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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: March 15, 2023.



Enzalutamide is a third generation, oral nonsteroidal antiandrogen used in the treatment of metastatic castration-resistant prostate cancer. Enzalutamide is associated with a low rate of serum enzyme elevation during therapy but has not been linked to cases of clinically apparent liver injury with jaundice.


Enzalutamide (en" za loo' ta mide) is an androgen receptor antagonist which binds to the intracellular receptor and prevents its translocation to the nucleus and subsequent DNA binding thereby blocking its activity. Therapy with enzalutamide has been shown to prolong relapse free as well as overall survival in men with metastatic, castration-resistant prostate cancer who had previously failed other forms of treatment. Enzalutamide was approved for use in the United States in 2012. Current indications are for castration-resistant prostate cancer and for metastatic, high risk castration-sensitive prostate cancer. In patients without previous bilateral orchiectomy, enzalutamide should be used in combination with a gonadotropin releasing hormone (GnRH) analog to insure optimal androgen suppression. Enzalutamide is available as capsules of 40 mg and tablets of 40 mg and 80 mg under the brand name Xtandi. The recommended dose is 160 mg by mouth once daily. Common side effects include fatigue, diarrhea, anorexia, weight loss, constipation, joint and muscle pain, hot flushes, headaches, dizziness, hypertension, hypokalemia, fluid retention, and edema. Rare, but potentially serious side effects include seizures and posterior reversible encephalopathy.


In preregistration controlled trials, serum aminotransferase elevations occurred in up to 10% patients treated with enzalutamide, but similar somewhat high rates occurred in patients receiving placebo (~9%). The liver test abnormalities were generally mild, transient and not associated with symptoms or jaundice. ALT elevations above 5 times the ULN were rare (0.2%) and also no more frequent than with placebo therapy. In addition, clinically apparent liver injury with jaundice was not reported in the preregistration trials of enzalutamide, and clinically apparent liver injury and hepatitis are not mentioned in the product label. Since the approval and more wide scale use of enzalutamide, there have been no publications or descriptions of the clinical features of hepatotoxicity with jaundice associated with its use. Thus, clinically apparent liver injury due to enzalutamide must be rare, if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the liver enzyme elevations that occur during enzalutamide therapy is unknown. Enzalutamide is extensively metabolized in the liver predominantly by CYP 3A4 and 2D6 and is a strong inducer of CYP 3A4 and a moderate inducer of 2D6. Enzalutamide is susceptible to drug-drug interactions with inhibitors, inducers or substrates of these microsomal enzymes.

Outcome and Management

The liver injury linked to enzalutamide therapy has been generally mild, consisting of transient and asymptomatic elevations in serum aminotransferase levels. Enzalutamide has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between enzalutamide and other antiandrogens, such as flutamide, bicalutamide, or abiraterone.

Drug Class: Antineoplastic Agents, Antiandrogens



Enzalutamide – Xtandi®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Enzalutamide 915087-33-1 C21-H16-F4-N4-O2 image 135261179 in the ncbi pubchem database


References updated: 15 March 2023

Abbreviations: LHRH, luteinizing hormone releasing hormone; PSA, prostate-specific antigen.

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    (Expert review of hepatotoxicity of cancer chemotherapeutic agents published in 1999 before the availability of enzalutamide).
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    (Among 165 patients with advanced hepatocellular carcinoma treated with enzalutamide [160 mg] or placebo once daily, the median overall survival rates were similar in both groups [7.8 vs 7.1 months] and adverse event rates were higher with enzalutamide [98% vs 89%] including fatigue [35% vs 18%], decreased appetite [32% vs 22%] and nausea [32% vs 22%], while rates of AST elevation above 5 times ULN were similar [11% vs 11%]; no mention of serious hepatic adverse events).
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    (Among 71 men with advanced prostate cancer treated with either enzalutamide [160 mg] or bicalutamide [50 mg] daily with androgen-depletion therapy using a LHRH analog, the biochemical and overall survival outcomes were greater with enzalutamide than bicalutamide, particularly in Black subjects; no mention of hepatic adverse events).
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    (Comparison of outcome and adverse events in published randomized, placebo controlled trials of darolutamide, apalutamide and enzalutamide for castration-resistant prostate cancer suggested that efficacy as assessed by improvement in metastasis-free survival was similar for all three agents, but that darolutamide therapy was associated with lower rates of adverse events, particularly fatigue, rash, falls, seizures, fractures and cognitive disorders; no mention of ALT elevations or hepatotoxicity).
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    (Among 828 patients with prostate cancer who received abiraterone or enzalutamide or both, adverse events arose in 29% on abiraterone, 26% on enzalutamide, usually within the first 3 months; abnormal liver tests arose in 48% vs 23% and hypertension in 47% vs 77%, but there were no adverse event related deaths).
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    (Among 1732 men with metastatic castration-resistant prostate cancer in a prospective, open-label study, the mean time to treatment failure was 12.9 months and adverse event rates ranged from 51-62% per year; no mention of liver related adverse events).
  • Scailteux LM, Despas F, Balusson F, Campillo-Gimenez B, Mathieu R, Vincendeau S, Happe A, et al. Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: A French population-based study on prostate cancer patients. Br J Clin Pharmacol. 2022;88:336–346. [PubMed: 34224605]
    (Among 11,534 patients newly started on abiraterone or enzalutamide therapy for prostate cancer who were enrolled in the French National Health Insurance System Database between 2013 and 2017, liver test abnormalities were more frequent with abiraterone [17% vs 6%] as were acute kidney injury and atrial fibrillation, while “hepatitis” was rare [<0.1%]).


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