What is the role of apalutamide (Androgen Receptor Inhibitor), darolutamide (Androgen Receptor Inhibitor), and enzalutamide (Androgen Receptor Inhibitor) in the treatment of prostate cancer?

Role of Apalutamide, Darolutamide, and Enzalutamide in Prostate Cancer

All three second-generation androgen receptor inhibitors—apalutamide, darolutamide, and enzalutamide—are NCCN Category 1, preferred treatment options for non-metastatic castration-resistant prostate cancer (nmCRPC) with PSA doubling time ≤10 months, with all three demonstrating significant improvements in metastasis-free survival and overall survival. 1, 2

Clinical Indications and Settings

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Primary indication: All three agents are FDA-approved and recommended for nmCRPC patients with PSADT ≤10 months while maintaining castrate testosterone levels (<50 ng/dL) with concurrent ADT. 1, 2

Efficacy data for nmCRPC:

• Enzalutamide (160 mg daily): Metastasis-free survival of 36.6 vs 14.7 months (HR 0.29; P<0.0001) and overall survival of 67.0 vs 56.3 months (HR 0.73; P=0.001) in the PROSPER trial. 1

• Apalutamide (240 mg daily): Metastasis-free survival of 40.5 vs 16.2 months (HR 0.28; P<0.001) and final overall survival of 73.9 vs 59.9 months (HR 0.78; P=0.016) in the SPARTAN trial. 1

• Darolutamide (600 mg twice daily with food): Metastasis-free survival of 40.4 vs 18.4 months (HR 0.41; P<0.001) and 31% lower risk of death (HR 0.69; P=0.003) in the ARAMIS trial. 1, 2

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

• Enzalutamide is a Category 1, preferred treatment option for patients without prior novel hormone therapy in the mCRPC setting, demonstrating superior progression-free survival compared to bicalutamide (HR 0.24; 95% CI 0.18-0.32). 1

• For patients with mCRPC and prior novel hormone therapy, enzalutamide is included in the "other recommended regimens" group. 1

Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

• Apalutamide plus ADT improved 24-month overall survival (82.4% vs 73.5%; HR 0.67, P=0.005) and radiographic progression-free survival at 24 months (68.2% vs 47.5%; HR 0.48, P<0.001). 2

Comparative Efficacy Analysis

When comparing the three agents indirectly:

• In nmCRPC, enzalutamide and apalutamide showed slightly superior metastasis-free survival compared to darolutamide (HR 0.71 and 0.68 respectively), though all three remain highly effective. 3, 4

• No significant difference exists between enzalutamide and apalutamide for metastasis-free survival (HR 0.97; 95% CI 0.73-1.28). 3, 4

• Overall survival benefits are comparable across all three agents with no statistically significant differences in indirect comparisons. 3, 4

Mechanism of Action Distinctions

All three agents work as androgen receptor inhibitors but with distinct molecular characteristics:

• Apalutamide binds to the AR ligand-binding domain with 7- to 10-fold greater affinity than bicalutamide and impedes AR-DNA binding in the nucleus. 5, 6

• Enzalutamide competitively inhibits androgen binding with 5- to 8-fold higher affinity than bicalutamide, prevents AR nuclear translocation, inhibits DNA binding, and blocks coactivator recruitment with reduced agonist activity. 7

• Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription, with its major metabolite ketodarolutamide exhibiting similar activity. 8

Adverse Event Profiles and Selection Considerations

Key safety differences guide agent selection:

Enzalutamide

• Higher rates of fatigue (33% vs 14%), hypertension (12% vs 5%), major adverse cardiovascular events (5% vs 3%), and mental impairment disorders (5% vs 2%). 1
• Increased risk of seizures (contraindicated in patients with seizure history). 1
• QTc prolongation: maximum mean change 12.4 ms. 6
• No food restrictions; concurrent prednisone permitted but not required. 1

Apalutamide

• Rash (24% vs 5.5%), fractures (11% vs 6.5%), hypothyroidism (8% vs 2%), and falls (particularly in elderly: 19% in patients ≥75 years). 1
• Grade 3-4 adverse reactions increase with age (49% in patients ≥75 years vs 39% in younger patients). 6
• Slightly higher rate of Grade 3+ adverse events and drug withdrawals compared to other agents. 9

Darolutamide

• Most favorable adverse event profile with highest SUCRA value for tolerability. 4, 9
• No large mean QTc increase (>20 ms) detected. 8
• Must be taken with food (2.0- to 2.5-fold increase in bioavailability). 8
• Dose reduction required for severe renal impairment (eGFR 15-29 mL/min/1.73 m²) and moderate hepatic impairment (Child-Pugh B). 8

Dosing Specifications

• Enzalutamide: 160 mg once daily (no food restrictions). 1
• Apalutamide: 240 mg once daily. 1, 6
• Darolutamide: 600 mg (two 300 mg tablets) twice daily with food. 1, 8

Monitoring Requirements During Therapy

• Serial PSA every 3-6 months. 2
• Conventional imaging every 6-12 months. 2
• Baseline and periodic monitoring of testosterone (confirm castrate levels <50 ng/dL), LDH, hemoglobin, alkaline phosphatase, and thyroid function. 2
• Blood pressure monitoring for all agents (particularly enzalutamide). 2

Sequential Therapy Considerations

Cross-resistance exists but is incomplete:

• Switching from enzalutamide or apalutamide to darolutamide in nmCRPC patients showed 55.5% achieved >50% PSA decline with median progression-free survival of 6 months, suggesting darolutamide's distinct chemical structure may overcome some cross-resistance. 10

• This represents a potential therapeutic option after progression on first-line androgen receptor inhibitor therapy, though validation in larger cohorts is needed. 10

Critical Pitfalls to Avoid

• Never initiate these agents without confirming castrate testosterone levels (<50 ng/dL). 2
• Always calculate PSADT to identify high-risk patients (≤10 months) who benefit most from treatment. 2
• Continue concurrent ADT (LHRH agonist/antagonist) throughout therapy—these agents do not replace ADT. 2
• Do not confuse mechanism with abiraterone: These agents directly block the androgen receptor at multiple steps, while abiraterone inhibits androgen synthesis via CYP17A1 blockade. 7
• For darolutamide, ensure administration with food to achieve adequate bioavailability. 8

Clinical Decision Algorithm

For nmCRPC with PSADT ≤10 months:

1. If cardiovascular disease, seizure history, or significant mental impairment concerns exist: Choose darolutamide (most favorable cardiovascular and CNS profile). 1, 4, 9

2. If skin reactions, fracture risk, or thyroid dysfunction are primary concerns: Avoid apalutamide; choose darolutamide or enzalutamide. 1, 9

3. If cost and convenience are priorities: Enzalutamide offers once-daily dosing without food requirements. 1

4. If maximizing metastasis-free survival is the sole priority: Enzalutamide or apalutamide show marginally superior MFS compared to darolutamide, though all three provide substantial benefit. 3, 4

5. For elderly patients (≥75 years): Consider darolutamide due to lower fall risk compared to apalutamide (19% vs lower rates with darolutamide). 6, 4

For mCRPC without prior novel hormone therapy: Enzalutamide is the Category 1 preferred option. 1

For mCSPC: Apalutamide plus ADT has demonstrated overall survival benefit. 2