Drug Monograph
Xtandi (Enzalutamide)
enzalutamide
Pharmacokinetic Profile
Half-Life
5.8 days (parent); ~8 days (active metabolite)
Metabolism
CYP2C8 (primary), CYP3A4
Protein Binding
97–98% (albumin)
Bioavailability
High (food has no clinically meaningful effect)
Volume of Distribution
110 L
Clinical Information
Drug Class
Androgen Receptor Inhibitor
Available Doses
40 mg capsule; 40 mg & 80 mg tablets
Route
Oral
Renal Adjustment
None for CrCl ≥30 mL/min; not studied <30
Hepatic Adjustment
None (Child-Pugh A, B, or C)
Pregnancy
Contraindicated — embryo-fetal toxicity
Lactation
Not indicated for use in women
Schedule / Legal Status
Rx Only (not a controlled substance)
Generic Available
Yes
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Castration-resistant prostate cancer (CRPC) | Adult males | Monotherapy + concurrent GnRH analog or bilateral orchiectomy | FDA Approved |
| Metastatic castration-sensitive prostate cancer (mCSPC) | Adult males | Combined with GnRH analog or bilateral orchiectomy | FDA Approved |
| Non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence (nmCSPC with high-risk BCR) | Adult males with PSA doubling time ≤9 months after definitive local therapy | With or without GnRH analog | FDA Approved |
Enzalutamide is one of the most broadly indicated androgen receptor inhibitors in prostate cancer, covering the disease spectrum from high-risk biochemical recurrence through metastatic castration-resistant disease. Its approval across these clinical stages was established through five pivotal randomized controlled trials (AFFIRM, PREVAIL, PROSPER, ARCHES, and EMBARK), each demonstrating meaningful improvements in progression-free survival or overall survival endpoints. Enzalutamide is not indicated for use in women or pediatric patients.
Off-Label Uses
Combination with talazoparib for HRR-mutated mCRPC: In June 2023, the FDA approved talazoparib in combination with enzalutamide for HRR gene-mutated mCRPC based on the TALAPRO-2 trial. While the combination is FDA-approved for talazoparib’s label, prescribers may encounter this regimen in clinical practice. Evidence quality: High (phase 3 RCT).
Dosing
Primary Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| mCRPC — post-docetaxel | 160 mg once daily | 160 mg once daily | 160 mg/day | Continue concurrent GnRH analog. No titration required. Treat until disease progression or unacceptable toxicity. AFFIRM trial setting |
| mCRPC — chemotherapy-naive | 160 mg once daily | 160 mg once daily | 160 mg/day | Requires concurrent GnRH analog or prior bilateral orchiectomy. PREVAIL trial setting |
| Non-metastatic CRPC | 160 mg once daily | 160 mg once daily | 160 mg/day | Continue GnRH analog. PSA doubling time ≤10 months. PROSPER trial setting |
| Metastatic castration-sensitive prostate cancer | 160 mg once daily | 160 mg once daily | 160 mg/day | Combine with GnRH analog or after bilateral orchiectomy. Concurrent docetaxel is not permitted. ARCHES trial setting |
| nmCSPC with high-risk BCR | 160 mg once daily | 160 mg once daily | 160 mg/day | May be given with or without GnRH analog. Treatment can be suspended if PSA <0.2 ng/mL after 36 weeks. Reinitiate at PSA ≥2.0 ng/mL (post-prostatectomy) or ≥5.0 ng/mL (post-radiation). EMBARK trial setting |
Dose Modifications
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Grade ≥3 or intolerable adverse reaction | Withhold for 1 week or until ≤ Grade 2 | 160 mg/day | Resume at same or reduced dose (120 mg or 80 mg) as clinically warranted | |
| Concurrent strong CYP2C8 inhibitor (e.g., gemfibrozil) | 80 mg once daily | 80 mg once daily | 80 mg/day | Return to prior dose when inhibitor is discontinued. Avoid combination if possible. |
| Concurrent strong CYP3A4 inducer (e.g., rifampin) | 240 mg once daily | 240 mg once daily | 240 mg/day | Return to prior dose when inducer is discontinued. Avoid combination if possible. |
Clinical Pearl: Treatment Suspension in nmCSPC
Enzalutamide is the first androgen receptor inhibitor to incorporate a structured treatment-suspension protocol for biochemical recurrence. In the EMBARK trial, approximately 86–91% of patients achieved undetectable PSA at week 36 and had treatment suspended, with reintroduction guided by PSA thresholds. This approach may reduce cumulative side effect burden while preserving metastasis-free survival benefit. Capsules and tablets may be taken with or without food; swallow whole without crushing, chewing, or opening.
Pharmacology
Mechanism of Action
Enzalutamide acts on multiple nodes of the androgen receptor (AR) signaling cascade, distinguishing it from first-generation antiandrogens such as bicalutamide. It competitively binds the ligand-binding domain of the AR with higher affinity than bicalutamide, preventing testosterone and dihydrotestosterone from activating the receptor. Beyond ligand blockade, enzalutamide inhibits nuclear translocation of the AR complex, blocks its binding to androgen response elements on DNA, and prevents recruitment of transcriptional co-activators. The active metabolite N-desmethyl enzalutamide demonstrates comparable in vitro potency. In preclinical xenograft models, enzalutamide induced tumor regression rather than merely slowing growth, and it lacks the agonist activity observed with older antiandrogens in AR-overexpressing tumour cells.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Median Tmax 1 h (capsules), 2 h (tablets); food has no clinically meaningful effect; dose-proportional across 30–360 mg range | Rapid oral absorption; can be taken without regard to meals, simplifying adherence |
| Distribution | Vd 110 L; protein binding 97–98% (albumin); N-desmethyl enzalutamide 95% bound | Extensive tissue distribution; high protein binding means free-fraction shifts possible with hypoalbuminaemia |
| Metabolism | CYP2C8 (primary) and CYP3A4 form active metabolite N-desmethyl enzalutamide; carboxylesterase 1 forms inactive carboxylic acid metabolite | Dual CYP pathway creates clinically significant interaction potential with CYP2C8 inhibitors and CYP3A4 inducers; dose adjustments are mandated (FDA PI) |
| Elimination | t½ 5.8 days (parent), 7.8–8.6 days (N-desmethyl); CL/F 0.56 L/h; steady state by Day 28; ~8.3-fold accumulation; primarily hepatic elimination | Very long half-life means washout takes approximately 1 month; supports once-daily dosing but delays both onset and offset of drug interactions |
Side Effects
Adverse reaction data are drawn from pooled analysis of five placebo-controlled trials (AFFIRM, PREVAIL, PROSPER, ARCHES, EMBARK; enzalutamide N = 3,526, placebo N = 2,636). Incidence rates reflect the enzalutamide arm unless otherwise stated. Rates vary substantially across trials depending on disease stage, concurrent ADT use, and treatment duration. Where ranges are shown, they represent the minimum and maximum observed rates across the five pivotal studies.
≥10%
Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fatigue / asthenic conditions | 33–54% | Most common treatment-limiting effect; dose reduction to 120 mg or 80 mg may help; most frequent reason for discontinuation across trials |
| Musculoskeletal pain | 43–50% | Includes back pain, arthralgia, and pain in extremities; assess for bone metastasis progression before attributing to treatment |
| Hot flush | 13–69% | Higher rates when combined with GnRH analog (EMBARK: 69%); lower with enzalutamide monotherapy (22%); reflects androgen deprivation |
| Decreased appetite | 10–19% | Monitor weight; rarely requires intervention |
| Hypertension | 12–25% | Grade 3–4 in 3–7% of patients; requires proactive BP monitoring and management (FDA PI) |
| Fall | 11–21% | Not associated with seizure or syncope in clinical trials; assess gait and fall risk routinely (FDA PI) |
| Diarrhea | 12–22% | Generally Grade 1–2; rarely treatment-limiting |
| Fracture | 10–18% | Includes all osseous fractures; Grade 3–4 in 2–4%; consider bone-targeted agents per guidelines (FDA PI) |
| Headache | 9–12% | Usually mild; if severe or associated with visual changes, evaluate for PRES |
| Dizziness / vertigo | 9–12% | Warn about driving and operating machinery; contributes to fall risk; highest in PROSPER (12%) |
| Hemorrhage | 15–21% | Includes epistaxis, haematuria, and other bleeding events; review anticoagulant use |
| Constipation | 9–23% | Highest in PREVAIL (23%); lower in PROSPER (9%); proactive bowel regimen recommended in elderly patients |
| Peripheral oedema | 8–15% | Highest in AFFIRM (15%); assess for cardiac or renal aetiology if significant |
| Nausea | 9–15% | Highest in EMBARK monotherapy (15%); generally mild; rarely requires antiemetics |
| Upper respiratory tract infection | 6–16% | Highest in PREVAIL (16%); includes nasopharyngitis, sinusitis, pharyngitis; generally self-limiting |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Cognitive / memory impairment | 4.5–10% | Includes amnesia, cognitive disorder, and attention disturbance; may be compounded by ADT effects |
| Weight loss | 6–12% | Monitor nutritional status, particularly in elderly patients receiving prolonged therapy |
| Insomnia | 6–9% | Often co-occurs with hot flushes; sleep hygiene counselling may help |
| Gynecomastia | 3–49% | Dramatically higher with enzalutamide monotherapy (49% in EMBARK) vs combination with GnRH analog (9%); reflects unopposed oestrogen action when androgens are blocked without castrate testosterone levels |
| Breast tenderness | 2.8–35% | Follows same pattern as gynecomastia: 35% with monotherapy (EMBARK) vs 5% with ADT combination; usually accompanies gynecomastia |
| Anxiety | 2.8–6% | Address concomitant factors including cancer-related distress |
| Restless legs syndrome | 2.1–2.4% | Reported in PREVAIL (2.1%) and ARCHES (2.4%); may impair sleep quality |
| Dysgeusia | 3.7–8% | Altered taste; may contribute to decreased appetite; generally reversible |
Serious
Serious Adverse Effects (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Seizure | 0.6% (2.2% with predisposing factors) | 13–2,250 days after initiation | Permanently discontinue enzalutamide; all seizures resolved upon discontinuation in clinical trials (FDA PI) |
| Posterior reversible encephalopathy syndrome (PRES) | Very rare | Variable | Discontinue enzalutamide; confirm diagnosis by brain MRI; manage hypertension and seizures supportively (FDA PI) |
| Ischemic heart disease | 3.5% (vs 2% placebo); Grade 3–4: 1.8% | Any time during treatment | Discontinue for Grade 3–4 events; optimize cardiovascular risk factors proactively; 0.4% fatal on enzalutamide vs 0.1% placebo (FDA PI) |
| Hypersensitivity reactions (face, tongue, lip oedema; pharyngeal oedema) | Uncommon (face 0.5%, tongue 0.1%, lip 0.1%); pharyngeal oedema post-marketing | Any time | Temporarily discontinue and seek medical evaluation; permanently discontinue for serious reactions (FDA PI) |
| Severe cutaneous adverse reactions (SJS, TEN, DRESS, AGEP) | Very rare (post-marketing) | Days to weeks | Immediately discontinue; specialist dermatology and supportive care; do not rechallenge (FDA PI) |
| Grade 3–4 fractures | 2–4% (vs 1.9% placebo in pooled analysis) | Median ~420 days | Evaluate fracture risk at baseline; consider bone-targeted agents; orthopaedic management as needed (FDA PI) |
Discontinuation
Discontinuation Rates
mCRPC (Post-Chemo — AFFIRM)
16% (enzalutamide arm)
Top reasons: Seizure (0.9%), fatigue, disease progression
nmCSPC with BCR (EMBARK)
21% vs 10% placebo + leuprolide
Top reasons: Fatigue (3.4%), hot flush (2%), nausea (1.1%), cognitive disorder (1.1%)
| Trial / Setting | Discontinuation Rate | Context |
|---|---|---|
| AFFIRM (mCRPC post-chemo) | 16% | Median treatment duration 8.3 months; seizure most common specific reason (0.9%) |
| PREVAIL (mCRPC chemo-naive) | 6% | Median treatment 17.5 months; fatigue/asthenia led to discontinuation in ~1% |
| PROSPER (nmCRPC) | 9% | Median treatment 18.4 months; fatigue 1.6% |
| ARCHES (mCSPC) | 4.9% | Median treatment 12.8 months; ALT/AST increase and seizure each 0.3% |
| EMBARK (nmCSPC + leuprolide) | 21% | Median total treatment 60.6 months; fatigue 3.4%, hot flush 2% |
| EMBARK (nmCSPC monotherapy) | 18% | Median total treatment 60.4 months; fatigue 3.7%, cognitive disorder 1.4% |
Managing Fatigue
Fatigue is the single most common treatment-limiting adverse effect of enzalutamide across all disease stages. It is dose-related and can be managed by dose reduction to 120 mg or 80 mg daily. Structured exercise programs and attention to sleep hygiene may also help. In the EMBARK trial, fatigue was the most frequent reason for dose reduction (3–10% of patients). If fatigue persists despite dose adjustment, treatment interruption should be considered.
Drug Interactions
Enzalutamide has a dual interaction profile: it is metabolized by CYP2C8 and CYP3A4, and it is itself a potent inducer of CYP3A4, CYP2C9, CYP2C19, and CYP2B6. This makes enzalutamide both a target of drug interactions and a perpetrator of interactions with co-prescribed medications. The very long half-life (5.8 days) means that induction effects persist for approximately one month after discontinuation.
Major
Gemfibrozil (strong CYP2C8 inhibitor)
MechanismCYP2C8 inhibition increases composite AUC of enzalutamide + N-desmethyl enzalutamide by 2.2-fold
EffectMarkedly increased enzalutamide exposure with greater adverse effect risk, including seizure
ManagementAvoid combination; if unavoidable, reduce enzalutamide to 80 mg daily
FDA PI
Major
Warfarin (CYP2C9 substrate)
MechanismEnzalutamide induces CYP2C9, reducing S-warfarin AUC by 56%
EffectSubstantially reduced anticoagulant effect; risk of sub-therapeutic INR
ManagementIncrease INR monitoring frequency; consider alternative anticoagulant (e.g., LMWH) if stable dosing cannot be achieved
FDA PI
Major
Rifampin (strong CYP3A4 inducer)
MechanismCYP3A4 and moderate CYP2C8 induction reduces composite AUC of enzalutamide + metabolite by 37%
EffectReduced enzalutamide efficacy
ManagementAvoid combination; if unavoidable, increase enzalutamide to 240 mg daily
FDA PI
Major
CYP3A4 substrates with narrow TI (e.g., midazolam, cyclosporine, tacrolimus)
MechanismStrong CYP3A4 induction by enzalutamide; midazolam AUC reduced by 86%
EffectNear-complete loss of efficacy for sensitive CYP3A4 substrates
ManagementAvoid substrates where minimal concentration decrease leads to therapeutic failure; increase substrate dose per its PI if unavoidable
FDA PI
Moderate
Omeprazole / PPIs (CYP2C19 substrates)
MechanismModerate CYP2C19 induction; omeprazole AUC reduced by 72%
EffectReduced acid suppression; potential breakthrough reflux or peptic ulcer disease
ManagementMay need to increase PPI dose; monitor symptom control; consider H2 blockers as alternative
FDA PI
Moderate
Digoxin (P-gp substrate)
MechanismPossible P-gp modulation; digoxin AUC increased by 33%
EffectModest increase in digoxin exposure; narrow TI drug — may reach toxic levels
ManagementMonitor digoxin levels and clinical signs of toxicity; consider dose reduction of digoxin
FDA PI
Minor
Itraconazole (strong CYP3A4 inhibitor)
MechanismCYP3A4 inhibition increases composite AUC by only 1.3-fold
EffectClinically modest increase in exposure; CYP2C8 is the more important metabolic pathway
ManagementNo dose adjustment required; monitor for adverse effects
FDA PI
Moderate
Medications lowering seizure threshold (e.g., tramadol, meperidine, certain antipsychotics)
MechanismAdditive seizure risk; enzalutamide independently lowers seizure threshold
EffectIncreased seizure risk above the baseline 0.6% rate
ManagementCarefully assess risk-benefit; avoid if safer alternatives exist; in XTANDI seizure study, 2.2% of patients with predisposing factors had seizures
FDA PIMonitoring
-
Blood Pressure
Baseline, then every 1–3 months
Routine Hypertension reported in 12–25% of patients (Grade 3–4 in 3–7%). Optimize antihypertensive therapy proactively, particularly in patients with pre-existing cardiovascular disease. -
PSA
Every 3–4 months (or per guideline)
Routine Primary marker of treatment response. In nmCSPC with BCR setting, undetectable PSA (<0.2 ng/mL) at week 36 triggers treatment suspension eligibility. -
Imaging (CT / bone scan)
Per institutional protocol (typically every 3–6 months)
Routine Assess radiographic progression. Consider bone scan at baseline and periodically given elevated fracture risk (10–18%). -
Bone Density / Fracture Risk
Baseline, then annually or as indicated
Routine Falls (11–21%) and fractures (10–18%) are significantly increased. Assess with DEXA scan; consider bone-protective agents (bisphosphonates, denosumab) per established guidelines. -
Fall Risk Assessment
Baseline, then at each visit
Routine Enzalutamide-related dizziness and fatigue contribute to fall risk. Ensure appropriate home safety measures, especially in elderly patients (≥75 years, who comprised 33% of trial populations). -
Cardiovascular Assessment
Baseline, then periodically
Routine Ischemic heart disease 3.5% vs 2% placebo; fatal events 0.4% vs 0.1%. Optimize modifiable cardiovascular risk factors (hypertension, diabetes, dyslipidaemia) before and during treatment. -
Seizure History / Neurological Assessment
Baseline (comprehensive review)
Trigger-based Screen for predisposing factors: history of seizure, TBI, stroke, brain metastases, concurrent seizure-threshold-lowering medications. Patients with risk factors had 2.2% seizure rate. -
Hepatic Transaminases
Periodically during treatment
Trigger-based ALT/AST elevations led to discontinuation in 0.3% (ARCHES). While no routine hepatic adjustment is needed, monitor if symptoms suggest hepatotoxicity. -
INR (if on warfarin)
At initiation, weekly initially, then regularly
Trigger-based Enzalutamide reduces S-warfarin AUC by 56% via CYP2C9 induction. Requires frequent INR monitoring and likely warfarin dose increases.
Contraindications & Cautions
Absolute Contraindications
- Pregnancy or potential pregnancy in female partners: Enzalutamide causes embryo-fetal toxicity and pregnancy loss based on animal data and mechanism of action. Males must use effective contraception during treatment and for 3 months after the last dose (FDA PI).
The FDA prescribing information for enzalutamide lists no absolute contraindications in the treated population (adult males with prostate cancer). However, the embryo-fetal toxicity risk effectively contraindicates use in any situation where reproductive harm could occur.
Relative Contraindications (Specialist Input Recommended)
- History of seizure or conditions predisposing to seizure: Patients with prior seizure, brain metastases, traumatic brain injury, stroke, or concurrent medications lowering seizure threshold had a 2.2% seizure rate in dedicated safety studies. Most pivotal trials excluded these patients. Prescribing requires documented risk-benefit discussion.
- Active or recent ischemic heart disease: Ischemic events occurred in 3.5% of enzalutamide-treated patients with fatal outcomes in 0.4%. Patients with unstable angina, recent MI, or decompensated heart failure require specialist cardiovascular assessment before initiation.
Use with Caution
- Severe renal impairment (CrCl <30 mL/min) or end-stage renal disease: Not studied; use with caution and close monitoring.
- Patients receiving narrow therapeutic index CYP3A4, CYP2C9, or CYP2C19 substrates: Enzalutamide is a strong CYP3A4 inducer. Near-complete loss of efficacy of co-administered sensitive substrates (e.g., midazolam AUC reduced by 86%). Dose adjustments or alternative agents may be required.
- Elderly patients (≥75 years): No dose adjustment needed, but falls (12% overall), fractures (13%), and fatigue (33–54%) are of particular concern. Proactive fall-risk assessment and bone health management are recommended.
- Patients at high fracture risk: Falls (11–21%) and fractures (10–18%) are increased. Consider bone-targeted therapy (bisphosphonates, denosumab) and routine DEXA monitoring.
- Concurrent use of anticoagulants: CYP2C9 induction may reduce efficacy of warfarin and potentially other vitamin K antagonists. Close INR monitoring and possible switch to LMWH or DOACs are recommended.
FDA Safety Communication
Seizure Risk, Ischemic Heart Disease, Falls and Fractures
Enzalutamide carries warnings for seizure (0.6% overall; 2.2% in patients with predisposing factors), ischemic heart disease (3.5% vs 2% placebo; fatal events 0.4% vs 0.1%), and falls and fractures (12% and 13% respectively vs 6% each with placebo). Seizure is an absolute indication for permanent discontinuation. Ischemic heart disease Grade 3–4 requires discontinuation. Patients should be monitored for signs and symptoms of these conditions and managed with cardiovascular risk factor optimization and fracture-prevention strategies.
Patient Counselling
Purpose of Therapy
Enzalutamide works by blocking the action of male hormones (androgens) at multiple points in the signalling pathway that drives prostate cancer growth. It is used across several stages of prostate cancer to delay disease progression, prevent metastasis, and extend survival. It does not cure prostate cancer but is an important part of the overall treatment plan alongside other therapies such as GnRH agonists or surgical castration.
How to Take
Take four 40 mg capsules or two 80 mg tablets (total 160 mg) at the same time each day, with or without food. Swallow capsules and tablets whole. Do not crush, chew, dissolve, or open capsules. If a dose is missed, take it as soon as remembered the same day. If the entire day’s dose is missed, take the regular dose the next day. Never take a double dose. Continue any concurrent GnRH therapy unless directed otherwise by the prescriber.
Fatigue
Tell patient
Tiredness is the most common side effect and affects up to half of patients. It often improves over weeks to months. Light exercise and maintaining a regular sleep schedule may help. The dose can be reduced if fatigue significantly affects daily activities.
Call prescriber
If fatigue is severe enough to prevent normal daily activities, or if it worsens rather than improving over time.
Seizure Risk
Tell patient
There is a small risk of seizure (less than 1 in 100 patients). Avoid activities where sudden loss of consciousness could be dangerous, such as swimming alone or operating heavy machinery, if at increased risk. Tell the prescriber about any history of seizures, head injury, or stroke before starting treatment.
Call prescriber
Immediately if a seizure occurs or if there is any loss of consciousness. Treatment will be permanently stopped.
Falls & Bone Fractures
Tell patient
Risk of falls and bone fractures is increased during treatment. Take precautions to prevent falls: remove tripping hazards at home, use handrails, wear appropriate footwear, and avoid rushing. Calcium and vitamin D supplementation may be recommended.
Call prescriber
If a fall results in injury, or if new or worsening bone pain develops, as this could indicate a fracture or disease progression.
Heart Health
Tell patient
Blood pressure and heart health will be monitored regularly. Maintain a healthy lifestyle with regular exercise (as tolerated), a balanced diet, and adherence to any prescribed blood pressure or cholesterol medications.
Call prescriber
Immediately if experiencing chest pain, shortness of breath at rest or with exertion, or symptoms of a heart attack or stroke.
Contraception & Fertility
Tell patient
Enzalutamide can harm an unborn baby. Male patients with female partners of childbearing potential must use reliable contraception during treatment and for 3 months after the last dose. Use a condom during sex with a pregnant partner. Enzalutamide may impair male fertility.
Call prescriber
If a female partner becomes pregnant or suspects pregnancy during treatment.
Drug Interactions
Tell patient
Enzalutamide can affect how many other medications work, including blood thinners, certain heart medications, anti-seizure drugs, and even common acid-reflux medicines. Always inform every healthcare provider about enzalutamide use before starting any new medication, including over-the-counter drugs and supplements.
Call prescriber
Before starting or stopping any medication, including herbal supplements, while on enzalutamide.
Sources
Regulatory (PI / SmPC)
- Xtandi (enzalutamide) prescribing information. Astellas Pharma US, Inc. Revised November 2023. FDA Label Primary regulatory source for all dosing, safety, pharmacokinetic, and drug interaction data cited in this monograph.
- FDA approval notice: Enzalutamide for non-metastatic castration-sensitive prostate cancer with biochemical recurrence. November 16, 2023. FDA.gov Regulatory approval notification documenting the most recent indication expansion (nmCSPC with high-risk BCR).
- FDA approval notice: Talazoparib with enzalutamide for HRR gene-mutated mCRPC. June 20, 2023. FDA.gov Documents the combination approval with talazoparib based on TALAPRO-2 trial results.
Key Clinical Trials
- Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197. doi:10.1056/NEJMoa1207506 AFFIRM trial — pivotal phase 3 RCT establishing enzalutamide efficacy in post-docetaxel mCRPC with 4.8-month OS benefit.
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–433. doi:10.1056/NEJMoa1405095 PREVAIL trial — extended enzalutamide indication to chemotherapy-naive mCRPC with significant rPFS and OS improvements.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465–2474. doi:10.1056/NEJMoa1800536 PROSPER trial — demonstrated MFS benefit in nmCRPC patients with rapidly doubling PSA.
- Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197–2206. doi:10.1056/NEJMoa2003892 PROSPER overall survival update confirming OS benefit (HR 0.73) in nmCRPC.
- Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974–2986. doi:10.1200/JCO.19.00799 ARCHES trial — established enzalutamide in mCSPC with significant rPFS improvement (HR 0.39).
- Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2022;40(15):1616–1622. doi:10.1200/JCO.22.00193 ARCHES overall survival update confirming OS benefit in mCSPC (HR 0.66).
- Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453–1465. doi:10.1056/NEJMoa2303974 EMBARK trial — supported the most recent indication expansion to nmCSPC with high-risk BCR, including treatment-suspension protocol.
- Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17(2):153–163. doi:10.1016/S1470-2045(15)00518-5 TERRAIN trial — head-to-head comparison demonstrating enzalutamide superiority over bicalutamide in mCRPC.
Mechanistic / Basic Science
- Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787–790. doi:10.1126/science.1168175 Foundational study describing the rational design and preclinical characterisation of enzalutamide (MDV3100) as a next-generation AR inhibitor.
Pharmacokinetics / Special Populations
- Merseburger AS, Haas GP, von Klot C-A. An update on enzalutamide in the treatment of prostate cancer. Ther Adv Urol. 2015;7(1):9–21. doi:10.1177/1756287214555336 Comprehensive review of enzalutamide pharmacokinetics, efficacy across disease settings, and safety profile including subgroup analyses.
- Sternberg CN, de Bono JS, Chi KN, et al. Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. Ann Oncol. 2014;25(2):429–434. doi:10.1093/annonc/mdt571 Post hoc AFFIRM analysis confirming comparable safety and efficacy of enzalutamide in patients aged 75 years and older.