What is the comparative efficacy of Xtandi (enzalutamide) versus Erleada (apalutamide) for a male patient with prostate cancer?

Comparative Efficacy of Xtandi (Enzalutamide) vs Erleada (Apalutamide) for Prostate Cancer

Both Xtandi (enzalutamide) and Erleada (apalutamide) demonstrate equivalent efficacy for prostate cancer treatment across all disease states, with no clinically meaningful differences in survival outcomes, though they differ in their adverse event profiles.

Guideline-Based Recommendations

Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Both agents receive Category 1, strong recommendations from ASCO guidelines for treatment of metastatic noncastrate (castration-sensitive) prostate cancer 1:

• Enzalutamide plus ADT demonstrated significant benefits in PSA progression-free survival, clinical progression-free survival, and overall survival compared to ADT alone in the ENZAMET trial 1
• Apalutamide plus ADT showed significantly longer radiographic progression-free survival (HR 0.48,95% CI: 0.39-0.60, P<0.001) and overall survival (HR 0.67,95% CI: 0.51-0.89, P=0.005) compared to placebo plus ADT in the TITAN trial 1

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Direct comparative analyses show no significant efficacy differences:

• Network meta-analysis found no evidence of significant difference in metastasis-free survival between enzalutamide and apalutamide (HR 1.04,95% CI: 0.78-1.37) 2
• A 2024 real-world multicenter study confirmed comparable oncological outcomes between the two agents, with no significant differences in PSA-PFS, MFS, CSS, or OS 3
• Matching-adjusted indirect comparison showed Bayesian probabilities favoring apalutamide of 73.6% for MFS and 83.5% for OS, but these differences were not statistically significant 4

Dosing Regimens

• Enzalutamide: 160 mg orally once daily with continued ADT, no food restrictions required 5, 6
• Apalutamide: 240 mg orally once daily with continued ADT 1

Adverse Event Profile Differences

This is where the two agents meaningfully differ and should guide selection:

Enzalutamide-Specific Adverse Events 5, 6, 7:

• Fatigue: 33-34% (vs 14% placebo)
• Hypertension: 12% (vs 5% placebo)
• Mental impairment disorders: 5% (vs 2% placebo)
• Seizure risk: 0.6-0.9% (requires permanent discontinuation)
• Major adverse cardiovascular events: 5% (vs 3% placebo)
• No significant hypercholesterolemia 7

Apalutamide-Specific Adverse Events 3:

• Skin rash: 27.8% (most common AE, distinct from enzalutamide)
• Fatigue: comparable rates to enzalutamide
• Overall AE rates similar between agents (56-57% all grades) 3

Comparative Safety Analysis

A network meta-analysis evaluating nmCRPC treatments found that while apalutamide and enzalutamide showed superior efficacy to darolutamide, darolutamide had the most favorable tolerability profile overall 8. Between apalutamide and enzalutamide specifically, the 2024 real-world study showed comparable rates of all-grade AEs (56.2% vs 57.4%) and grade ≥3 AEs (4.3% vs 7.4%), with the key difference being the type rather than frequency of adverse events 3.

Clinical Decision Algorithm

Select enzalutamide when:

• Patient has history of dermatologic conditions or concerns about skin reactions
• Cost considerations favor enzalutamide in your healthcare system
• Patient has no seizure history or risk factors 5, 6

Select apalutamide when:

• Patient has seizure history or significant risk factors for seizures
• Patient has concerns about cognitive/mental impairment
• Skin reactions are acceptable to the patient 3

Either agent is appropriate when:

• No specific contraindications exist for either medication
• Patient preference after discussing distinct AE profiles
• Both are equally accessible and affordable 1

Special Population Considerations

Prior Docetaxel Treatment

Important caveat: For patients previously treated with docetaxel, evidence is less conclusive for both agents 1:

• Enzalutamide showed benefits in the ENZAMET trial among docetaxel-treated patients, though longer follow-up was needed 1
• Apalutamide's effect on radiographic PFS in the docetaxel subgroup favored treatment but was not statistically significant in TITAN trial 1
• Both agents remain reasonable options, but patients should be counseled about the less definitive data in this subgroup 1

Key Clinical Pitfalls to Avoid

• Do not discontinue LHRH agonist/antagonist therapy when initiating either agent 5, 6
• Screen for seizure history before initiating enzalutamide; if seizure occurs, permanent discontinuation is required 5, 7
• Monitor for skin reactions with apalutamide, particularly in the first months of therapy 3
• Do not assume superiority of one agent over the other based on marketing claims; guideline evidence supports equivalence 1, 2
• Counsel patients on costs, as both are expensive medications and may influence treatment selection without compromising efficacy 1