What is the role of androgen degrader therapy, such as darolutamide (generic name: darolutamide) or apalutamide (generic name: apalutamide), in treating prostate cancer?

Androgen Degrader Therapy in Prostate Cancer

Androgen receptor inhibitors—specifically darolutamide, apalutamide, and enzalutamide—are Category 1, preferred treatment options for non-metastatic castration-resistant prostate cancer (nmCRPC) when PSA doubling time is ≤10 months, with all three agents demonstrating significant improvements in metastasis-free survival (approximately 40 months vs 16-18 months with placebo) and overall survival. 1

Clinical Context and Terminology

The term "androgen degrader" in your question likely refers to androgen receptor (AR) inhibitors or AR antagonists, which are the established therapeutic class. 1 These agents work by:

• Competitively inhibiting androgen binding to the AR 2
• Blocking AR nuclear translocation 1, 2
• Preventing AR-mediated transcription 1, 2

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Patient Selection Criteria

Offer AR inhibitor therapy when: 1

• PSA doubling time (PSADT) ≤10 months (calculate using serial PSA measurements at 3-6 month intervals starting at castration-resistance) 1
• No visible metastatic disease on conventional imaging (bone scan, CT, MRI) 1
• Castrate testosterone levels maintained (<50 ng/dL) 1

Treatment Options (All Category 1, Preferred)

Darolutamide 600 mg twice daily with food: 1

• Metastasis-free survival: 40.4 vs 18.4 months (HR 0.41; P<0.001) 1, 3
• 3-year overall survival: 83% vs 77% (HR 0.69; P=0.003) 1, 4
• Favorable safety profile: Fracture rate similar to placebo (4.2% vs 3.6%), lower rates of falls, seizures, and cardiovascular events compared to other AR inhibitors 1, 3
• Most common adverse events: fatigue (12.1%), pain in extremity (5.8%), rash (2.9%) 1

Apalutamide 240 mg daily: 1

• Metastasis-free survival: 40.5 vs 16.2 months (HR 0.28; P<0.001) 1
• Final overall survival: 73.9 vs 59.9 months (HR 0.78; P=0.016) 1
• Monitor for: Rash (24%), fractures (11.7%), hypothyroidism (8.1%), falls (15.6%) 1, 5
• Critical monitoring: Check TSH regularly, especially in patients with known hypothyroidism 1

Enzalutamide 160 mg daily: 1

• Metastasis-free survival: Similar to other agents 1
• Overall survival: 67.0 vs 56.3 months (HR 0.73; P=0.001) 1
• Higher risk of: Hypertension (12%), major adverse cardiovascular events (5%), mental impairment (5%), seizures 1
• No food restrictions; prednisone permitted but not required 1

Metastatic Castration-Sensitive Prostate Cancer

AR inhibitors are also FDA-approved for metastatic castration-sensitive disease in combination with ADT: 1, 6

• Apalutamide plus ADT improved 24-month overall survival (82.4% vs 73.5%; HR 0.67, P=0.005) 6
• Radiographic progression-free survival at 24 months: 68.2% vs 47.5% (HR 0.48, P<0.001) 6

Sequencing After Prior AR Inhibitor Therapy

Critical Consideration for Treatment Selection

When patients progress on one AR inhibitor in the nmCRPC or castration-sensitive setting, cross-resistance is common but not absolute: 1, 7

• Darolutamide after enzalutamide/apalutamide failure: In a small retrospective study, 55.5% of nmCRPC patients achieved >50% PSA decline when switched to darolutamide after progression on enzalutamide or apalutamide, with median PFS of 6 months 7
• For metastatic CRPC after prior AR inhibitor: Real-world data shows limited benefit—median PFS only 1.61 months in 2GARA-resistant patients vs 2.43 months in CYP17I-only resistant patients 8

Recommended approach after AR inhibitor progression: 1

• Patients who received AR inhibitors for nmCRPC or castration-sensitive disease should receive chemotherapy (docetaxel), radium-223 (if bone-only disease), or other non-AR-targeted therapies when progressing to metastatic CRPC 1
• Do not repeat the same AR inhibitor class 1

Monitoring Requirements

During AR inhibitor therapy: 1

• Serial PSA every 3-6 months 1
• Conventional imaging (bone scan, CT) every 6-12 months to detect metastatic progression 1
• Baseline and periodic monitoring: testosterone, LDH, hemoglobin, alkaline phosphatase 1
• Thyroid function (especially with apalutamide) 1
• Blood pressure monitoring (all agents) 1

Common Pitfalls to Avoid

Do not use AR inhibitors without: 1

• Confirming castrate testosterone levels (<50 ng/dL) 1
• Calculating PSADT to identify high-risk patients (≤10 months) 1
• Continuing concurrent ADT (LHRH agonist/antagonist) 1

Darolutamide-specific: 2

• Must be taken with food (bioavailability increases 2.0-2.5 fold with food) 2
• Dose is 600 mg (two 300-mg tablets) twice daily 2

Safety monitoring failures: 1, 5

• Missing hypothyroidism with apalutamide (occurs in 8.1%, typically grade 1-2, identified early) 1
• Not counseling on fall risk (15.6% with apalutamide vs 9% placebo) 1, 5
• Inadequate seizure precautions with enzalutamide 1

Mechanism and Pharmacology

Darolutamide has structural distinctions from other AR inhibitors: 2, 7

• Competitively inhibits androgen binding and AR nuclear translocation 2
• Active metabolite ketodarolutamide has similar activity with 1.7-fold higher exposure 2
• Primarily metabolized by CYP3A4, UGT1A9, and UGT1A1 2
• Effective half-life approximately 20 hours 2
• Steady-state reached in 2-5 days with 2-fold accumulation 2