Enzalutamide (Xtandi): Androgen Receptor Signaling Inhibitor for Prostate Cancer
Enzalutamide (brand name Xtandi) is a next-generation androgen receptor (AR) signaling inhibitor (ARSI), sometimes classified as a second-generation antiandrogen, used in the treatment of prostate cancer. Unlike first-generation antiandrogens such as bicalutamide, enzalutamide was rationally designed to overcome the resistance mechanisms that emerge with earlier agents, particularly AR gene amplification and mutations that convert first-generation antiandrogens into AR agonists.
Enzalutamide inhibits androgen signaling at three distinct levels within the AR activation pathway, providing a more complete and durable suppression of AR-driven transcription than single-mechanism antiandrogens. This triple mechanism of action has established enzalutamide as a pivotal treatment across multiple stages of prostate cancer, from castration-resistant prostate cancer after chemotherapy to hormone-sensitive metastatic disease in combination with androgen deprivation therapy. Enzalutamide is a strong inducer of cytochrome P450 enzymes, particularly CYP3A4, which creates a complex and clinically important drug interaction profile.
Mechanism of Action
Under normal conditions, androgens (primarily testosterone and dihydrotestosterone) bind to the androgen receptor in the cytoplasm. Ligand binding activates the AR by inducing conformational change, dissociation from chaperone proteins (heat shock proteins), and AR dimerization. The activated AR complex translocates into the nucleus where it binds to androgen response elements (AREs) in the promoter regions of target genes, recruiting coactivators and driving the transcription of genes that promote prostate cancer cell proliferation, survival, and differentiation. Enzalutamide disrupts this pathway at three critical steps. First, it competitively binds to the AR ligand-binding domain with approximately 5 to 8 times greater affinity than bicalutamide, effectively blocking androgen binding. Second, even when enzalutamide is bound to the AR, it prevents the conformational changes necessary for nuclear translocation, keeping the receptor trapped in the cytoplasm. Third, enzalutamide impairs the binding of the AR to DNA at androgen response elements, preventing recruitment of transcriptional coactivators even if some nuclear translocation occurs. The combined result is near-complete inhibition of AR-driven transcriptional activity. Enzalutamide does not exhibit the agonist activity at amplified or mutant ARs that is seen with first-generation antiandrogens such as bicalutamide. It also does not inhibit CYP17A1 (unlike abiraterone) and does not itself suppress androgen synthesis, acting solely at the receptor level. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19 and CYP2C9, which creates extensive and clinically important drug-drug interactions.
Indications
Enzalutamide is approved across multiple stages of prostate cancer. For metastatic castration-resistant prostate cancer (mCRPC), enzalutamide is approved both in patients who have received prior docetaxel chemotherapy (based on the AFFIRM trial) and in chemotherapy-naive patients (based on the PREVAIL trial). In both settings, enzalutamide demonstrated significant improvements in overall survival compared to placebo on a background of androgen deprivation therapy. For non-metastatic castration-resistant prostate cancer (nmCRPC), enzalutamide is approved for patients with rapidly rising PSA (PSA doubling time of 10 months or less) who are at high risk of developing metastatic disease, based on the PROSPER trial which showed significantly prolonged metastasis-free survival. For metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide was approved based on the ARCHES and ENZAMET trials, which demonstrated improved overall survival and radiographic progression-free survival when enzalutamide was added to standard androgen deprivation therapy in newly diagnosed metastatic hormone-sensitive disease. The expanding indication landscape reflects enzalutamide's activity across the spectrum of prostate cancer progression stages.
Dosage and Administration
The approved dose of enzalutamide is 160 mg (four 40 mg capsules) taken orally once daily, with or without food. Consistent daily dosing at approximately the same time is recommended for stable plasma concentrations. Enzalutamide should be taken whole and not chewed or crushed. If a dose is missed, it should be taken as soon as remembered on the same day; if not remembered until the next day, the missed dose should be skipped. Enzalutamide must be used in conjunction with androgen deprivation therapy (medical castration with a GnRH agonist or antagonist, or prior surgical orchiectomy) for most approved indications, as the drug does not independently suppress testosterone production. In patients with moderate hepatic impairment (Child-Pugh B), enzalutamide can be used without dose adjustment but requires monitoring. Severe hepatic impairment is a contraindication. No dose adjustment is required for renal impairment. The drug should be stored at room temperature and is available as soft gel capsules.
Side Effects
The adverse effects of enzalutamide include both expected consequences of further androgen suppression and drug-specific toxicities. Hot flashes are very common, reflecting enhanced suppression of androgen activity. Fatigue is a common and often clinically significant adverse effect that may limit daily functioning. Hypertension has been observed more frequently with enzalutamide than with placebo in clinical trials and requires monitoring and management. Falls and fractures are relevant safety concerns, related both to physical fatigue and to the bone loss associated with androgen deprivation therapy. Cognitive effects including memory impairment, attention difficulties, and mental fatigue have been reported and may be related to enzalutamide's partial CNS penetration (crossing the blood-brain barrier). Seizures represent a rare but serious adverse effect of enzalutamide; the drug was originally developed from a class of compounds with potential CNS toxicity and the clinical development program identified seizure risk, resulting in a contraindication in patients with a history of seizure or other risk factors for seizure (severe brain injury, prior seizure, stroke, brain metastasis). The incidence of seizures in clinical trials was approximately 0.5 percent. Headache, dizziness, and insomnia are commonly reported. Hematological abnormalities including neutropenia are uncommon. Anemia, related to androgen deprivation, can be clinically relevant.
Interactions
Enzalutamide's most clinically important pharmacological property relevant to interactions is its strong induction of CYP3A4, with moderate induction of CYP2C9 and CYP2C19. This makes enzalutamide one of the most potent CYP3A4 inducers in clinical use, comparable to rifampicin. When enzalutamide is co-administered with drugs that are CYP3A4 substrates, their plasma concentrations may fall dramatically, potentially to sub-therapeutic levels. Clinically critical examples include: docetaxel and cabazitaxel (chemotherapy agents commonly used in prostate cancer), whose plasma levels may be significantly reduced by enzalutamide, compromising treatment efficacy; direct oral anticoagulants (apixaban, rivaroxaban, edoxaban) are CYP3A4 substrates and their exposure is reduced by enzalutamide, potentially losing anticoagulant protection; immunosuppressants such as cyclosporine and tacrolimus; analgesics and other medications. For patients requiring concurrent medications, CYP3A4 interaction potential should be evaluated for each co-prescribed drug, and dose adjustments or therapeutic substitutions made as appropriate. Strong CYP3A4 inhibitors (clarithromycin, ketoconazole, ritonavir) would be expected to increase enzalutamide exposure, potentially increasing adverse effects. Enzalutamide is also a P-gp inducer and a breast cancer resistance protein (BCRP) inhibitor, adding to the complexity of its interaction profile. QT-prolonging drugs should be used with caution given that enzalutamide has been associated with modest QT interval changes in some studies.
Special Notes
Before initiating enzalutamide, patients should be screened for seizure risk factors. A personal or family history of seizure, prior brain surgery, recent stroke, or known brain metastases are relative or absolute contraindications depending on risk assessment. Seizure risk should be discussed with patients and families, and they should be advised to contact their physician immediately if a seizure occurs. Given the extensive CYP3A4 induction by enzalutamide, a comprehensive review of all concurrent medications is essential at treatment initiation, with regular review at follow-up as new medications are added. A clinical pharmacist review of the medication list is strongly recommended. Enzalutamide is not approved for use in women; it should not be used in patients who are pregnant or may become pregnant. Men treated with enzalutamide should use effective contraception during and for three months after treatment, as enzalutamide may harm a developing fetus. Bone health monitoring with DEXA scanning and appropriate supplementation (calcium, vitamin D) and antiresorptive therapy should be part of long-term management. Prostate-specific antigen (PSA) monitoring provides important information about treatment response, though PSA changes do not always reliably predict radiographic response or clinical outcomes and should be interpreted alongside clinical and imaging assessment.
Related Topics
Frequently Asked Questions
How does enzalutamide differ from bicalutamide?
Bicalutamide is a first-generation non-steroidal antiandrogen that competitively blocks the androgen receptor. While effective initially, prostate cancer cells adapt to bicalutamide through AR gene amplification, which increases the amount of AR protein and overcomes competitive blockade, and through specific AR mutations that convert bicalutamide from an antagonist to a partial agonist, actually stimulating tumor growth. Enzalutamide was specifically designed to have much greater AR affinity than bicalutamide and to maintain antagonist activity even at amplified or mutant ARs. Additionally, enzalutamide's triple mechanism blocking AR binding, nuclear translocation, and DNA binding provides more comprehensive AR pathway inhibition. Clinical trials have demonstrated superior survival outcomes with enzalutamide compared to bicalutamide in castration-resistant prostate cancer, leading to enzalutamide replacing bicalutamide as the preferred AR-targeting agent in this setting.
Why does enzalutamide increase the risk of seizures?
Enzalutamide was developed from a series of diarylthiohydantoin compounds that were found to have GABA-A receptor inhibitory activity in addition to AR antagonism. GABA-A receptors are the primary inhibitory neurotransmitter receptors in the CNS; their inhibition reduces the threshold for seizure generation. Enzalutamide crosses the blood-brain barrier to some extent and can inhibit GABA-A receptors in the brain, predisposing susceptible individuals to seizures. The risk is dose-dependent and is significantly higher in patients with pre-existing risk factors for seizures such as prior CNS pathology, stroke, or use of medications that lower the seizure threshold. At the approved 160 mg dose, the seizure incidence in clinical trials was approximately 0.5 percent in unselected populations, which is low but represents a clinically meaningful risk requiring patient counseling and screening before prescribing.
How should patients on enzalutamide manage potential drug interactions?
Enzalutamide is a strong inducer of CYP3A4 and can significantly reduce the plasma concentrations of many co-administered drugs that are CYP3A4 substrates. Patients and their oncologists should conduct a thorough review of all medications (including over-the-counter drugs, supplements, and herbal products) before starting enzalutamide and at each follow-up. St. John's Wort (a popular herbal supplement and strong CYP3A4 inducer that adds to enzalutamide's inducing effect) should be avoided entirely. Warfarin anticoagulation may be significantly affected, requiring more frequent INR monitoring or transition to an alternative anticoagulant. Patients should inform all healthcare providers including dentists and surgeons that they are taking enzalutamide. If a new medication needs to be started, checking whether it is a CYP3A4 substrate and what clinical impact enzalutamide induction might have on its levels is essential. Resources such as drug interaction databases should be used routinely by prescribing physicians and clinical pharmacists in this context.
Sources
- Beer TM et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy (PREVAIL). N Engl J Med. 2014.
- Scher HI et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy (AFFIRM). N Engl J Med. 2012.
- EMA: Xtandi (enzalutamide) Summary of Product Characteristics, current version.