Xtandi (Enzalutamide) in Castration-Resistant Prostate Cancer
Enzalutamide (Xtandi) is a Category 1, FDA-approved androgen receptor inhibitor indicated for all stages of castration-resistant prostate cancer—including non-metastatic, metastatic castration-sensitive, and metastatic castration-resistant disease—with demonstrated mortality benefits across all populations. 1, 2
Mechanism of Action and Pharmacology
Enzalutamide is a potent androgen receptor (AR) signaling inhibitor that binds AR with 5-8 fold higher affinity than bicalutamide, competitively inhibits androgen binding, blocks nuclear translocation of the AR, prevents DNA binding, and inhibits coactivator recruitment. 3, 2 This multi-step blockade of AR signaling distinguishes it from first-generation antiandrogens and provides superior clinical efficacy. 1
Clinical Indications and Evidence
Metastatic Castration-Sensitive Prostate Cancer (M1 mCSPC)
Enzalutamide 160 mg daily plus ADT is a Category 1 option for M1 castration-sensitive disease, FDA-approved December 2019. 1
Key supporting trials:
ENZAMET trial (1,125 patients): Compared enzalutamide plus ADT versus first-generation antiandrogen plus ADT. At 68 months median follow-up, the 5-year OS rate demonstrated a 30% reduction in death risk (HR 0.70; 95% CI 0.58-0.84; P<0.0001), with median OS not reached in the enzalutamide group. 1
ARCHES trial (1,150 patients): Enzalutamide plus ADT versus placebo plus ADT showed dramatic improvement in radiographic PFS (19.0 months vs not reached; HR 0.39; 95% CI 0.30-0.50; P<0.001). Final OS analysis demonstrated 34% reduction in death risk (HR 0.66; 95% CI 0.53-0.81; P<0.001), though this likely underestimates benefit as 32% of placebo patients crossed over to enzalutamide. 1
Non-Metastatic Castration-Resistant Prostate Cancer (M0 CRPC)
For M0 CRPC with PSA doubling time ≤10 months, enzalutamide 160 mg daily is a standard therapy with Grade A evidence. 1, 2
PROSPER trial (1,401 patients): Enzalutamide versus placebo in M0 CRPC with rapidly rising PSA (median doubling time 3.7 months). Median metastasis-free survival was 36.6 months versus 14.7 months (HR 0.29; 95% CI 0.24-0.35; P<0.001)—a 22-month improvement. 1 Final OS analysis showed median OS of 67.0 months with enzalutamide versus 56.3 months with placebo (HR 0.73; 95% CI 0.61-0.89; P=0.001), representing a 27% reduction in death risk. 4
Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Enzalutamide is a Grade A standard option for treatment-naïve mCRPC patients with good performance status. 3 It is effective both pre- and post-chemotherapy, with the AFFIRM trial demonstrating 4.8-month survival benefit in post-docetaxel patients. 5, 6
Dosing and Administration
Standard dose: 160 mg orally once daily with or without food. 2 Patients must take each capsule or tablet whole with sufficient water to ensure complete swallowing. 2 Available formulations include 40 mg capsules and 40 mg or 80 mg tablets. 2
Critical dosing considerations:
- Patients with castration-resistant or metastatic castration-sensitive disease must receive concurrent GnRH analog or have had bilateral orchiectomy. 2
- Patients with non-metastatic castration-sensitive disease with biochemical recurrence at high risk may be treated with or without GnRH analog. 2
- Dose reduction required with strong CYP2C8 inhibitors; dose increase required with strong CYP3A4 inducers. 2
Sequencing Strategy and Cross-Resistance
When using both novel hormone therapies sequentially, NCCN guidelines recommend starting with abiraterone followed by enzalutamide, as this sequence provides superior outcomes compared to the reverse. 3
Do not switch from enzalutamide to abiraterone or vice versa in patients who have progressed on one agent due to documented cross-resistance. 3 After progression on either agent plus docetaxel, cabazitaxel is the preferred option, with radiographic PFS of 8.0 months versus 3.7 months for switching between enzalutamide and abiraterone (HR 0.54; P<0.0001). 3
Adverse Event Profile and Safety Monitoring
Most common adverse events (≥10%) occurring more frequently with enzalutamide include musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. 2
Critical safety warnings:
Seizure risk: 0.6% overall, 2.2% in patients with predisposing factors. 1, 2 Permanently discontinue enzalutamide if seizure occurs. 7, 2 Predisposing factors include history of seizure, underlying brain injury, stroke, brain metastases, or concurrent medications that lower seizure threshold. 1
Posterior reversible encephalopathy syndrome (PRES): Discontinue enzalutamide immediately if PRES develops. 2
Ischemic heart disease: Optimize cardiovascular risk factor management; discontinue for Grade 3-4 cardiac adverse reactions. 2
Falls and fractures: Evaluate fracture and fall risk at baseline; treat with bone-targeted agents per established guidelines. 2 Fall rates were 15.6% with enzalutamide versus 9.0% with placebo in SPARTAN trial. 1
Severe dysphagia or choking: Consider using smaller tablet formulations in patients with swallowing difficulty; discontinue if patient cannot swallow capsules or tablets. 2
Hypertension, neutropenia, memory impairment disorders, and major cardiovascular events occur more frequently with enzalutamide. 1
Drug Interactions
Avoid strong CYP2C8 inhibitors (e.g., gemfibrozil); if unavoidable, reduce enzalutamide dose. 2 Avoid strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine); if unavoidable, increase enzalutamide dose. 2
Avoid coadministration with CYP3A4, CYP2C9, or CYP2C19 substrates where minimal concentration decreases may cause therapeutic failure, as enzalutamide is a strong inducer of these enzymes. 2
Contraindications and Special Populations
No absolute contraindications exist. 2 However, enzalutamide causes fetal harm and pregnancy loss; males with female partners of reproductive potential must use effective contraception during treatment and for 3 months after the final dose. 2
Clinical Pearls and Common Pitfalls
PSA flare phenomenon: A small proportion of responders to enzalutamide may experience transient PSA elevation before decline—do not prematurely discontinue therapy based on early PSA rise alone. 8
Response rates by prior treatment: In docetaxel-naïve patients, 61.4% achieved ≥50% PSA reduction, compared to only 24.1% in docetaxel-pretreated patients, indicating superior efficacy in earlier disease states. 8
Exposure-adjusted adverse event rates: Grade 3+ adverse events occurred at 17 per 100 patient-years with enzalutamide versus 20 per 100 patient-years with placebo, demonstrating favorable tolerability. 4
Avoid in patients with uncontrolled seizure disorders or multiple seizure risk factors, as permanent discontinuation is required if seizure occurs. 2