] The applicant for this medicinal product is Viatris Limited.[66] Enzalutamide Viatris is ageneric of Xtandi.[66]
Research suggests that enzalutamide may be effective in the treatment of certain types ofbreast cancer in women.[69][70] It has been tested for the treatment of triple-negative, AR-positive breast cancer in aphase IIclinical trial.[71][72]
^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.doi:10.1007/s12272-015-0592-9.PMID25956695.S2CID26903608.
^abSaad F, Heinrich D (2013). "New Therapeutic Options for Castration-resistant Prostate Cancer".The Journal of Oncopathology.1 (4):23–32.doi:10.13032/tjop.2052-5931.100072 (inactive 11 November 2024).{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^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.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Fishman SL, Paliou M, Poretsky L, Hembree WC (2019). "Endocrine Care of Transgender Adults".Transgender Medicine. Contemporary Endocrinology. pp. 143–163.doi:10.1007/978-3-030-05683-4_8.ISBN978-3-030-05682-7.ISSN2523-3785.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.
^abcdeTombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, et al. (May 2014). "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study".The Lancet. Oncology.15 (6):592–600.doi:10.1016/S1470-2045(14)70129-9.PMID24739897.
^Vogelzang NJ (September 2012). "Enzalutamide--a major advance in the treatment of metastatic prostate cancer".The New England Journal of Medicine.367 (13):1256–7.doi:10.1056/NEJMe1209041.PMID23013078.
^abFoster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, et al. (2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists".The Prostate.71 (5):480–8.doi:10.1002/pros.21263.PMID20878947.S2CID24620044.
^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.doi:10.1016/j.jsbmb.2014.05.012.PMID24925260.S2CID23102323.
^Keating GM (March 2015). "Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer".Drugs & Aging.32 (3):243–9.doi:10.1007/s40266-015-0248-y.PMID25711765.S2CID29563345.
^Claessens F, Helsen C, Prekovic S, Van den Broeck T, Spans L, Van Poppel H, et al. (December 2014). "Emerging mechanisms of enzalutamide resistance in prostate cancer".Nature Reviews Urology.11 (12):712–6.doi:10.1038/nrurol.2014.243.PMID25224448.S2CID13313385.
^abc"Enzalutamide Viatris EPAR".European Medicines Agency. 27 June 2024. Retrieved29 June 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^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.doi:10.1158/1538-7445.SABCS14-P5-19-09.
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