Oncology

Medical Pharmacology Chapter 33-34: Anticancer Drugs

Hormonal Anticancer Drugs:

Androgen receptor "superantagonist"³

Pharmacology of Enzalutamide (Xtandi) in Prostate Cancer Therapeutics

**(Gemini AI Assisted) [May 20, 2025]**

Overview Enzalutamide, marketed under the brand name Xtandi, is an oral androgen receptor (AR) signaling inhibitor. This agent represents a significant advancement in the treatment of various stages of advanced prostate cancer [1, 2]. Unlike first-generation antiandrogens, enzalutamide potently targets multiple steps in the AR signaling pathway, leading to improved clinical outcomes in patients with both castration-sensitive and castration-resistant prostate cancer [2, 3]. Its development was driven by the understanding that prostate cancer, even in castration-resistant states, often remains dependent on AR signaling for growth and progression [2]. Mechanism of Action Enzalutamide functions as a potent and selective androgen receptor inhibitor with a multi-faceted mechanism of action that distinguishes it from older antiandrogen agents [4]. Its primary actions include: Competitive Inhibition of Androgen Binding: Enzalutamide binds with high affinity to the ligand-binding domain of the AR, directly competing with androgens like testosterone and dihydrotestosterone (DHT). This prevents the conformational changes in the AR that are necessary for its activation [5]. Enzalutamide demonstrates a significantly higher binding affinity for the AR compared to first-generation nonsteroidal antiandrogens such as bicalutamide [5]. Inhibition of AR Nuclear Translocation: Upon activation, the AR typically translocates from the cytoplasm to the nucleus. Enzalutamide impairs this critical step, preventing the activated AR from reaching its target genes within the cell nucleus [6]. Impairment of AR Binding to DNA: Even if some ARs manage to translocate to the nucleus, enzalutamide hinders the ability of the AR to bind to specific DNA sequences known as androgen response elements (AREs) in the promoter and enhancer regions of target genes [7]. Inhibition of Coactivator Recruitment: The binding of coactivator proteins to the AR-DNA complex is essential for the transcriptional activation of androgen-responsive genes. Enzalutamide blocks the recruitment of these necessary coactivators, further preventing AR-mediated gene expression [1,8]. Pharmacokinetics Enzalutamide exhibits predictable pharmacokinetic properties with once-daily oral dosing [9]. Absorption: Following oral administration, the median time to reach maximum plasma concentration (Tmax) for enzalutamide is approximately 1 to 2 hours [10]. Food does not have a clinically meaningful effect on the extent of enzalutamide absorption, allowing it to be taken with or without meals [10]. Distribution: Enzalutamide is highly bound to plasma proteins (approximately 97-98%), primarily albumin. The mean apparent volume of distribution at steady state is about 110 L [11]. Metabolism: Enzalutamide is extensively metabolized in the liver, primarily by the cytochrome P450 (CYP) enzyme CYP2C8, and to a lesser extent by CYP3A4/5 [11]. Elimination: Enzalutamide has a long terminal elimination half-life of approximately 5.8 days (range 2.8 to 10.2 days) after a single oral dose [12]. The active metabolite, N-desmethyl enzalutamide, has an even longer half-life of about 7.8 to 8.6 days. With daily dosing, steady-state concentrations of enzalutamide are achieved by day 28 [12]. Elimination occurs mainly by liver metabolism, with about 71% of the administered dose recovered in urine (mainly as inactive metabolites) and 14% in feces after 30 days [12]. Renal excretion of unchanged enzalutamide and its active metabolite is very limited [12]. Drug Interactions Enzalutamide has significant potential for drug-drug interactions, primarily due to its effects on CYP enzymes [13]. Effects of Other Drugs on Enzalutamide: Strong CYP2C8 Inhibitors: Co-administration with strong CYP2C8 inhibitors (e.g., gemfibrozil) can significantly increase the plasma exposure of enzalutamide and its active metabolite. [13] If concomitant use is necessary, the enzalutamide dosage should be reduced . Strong CYP3A4 Inhibitors: While CYP3A4 plays a lesser role in enzalutamide metabolism, strong CYP3A4 inhibitors may increase enzalutamide exposure.[14]. CYP Inducers: Strong CYP3A4 inducers ( or moderate CYP2C8/CYP3A4 inducers may decrease enzalutamide exposure, potentially reducing its efficacy. Avoid co-administration if possible, or consider increasing the enzalutamide dose if clinically indicated [13,15]. Effects of Enzalutamide on Other Drugs: CYP3A4 Substrates: Enzalutamide is a strong inducer of CYP3A4. Enzalutamide can significantly decrease the plasma concentrations of drugs that are metabolized by CYP3A4, potentially reducing their efficacy. [16]. CYP2C9 and CYP2C19 Substrates: Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19. It can decrease the plasma concentrations of drugs metabolized by these enzymes. Monitor for efficacy and consider dose adjustments of the concomitant drug [16]. Clinical Use Enzalutamide (Xtandi) is approved for the treatment of adult men with prostate cancer in several settings [17] Metastatic Castration-Resistant Prostate Cancer (mCRPC): Enzalutamide is indicated for patients with mCRPC, both those who have previously received docetaxel and those who are chemotherapy-naïve. [18] Clinical trials like AFFIRM (post-chemotherapy) and PREVAIL (chemotherapy-naïve) demonstrated significant improvements in overall survival and radiographic progression-free survival with enzalutamide compared to placebo [19]. Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC): For patients with nmCRPC who are at high risk of developing metastases (typically defined by a rapid PSA doubling time), enzalutamide has been shown to significantly delay the time to metastasis and improve metastasis-free survival, as demonstrated in the PROSPER trial [20]. Non-Metastatic Castration-Sensitive Prostate Cancer (nmCSPC) with High-Risk Biochemical Recurrence (BCR): Enzalutamide has been approved for patients with nmCSPC with high-risk BCR (defined by PSA doubling time ≤ 9 months and PSA ≥ 2 ng/mL above nadir after radiation therapy or ≥ 1 ng/mL after radical prostatectomy with or without radiation therapy) in combination with leuprolide, or as monotherapy following radical prostatectomy for patients not receiving ADT and with PSA ≥ 0.2 ng/mL. The EMBARK trial supported this indication, showing improved metastasis-free survival [21]. Adverse Effects: Common adverse effects: [22] Fatigue/Asthenia Musculoskeletal pain Hot flashes Hypertension Diarrhea Headache Falls/fracture Peripheral edema Dizziness Reduced appetite Constipation Cognitive impairment Serious adverse effects: [23] Seizures Posterior Reversible Encephalopathy Syndrome (PRES) Hypersensitivity Reactions Ischemic Heart Disease Falls and Fractures Embryo-Fetal Toxicity Mechanism of Resistance AR dependent and AR independent [for details see reference [24] Conclusion Enzalutamide has revolutionized the treatment landscape for advanced prostate cancer by providing a potent, multi-targeted inhibition of the androgen receptor signaling pathway. Efficacy has been demonstrated across various disease states, from metastatic castration-sensitive disease to non-metastatic and metastatic castration-resistant prostate cancer, offering significant improvements in survival and quality of life for many patients. Drug interactions require careful management, and the eventual development of resistance remains a major clinical challenge. References 1. Enzalutamide (XTANDI) https://en.wikipedia.org/wiki/Enzalutamide 2. Schalken J Fitz J Enzalutamide: targeting the androgen signaling pathway in metastatic castration-resistant prostate cancer. BJU Int. 2015 June 6; 117(2) 215-225. https://pmc.ncbi.nlm.nih.gov/articles/PMC4744713/ 3. Davia I Martin A Stockler M et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381: 121-131. https://www.nejm.org/doi/full/10.1056/NEJMoa1903835 4. Park S Yoder B Li T Comparison of Second-Generation Antiandrogens for the Treatment of Prostate Cancer. JHOP April 2022 volume 12, No 2. (Review Article, Prostate Cancer, Antiandrogens) https://www.jhoponline.com/issue-archive/2022-issues/april-2022-vol-12-no-2/19338-comparison-of-second-generation-antiandrogens-for-the-treatment-of-prostate-cancer 5. Linder S van de Poel H Bergman A Zwart W Prekovic S Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond. Endocr Relat Cancer. 2018 September 14; 26(1): R31-R-52. https://pmc.ncbi.nlm.nih.gov/articles/PMC6215909/ (drug-induced conformational AR change, binding affinity) 6. Pollock J Wardell S Parent A et al. Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer. Nat Chem Biol 2016 August 8; 12(10): 795-801.https://pmc.ncbi.nlm.nih.gov/articles/PMC5030124/ (Blockade of androgen receptor nuclear entry) 7. Ito Y Sadar M Enzalutamide in blocking androgen receptor in advanced prostate cancer: lessons learned from the history of drug development of antiandrogens. Res Rep Urol. 2018 February 16; 10: 23-32. https://pmc.ncbi.nlm.nih.gov/articles/PMC5818862/ (Enzalutamide section; also Enzalutamide pharmacokinetics) 8. Tran C Ouk S Clegg N et al. Development of the Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer. Science. 2009 April 9; 324(5928): 787-790. 9. Gibbons J Ouatas T et al Clinical Pharmacokinetic Studies of Enzalutamide. Clin Pharmacokinet. 2015 April 28;54(21): 1043-1055. https://pmc.ncbi.nlm.nih.gov/articles/PMC4580721/ (Single day dosing) 10. Adeniji A Lynch L Kaland D Mody V Enzalutamide in the Treatment of Patients with Metastatic Castrate-Resistant Prostate Cancer JHOP Journal Hematology Oncology Pharmacy September 2017 volume 7, number 3.https://jhoponline.com/issue-archive/2017-issues/jhop-september-2017-vol-7-no-3/17188:enzalutamide-in-the-treatment-of-patients-with-metastatic-castrate-resistant-prostate-cancer-b (Time to reach maximal plasma levels; effect of food). 11. Enzalutamide: DrugBank https://go.drugbank.com/drugs/DB08899 (Volume of distribution protein binding) 12. Enzalutamide FDA package-insert https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf 13. Lennep B Mack J Poondru S Hood E Looney B Williams M Bianco J Morgans A Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy. Drug Saf. 2024 April 12;47(7): 617-641. https://pmc.ncbi.nlm.nih.gov/articles/PMC11182822/ 14. Gibbons J de Vries M Kauwinkel W Ohtsu Y Noukens J van der Walt J-S Mol R Mordenti J Quantas T Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet,. 2015 May 1;54(10): 1057-1069. https://pmc.ncbi.nlm.nih.gov/articles/PMC4580724/ 15. Poondru S Ghicavii V Khosravan R et al. Effective Enzalutamide on PK of P-gp and BCRP substrate in cancer patients: CYP450 induction may not always predict overall effect on transporters. CTS Clinical and Translational Science February 4, 2022. https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.13229 16. Enzalutamide: FDA package-insert (2012): section 7.2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf 17. Hoffman-Censits J Kelly W Practical guide to the use of Enzalutamide. Can J Urol 2014 April;21(2 Suppl 1): 64-69. https://pubmed.ncbi.nlm.nih.gov/24775726/ 18. Rodriguiz-Vida A Galazi M Rudman S Choudhury S Sternberg C Enzalutamide for the treatment of metastatic castration-resistant prostate cancer. Drug Des Devel Ther. 2015 June 29;9: 3325-3339. https://pmc.ncbi.nlm.nih.gov/articles/PMC4492664/ 19. Merseburger A Haas G von Klot C An update on Enzalutamide in the treatment of prostate cancer. Ther Adv Urol. 2015 February; 7(1): 9-21. https://pmc.ncbi.nlm.nih.gov/articles/PMC4294802/ 20. Sternberg C Fizazi K Saad F ... Hussain M Final overall survival (OS ) from PROSPER: A phase III, randomized, double-blind, placebo-controlled study of (EnzalutamideENZA) in men with nonmetastatic castration-resistant (prostate cancernmCRPC). Meeting abstract: 2020 ASCO Annual Meeting I May 25, 2020 : Abstract 5515 ; Journal of Clinical Oncology 38(_15suppl) May 2020. https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.5515 21. Freedland S de Almeida M De Giogi U ... Shore N Improve Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2023; 389(6): 1453-1465. https://www.nejm.org/doi/full/10.1056/NEJMoa2303974 22. XTANDI (Enzalutamide): Side Effects. https://www.xtandi.com/side-effects 23. XTANDI (Enzalutamide) Safety Profile. https://www.xtandihcp.com/safety 24. Blatt E Raj G Molecular mechanisms of Enzalutamide resistance in prostate cancer Cancer Drug Resist. 2019 June 19;20 (2) 189-197. https://pmc.ncbi.nlm.nih.gov/articles/PMC8992629/

Enzalutamide blocks binding of coactivator proteins to the androgen receptor-DNA complex

Overview: Enzalutamide (Xtandi)

Enzalutamide (Xtandi)

**Enzalutamide: Metastatic Prostate Cancer Treatment**¹¹

Attribution: Davis I Enzamet: Enzalutamide for metastate prostate cancer https://www.youtube.com/watch?v=2QDfcLrdCQ0 (6/2019). VJOncology Youtube Channel: https://www.youtube.com/channel/UCn3u5oMgE00_qIex2IzGjYg

Mechanism of Action:
- Enzalutamide (Xtandi) is considered a "superantagonist" because of its pure androgen receptor "signaling" inhibitor characteristics.⁵
  - Enzalutamide has not been shown to exhibit agonist characteristics.
  - Enzalutamide androgen receptor inhibition includes:⁵
    - Inhibition of androgen receptor nuclear translocation
    - Inhibition of DNA binding
    - Inhibition of coactivator mobilization
- Enzalutamide administration promotes:
  - Apoptosis
  - Decreased prostate tumor volume.
- Enzalutamide (Xtandi) is a recently approved second-generation antiandrogen agent.
  - Initially approved in 2018 for castration-resistant prostate cancer treatment, Enzalutamide (Xtandi) was subsequently approved by the FDA for castration-sensitive prostate cancer in 2019.
    1. Enzalutamide joins apalutamide (Erleada) in the second-generation nonsteroidal antiandrogen category¹.
  - Enzalutamide, and antagonist acting at the androgen receptor, is a diarylthiohydantoin agent that binds to the androgen receptor within affinity notably greater that that observed with bicalutamide or flutamide.³
  - In addition to acting at the receptor:³
    - Enzalutamide interferes with nuclear translocation of androgen receptor
    - Impairs DNA-binding to androgen response elements
    - Inhibits coactivator recruitment.³
Absorption, Distribution, Biotransformation, Excretion:¹³
- Absorption:
  - Enzalutamide is administered by the oral route of administration and can be taken with or without food.
- Distribution:
  - This drug is substantially bound to plasma proteins (about 98%), mainly to serum albumin.
- Biotransformation: Its active metabolite, N-desmethyl enzalutamide is also substantially bound (95%) to plasma proteins.
  - Enzalutamide is metabolized by the cytochrome P450 isoform CYP2C8 to an active metabolite N-desmethyl enzalutamide as well as by the isoform CYP3A4.
- Excretion:
  - Elimination is mainly by liver metabolism.
    - The enzalutamide half-life (t1/2) is about 6 days.
    - The mean N-desmethyl enzalutamide terminal t1/2 is about 8 days.

Clinical Uses:

**"Enzalutamide inproves survival for men with metastatic hormone-sensitive prostate cancer"**¹²

Attribution: Sweeney C Enzalutamide improves survival for men with metastatic hormone-sensitive prostate cancer https://www.youtube.com/watch?v=gNesz3lGMUY (6/2019) ecancer Youtube Channel https://www.youtube.com/channel/UCGb_Xmf5mzvyXC7NOjsonkg

Adverse Effects:
- Common adverse reactions (>10%) (partial list) include:
  - Cardiovascular effects such as:
    - Peripheral edema
    - Hypertension
  - CNS effects including:
    - Fatigue
    - Dzziness
    - Headache
  - Endocrine and metabolic abnormalities such as:
    - Hyperglycemia
  - Gastrointestinal effects such as
    - Constipation
    - Diarrhea
    - Nausea
    - Appetite reduction.
  - Hematological effects including
    - Reduced neutrophils and
    - Decreased white blood cell count.
  - Respiratory and neuromuscular/skeletal effects also occur.

References
Isaacs C Wellstein A Riegel AT Chapter 68 Hormones and Related Agents in the Therapy of Cancer in Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e, Brunton LL Hilal-Dandan R Knollmann BC, eds) 2018. Spring LM Moy B Endocrine Therapy of Breast Cancer Chapter 27 in: Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019. Giridhar KV Kohli M Goetz MP Chapter 30: Hormonal Agents in Principles & Practice of Oncology (DeVita, JR VT Lawrence TS Rosenberg SA, eds) 11e Wolters Kluwer Health 2019. Chu E Cancer Chemotherapy Chapter 54 in Basic & Clinical Pharmacology, 14 e (Katzung BG The McGraw-Hill Companies, 2018 (on-line edition) Roche VF Cancer and Chemotherapy Chapter 37 in Foye's Principles of Medicinal Chemistry (Lemke TL Williams DA Roche VF Zity SW, eds) Wolters Kluwer \| Lippincott Williams & Wilkins, Health, Philadelphia, 7e, 2013. Sausville EA Longo DL Chapter 69e Principles of Cancer Treatment, in Harrison's Online (J L Jamesonr, DL Kasper, DL Longo AS Fauci SL Hauser J Loscalzo, Eds.), Harrison's Principles of Internal Medicine, 20th edition, The McGraw-Hill Companies, Inc. 2018. Molitch ME Schimmer BP Chapter 42 Introduction to Endocrinology: The Hypothalamid-Pituitary Axis in the Therapy of Cancer in Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e, Brunton LL Hilal-Dandan R Knollmann BC, eds) 2018. Scher HI Eastham JA Chapter 83 Benign and Malignant Diseases of the Prostate in Harrison's Online (J L Jamesonr, DL Kasper, DL Longo AS Fauci SL Hauser J Loscalzo, Eds.), Harrison's Principles of Internal Medicine, 20th edition, The McGraw-Hill Companies, Inc. 2018. Whetstone JL Mohler ML Narayanan R Dalton JT Drugs Used to Advance Men's and Women's Health Chapter 24 in Foye's Principles of Medicinal Chemistry (Roche VF Zito SW Lemke T Williams DA, eds) Wolters Kluwer \| Lippincott Williams & Wilkins, Health, Philadelphia, 8e, 2020. Lee RJ Hormone Therapy for Prostate Cancer Chapter 28 in: Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019. Davis I Enzamet: Enzalutamide for metastate prostate cancer (June, 2019).https://www.youtube.com/watch?v=2QDfcLrdCQ0; VJOncology: https://www.youtube.com/channel/UCn3u5oMgE00_qIex2IzGjYg Sweeney C Enzalutamide improves survival for men with metastatic hormone-sensitive prostate cancer (June, 2019); https://www.youtube.com/watch?v=gNesz3lGMUY; ecancer (ecancer.org): https://www.youtube.com/channel/UCGb_Xmf5mzvyXC7NOjsonkg Enzalutamide (Xtandi®) National Drug Monograph May 2013 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and BISN Pharmacist Executives. https://www.pbm.va.gov/pbm/clinicalguidance/drugmonographs/enzalutamidedrugmonograph.pdf
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