What is the efficacy of Xtandi (enzalutamide) in treating prostate cancer, particularly in patients with castration-resistant prostate cancer?

Xtandi (Enzalutamide) Efficacy in Prostate Cancer

Xtandi is highly effective for castration-resistant prostate cancer, demonstrating a 71% reduction in risk of radiographic progression or death in non-metastatic disease and a 27% reduction in risk of death with median overall survival reaching 67 months. 1, 2

Efficacy in Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

The PROSPER trial provides the strongest evidence for enzalutamide in nmCRPC patients with rapidly rising PSA levels:

• Metastasis-free survival (MFS) was extended by approximately 22 months: 36.6 months with enzalutamide versus 14.7 months with placebo (HR=0.29; 95% CI 0.24-0.35; P<0.001), representing a 71% reduction in risk of metastasis or death. 1

• Overall survival demonstrated significant benefit with median OS of 67.0 months versus 56.3 months with placebo (HR=0.73; 95% CI 0.61-0.89; P=0.001), representing a 27% reduction in risk of death. 2

• PSA progression was dramatically delayed: median time to PSA progression was 37.2 months with enzalutamide versus 3.9 months with placebo (HR=0.07; P<0.001), representing a 93% reduction in relative risk. 1

• The trial enrolled 1,401 patients with PSA doubling time ≤10 months (median 3.7 months) and PSA ≥2 ng/mL, all continuing androgen deprivation therapy. 1

Efficacy in Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Enzalutamide demonstrates robust efficacy when initiated at the castration-sensitive stage:

• The ARCHES trial showed enzalutamide significantly improved radiographic PFS (19.0 months vs not reached; HR=0.39; 95% CI 0.30-0.50; P<0.001) in 1,150 patients with mCSPC. 1

• Overall survival in ARCHES showed a 34% reduction in risk of death (HR=0.66; 95% CI 0.53-0.81; P<0.001), though this may underestimate the true effect since 32% of placebo patients crossed over to enzalutamide. 1

• The ENZAMET trial compared enzalutamide to first-generation antiandrogens in 1,125 mCSPC patients, demonstrating a 33% reduction in risk of death at interim analysis (HR=0.67; 95% CI 0.52-0.86; P=0.002). 1

• At 68 months median follow-up in ENZAMET, the 5-year OS benefit persisted (HR=0.70; 95% CI 0.58-0.84; P<0.0001), with median OS not yet reached in the enzalutamide arm. 1

• Enzalutamide is a Category 1 recommendation for M1 castration-sensitive prostate cancer per NCCN guidelines, with FDA approval granted in December 2019. 1

Efficacy in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

For chemotherapy-naïve mCRPC, the PREVAIL trial provides definitive evidence:

• Radiographic progression-free survival was dramatically improved: 20.0 months with enzalutamide versus 5.4 months with placebo (HR=0.32; 95% CI 0.28-0.37; P<0.0001), representing a 68% reduction in risk. 3

• Overall survival at final analysis showed median OS of 35.3 months versus 31.3 months with placebo (HR=0.77; 95% CI 0.67-0.88; P=0.0002), representing a 23% reduction in risk of death. 3

• The trial enrolled asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients, with 167 placebo patients crossing over to enzalutamide. 3

Mechanism of Action

Enzalutamide functions through multiple mechanisms that distinguish it from older antiandrogens:

• Competitive AR inhibition with 5- to 8-fold higher affinity than bicalutamide for androgen binding. 1, 4

• Blocks nuclear translocation of the androgen receptor, preventing it from entering the nucleus. 1, 4

• Inhibits DNA binding even if the receptor reaches the nucleus. 1, 4

• Prevents coactivator recruitment necessary for gene transcription. 1, 4

• This differs fundamentally from abiraterone, which inhibits androgen synthesis via CYP17A1 blockade rather than directly targeting the receptor. 4

Safety Profile and Common Adverse Events

The adverse event profile is generally manageable but requires monitoring:

• Treatment discontinuation due to adverse events occurred in 9% of enzalutamide patients versus 6% with placebo in PROSPER. 1

• Most common adverse events (occurring more frequently with enzalutamide) include fatigue, hypertension, convulsion, neutropenia, memory impairment disorders, and major cardiovascular events. 1

• Seizures occurred in 0.6% overall, but 2.2% in patients with predisposing factors; permanent discontinuation is required if seizure occurs. 5

• Cardiovascular events require optimization of cardiovascular risk factors, with discontinuation for Grade 3-4 events. 5

• Falls and fractures necessitate evaluation of fracture and fall risk, with consideration of bone-targeted agents per established guidelines. 5

• The exposure-adjusted rate of grade 3 or higher adverse events was 17 per 100 patient-years with enzalutamide versus 20 per 100 patient-years with placebo in the PROSPER trial. 2

Critical Dosing and Administration Details

• Standard dose is 160 mg orally once daily, taken with or without food. 5

• Capsules and tablets must be swallowed whole with sufficient water; severe dysphagia or choking related to product size may require smaller tablet formulations or discontinuation if swallowing is impossible. 5

• Concurrent ADT is required for castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer (via GnRH analog or bilateral orchiectomy). 5

• For non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, enzalutamide may be used with or without a GnRH analog. 5

Important Drug Interactions

• Avoid strong CYP2C8 inhibitors; if unavoidable, reduce enzalutamide dose. 5

• Avoid strong CYP3A4 inducers; if unavoidable, increase enzalutamide dose. 5

• Avoid coadministration with CYP3A4, CYP2C9, or CYP2C19 substrates where minimal concentration decreases could cause therapeutic failure. 5

Common Pitfalls to Avoid

• Do not confuse enzalutamide's mechanism with abiraterone—they target different points in the androgen signaling axis and are not interchangeable. 4

• Screen carefully for seizure risk factors before initiating therapy, as patients with predisposing factors have 2.2% seizure risk versus 0.6% overall. 5

• Monitor cardiovascular risk factors closely, particularly in patients with pre-existing cardiovascular disease, as hypertension and major cardiovascular events occur more frequently. 1

• Assess swallowing ability before prescribing, as severe dysphagia or choking can occur; consider smaller tablet formulations for at-risk patients. 5

• Continue ADT indefinitely in castration-resistant and metastatic castration-sensitive disease—enzalutamide does not replace ADT but augments it. 5