What is the difference in mechanism of action between Darolutamide (darolutamide), Xtandi (enzalutamide), and Zytiga (abiraterone acetate) in the treatment of prostate cancer?

Mechanism of Action Differences Between Darolutamide, Xtandi (Enzalutamide), and Zytiga (Abiraterone)

Darolutamide and Xtandi (enzalutamide) are both direct androgen receptor (AR) antagonists that block AR signaling, while Zytiga (abiraterone) works through a fundamentally different mechanism by inhibiting androgen synthesis at the CYP17A1 enzyme. 1

Fundamental Mechanistic Distinction

Androgen Receptor Antagonists (Darolutamide and Enzalutamide)

Both darolutamide and enzalutamide competitively inhibit androgen binding to the AR, block AR nuclear translocation, and prevent AR-mediated transcription. 1, 2 These agents work by directly interfering with the androgen receptor's ability to function, even when androgens are present. 3

• Enzalutamide requires steady-state trough concentrations >10 μg/mL despite being considered to have strong AR affinity, reflecting the need for high drug levels to maintain AR blockade. 3

• Darolutamide binds to the AR with high affinity and demonstrates a unique pharmacologic profile, though it shares the same fundamental mechanism as enzalutamide of direct AR antagonism. 1

Androgen Synthesis Inhibitor (Abiraterone)

Zytiga (abiraterone acetate) inhibits the CYP17A1 enzyme, which is essential for metabolizing testosterone and dihydrotestosterone from weak adrenal androgens, thereby blocking androgen synthesis rather than blocking the receptor itself. 4, 1 This represents a completely different therapeutic approach—reducing the fuel (androgens) rather than blocking the engine (AR). 4

• Abiraterone requires concurrent prednisone 5 mg daily to prevent mineralocorticoid excess that results from CYP17A1 inhibition, which causes accumulation of mineralocorticoid precursors. 1, 4

• This mechanism targets autocrine and paracrine androgen synthesis in the tumor microenvironment that occurs in castration-resistant disease. 4

Clinical Implications of Mechanistic Differences

Administration Requirements

• Darolutamide: 600 mg (two 300 mg tablets) twice daily with food, no corticosteroid required. 1

• Enzalutamide: 160 mg orally once daily, no corticosteroid required. 4

• Abiraterone: 1,000 mg once daily on empty stomach, mandatory prednisone 5 mg twice daily. 1, 4

Cross-Resistance Patterns

The shared mechanism between darolutamide and enzalutamide as direct AR antagonists results in cross-resistance between these agents and with abiraterone through the AKR1C3/AR-V7 axis. 5 Enzalutamide- and abiraterone-resistant prostate cancer cells demonstrate cross-resistance to both apalutamide and darolutamide, with the AKR1C3/AR-V7 complex conferring this cross-resistance. 5

• Sequential use of abiraterone followed by enzalutamide provides greater clinical benefit than the reverse sequence (median time to second PSA progression 19.3 vs 15.2 months; HR 0.66, p=0.036), with enzalutamide showing 36% PSA response rate as second-line therapy versus only 4% for abiraterone. 6

• Darolutamide may provide some benefit in CYP17 inhibitor-refractory metastatic CRPC patients (median PFS 2.43 months in CYP17I-only exposed vs 1.61 months in 2GARA-resistant patients, p=0.03), but prior resistance to other AR antagonists significantly decreases benefit. 7

Toxicity Profile Differences

The different mechanisms result in distinct adverse event profiles:

• Abiraterone causes mineralocorticoid excess-related toxicities including hypokalemia (28%), hypertension, peripheral edema, and cardiac events due to CYP17A1 inhibition. 4, 8

• Enzalutamide causes fatigue, hypertension, mental impairment disorders, and seizures (0.9%) related to AR antagonism and CNS penetration. 4

• Darolutamide demonstrates adverse events similar to placebo with most common being fatigue, pain in extremity, and rash, and does not significantly prolong QTc interval. 1, 9

Monitoring Differences

• Both AR antagonists require: Serial PSA every 3-6 months, conventional imaging every 6-12 months, baseline and periodic monitoring of testosterone, LDH, hemoglobin, alkaline phosphatase. 1, 2

• Abiraterone additionally requires: Liver function monitoring, electrolyte monitoring (potassium, sodium), and monitoring for signs of mineralocorticoid excess due to its mechanism of CYP17A1 inhibition. 1