What is the difference between Darolutamide (Nubeqa) and Zytiga (Abiraterone)?

Key Differences Between Darolutamide (Nubeqa) and Zytiga (Abiraterone)

Darolutamide and Zytiga work through fundamentally different mechanisms: darolutamide is a direct androgen receptor (AR) antagonist that blocks AR signaling, while Zytiga inhibits androgen synthesis by blocking CYP17A1, requiring concurrent prednisone administration. 1

Mechanism of Action

Darolutamide is a second-generation AR inhibitor that:

• Competitively inhibits androgen binding to the AR 2
• Blocks AR nuclear translocation and prevents AR-mediated transcription 2
• Inhibits transcriptional activity of AR mutant variants (F877L, F877L/T878A, H875Y/T878A) that confer resistance to other antiandrogens 3
• Does not significantly increase serum testosterone levels 4

Zytiga (abiraterone acetate) works differently by:

• Inhibiting CYP17A1 enzyme to block androgen synthesis 1
• Requiring concurrent prednisone 5mg daily to prevent mineralocorticoid excess 1
• Reducing testosterone production systemically 1

Dosing and Administration

Darolutamide:

• 600 mg (two 300 mg tablets) twice daily with food 1, 5
• Does not require concurrent corticosteroid therapy 6
• Must be given with ongoing ADT to maintain castrate testosterone levels 6

Zytiga:

• 1,000 mg (four 250 mg tablets) once daily 1
• Must be taken with prednisone 5mg daily 1
• Alternative dosing: 250 mg daily with fatty meal (reduces cost significantly) 1
• Must be given with ongoing ADT 1

Safety Profile and Adverse Events

Darolutamide demonstrates:

• Minimal blood-brain barrier penetration, reducing seizure risk 4
• Adverse events similar to placebo in ARAMIS trial 5
• Most common: fatigue (12.1% vs 8.7% placebo), pain in extremity (5.8% vs 3.2%), rash (2.9% vs 0.9%) 5
• Does not significantly prolong QTc interval, making it safer for cardiac patients 6
• Lower risk of falls, fractures, and cognitive impairment compared to other AR inhibitors 2

Zytiga has different toxicity concerns:

• Increased hypertension (primary toxicity in PEACE-1 trial) 1
• Mineralocorticoid excess if prednisone not co-administered 1
• Higher risk of atrial fibrillation (0.97% incidence, grade 3 AF <1%) 1
• Requires monitoring for hepatotoxicity, hypokalemia, and fluid retention 1

Drug-Drug Interaction Profile

Darolutamide has favorable DDI characteristics:

• Low potential for clinically relevant DDIs with CYP substrates 7
• Main interaction: increases BCRP substrate exposure (rosuvastatin increased 5.2-fold) 7
• Exposure increased 1.75-fold with CYP3A4 inhibitors (itraconazole) 7
• Exposure decreased 72% with CYP3A4 inducers (rifampicin) 7

Zytiga requires more caution:

• Metabolized via CYP pathways requiring monitoring with strong CYP3A4 inducers/inhibitors 1
• Interactions with corticosteroid metabolism 1

FDA-Approved Indications

Darolutamide is approved for:

• Non-metastatic CRPC (nmCRPC) with PSADT ≤10 months 5, 2
• Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with ADT and docetaxel 5

Zytiga is approved for:

• Metastatic castration-resistant prostate cancer (mCRPC) 1
• Metastatic castration-naïve (hormone-sensitive) prostate cancer 1

Clinical Efficacy Data

Darolutamide in nmCRPC (ARAMIS trial):

• Metastasis-free survival: 40.4 vs 18.4 months (HR 0.41; P<0.001) 5
• 3-year overall survival: 83% vs 77% (HR 0.69; P=0.003) 5

Darolutamide in mHSPC (ARASENS trial):

• 4-year overall survival: 62.7% vs 50.4% (HR 0.68; P<0.001) 5
• 32.5% reduction in risk of death 1
• Grade 3/4 events similar between treatment arms 1

Zytiga in mHSPC (LATITUDE trial):

• Median overall survival: 53.3 vs 36.5 months (HR 0.66; P<0.0001) 1

Cross-Resistance Considerations

Critical caveat: Enzalutamide- and abiraterone-resistant prostate cancer cells demonstrate cross-resistance to darolutamide through the AKR1C3/AR-V7 axis 8. This means:

• Switching from Zytiga to darolutamide (or vice versa) after progression is rarely effective 5
• Sequential use of AR-targeted therapies shows limited benefit 8
• After progression on Zytiga, docetaxel or cabazitaxel is preferred over switching to darolutamide 5

Cost Considerations

6-month treatment costs (Medicare pricing): 1

• Darolutamide: $72,768
• Zytiga (brand): $78,389.52 (1,000 mg daily) or $19,803.06 (250 mg with fatty meal)
• Abiraterone generic: $9,745.56 (1,000 mg daily) or $4,953 (250 mg with fatty meal)

The generic abiraterone option provides substantial cost savings compared to darolutamide, though this must be balanced against the requirement for concurrent prednisone and different toxicity profiles. 1

Monitoring Requirements

Both agents require: 5, 2

• Serial PSA every 3-6 months
• Conventional imaging every 6-12 months
• Baseline and periodic monitoring of testosterone, LDH, hemoglobin, alkaline phosphatase
• Blood pressure monitoring
• Concurrent ADT maintenance

Zytiga additionally requires: 1

• Liver function monitoring
• Electrolyte monitoring (potassium, sodium)
• Monitoring for signs of mineralocorticoid excess