Darolutamide for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Darolutamide is NOT currently FDA-approved as monotherapy for mCRPC, and current evidence does not support its routine use in this setting, particularly in patients who have already received other androgen receptor inhibitors. 1, 2
FDA-Approved Indications for Darolutamide
Darolutamide has two established FDA-approved indications, neither of which is mCRPC monotherapy:
Non-metastatic CRPC (M0 CRPC): Approved at 600 mg twice daily with food when PSA doubling time is ≤10 months, demonstrating metastasis-free survival of 40.4 vs 18.4 months (HR 0.41; P<0.001) and 3-year overall survival of 83% vs 77% (HR 0.69; P=0.003) 1, 3
Metastatic hormone-sensitive prostate cancer (mHSPC): FDA-approved in August 2022 in combination with ADT and docetaxel, showing 4-year overall survival of 62.7% vs 50.4% (HR 0.68; P<0.001), representing a 23-month survival gain 4, 1, 5
Evidence for Use in mCRPC: Limited and Context-Dependent
Current Guideline Positioning
The NCCN organizes mCRPC treatment based on prior therapeutic exposures rather than lines of therapy, and switching from one androgen receptor inhibitor to another is rarely effective due to cross-resistance 1:
For patients with no prior docetaxel and no prior novel hormone therapy: Options include abiraterone plus prednisone, enzalutamide, or docetaxel—but notably, darolutamide is not listed as a standard option 1
For patients with prior novel hormone therapy and no prior docetaxel: Docetaxel is preferred over switching to another AR inhibitor 1
For patients with prior docetaxel and prior novel hormone therapy: Cabazitaxel is Category 1 preferred (CARD trial: HR 0.64 for OS; P=0.008) 1
Real-World Evidence Shows Minimal Benefit in mCRPC
A 2025 real-world study of 44 mCRPC patients treated with darolutamide revealed disappointing results 6:
- Median progression-free survival was only 2.15 months in M1-CRPC patients 6
- Only 11.4% (5/44) achieved PSA reduction >50%, and all were previously 2GARA-naïve 6
- Patients resistant only to CYP17 inhibitors had slightly longer median PFS (2.43 vs 1.61 months; P=0.03) compared to those resistant to other 2GARAs 6
- Resistance to other 2GARAs significantly decreased benefit from darolutamide 6
Single-Center Study Shows Potential in Treatment-Naïve mCRPC
A 2024 single-center study examined darolutamide combined with docetaxel in previously untreated mCRPC patients 7:
- Median time to PSA50 was 1.5 months vs 3.0 months with placebo (p=0.0259) 7
- Median PSA decrease was -81.8% vs -69.4% with placebo 7
- The combination was well-tolerated without increased adverse events 7
However, this represents a highly selected population (treatment-naïve mCRPC) and is not the typical clinical scenario where darolutamide would be considered 7.
Mechanism and Pharmacology
Darolutamide competitively inhibits androgen binding to the androgen receptor, blocks AR nuclear translocation, and prevents AR-mediated transcription 2. The active metabolite ketodarolutamide exhibits similar activity 2. Importantly, darolutamide does not suppress testosterone production itself and must be continued with concurrent ADT 8.
Clinical Algorithm for Decision-Making
When considering treatment for mCRPC, follow this approach:
Assess prior exposures: Document all prior novel hormone therapies (abiraterone, enzalutamide, apalutamide) and chemotherapy (docetaxel, cabazitaxel) 1
If no prior novel hormone therapy: Choose abiraterone, enzalutamide, or docetaxel—not darolutamide 1
If prior novel hormone therapy but no docetaxel: Proceed with docetaxel, not another AR inhibitor 1
If both prior novel hormone therapy and docetaxel: Use cabazitaxel as Category 1 preferred 1
Consider darolutamide only in exceptional circumstances: Treatment-naïve mCRPC patients in combination with docetaxel, recognizing this is off-label and based on limited evidence 7
Important Caveats and Pitfalls
Cross-resistance is real: The CARD trial definitively showed that switching AR inhibitors after progression on one is inferior to chemotherapy 1
Maintain castrate testosterone levels: Always confirm testosterone <50 ng/dL before diagnosing CRPC, and continue ADT throughout darolutamide therapy 1, 8
Dose adjustments required: Reduce dose in severe renal impairment (eGFR 15-29 mL/min/1.73 m²) and moderate hepatic impairment (Child-Pugh B) 2
Favorable cardiac profile: Unlike some other AR inhibitors, darolutamide does not significantly prolong QTc interval 8, 2
Must be taken with food: Bioavailability increases 2.0- to 2.5-fold when administered with food 2
Monitoring During Therapy
If darolutamide is used (in approved indications or exceptional off-label circumstances):