What is the recommended use of Darolutamide (generic name: darolutamide) in patients with metastatic castration-resistant prostate cancer (mCRPC)?

Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Darolutamide is not currently FDA-approved as monotherapy for mCRPC, but it has established roles in earlier disease states: it is a Category 1 preferred option for non-metastatic CRPC (M0 CRPC) with PSA doubling time ≤10 months, and it is FDA-approved in combination with ADT and docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC). 1, 2

Current FDA-Approved Indications for Darolutamide

Non-Metastatic CRPC (M0 CRPC):

• Darolutamide 600 mg twice daily with food is FDA-approved for M0 CRPC when PSADT is ≤10 months 1, 3, 2
• The ARAMIS trial demonstrated metastasis-free survival of 40.4 vs 18.4 months compared to placebo (HR 0.41; P<0.001) 1, 4
• Overall survival at 3 years was 83% vs 77% (HR 0.69; P=0.003) 1, 3
• Adverse events were similar to placebo, with fatigue (12.1% vs 8.7%), pain in extremity (5.8% vs 3.2%), and rash (2.9% vs 0.9%) being most common 1

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC):

• Darolutamide is FDA-approved (August 2022) in combination with ADT and docetaxel for mHSPC 1
• The ARASENS trial showed 4-year overall survival of 62.7% vs 50.4% with placebo (HR 0.68; P<0.001), representing a 23-month OS gain 1, 5
• This triplet therapy is recommended by ESMO as first-line treatment for mHSPC, including patients with de novo disease and those who progressed to metastatic disease 1, 6

Use in Metastatic CRPC: Current Evidence and Positioning

For Previously Untreated mCRPC:

• While not FDA-approved as monotherapy for mCRPC, emerging evidence suggests darolutamide plus docetaxel may be effective 7
• A single-center study showed median time to PSA50 of 1.5 months and median PSA decrease of -81.8% when darolutamide was combined with docetaxel in previously untreated mCRPC 7
• However, this remains investigational and is not guideline-recommended 7

For mCRPC After Prior Novel Hormone Therapy:

• NCCN guidelines organize mCRPC treatment based on prior therapeutic exposures rather than lines of therapy 1
• For patients with prior novel hormone therapy (abiraterone/enzalutamide/darolutamide/apalutamide) given for earlier disease states, switching to another androgen receptor inhibitor is rarely effective due to cross-resistance 1
• Cabazitaxel is preferred over switching AR inhibitors in patients who have received docetaxel and a novel hormone therapy (CARD trial: HR 0.64 for OS; P=0.008) 1

Treatment Algorithm for mCRPC Based on Prior Exposures

No Prior Docetaxel/No Prior Novel Hormone Therapy:

• Options include abiraterone plus prednisone, enzalutamide, or docetaxel 1
• Darolutamide is not specifically listed as a preferred option in this setting 1

Prior Novel Hormone Therapy/No Prior Docetaxel:

• Docetaxel is preferred over switching to another AR inhibitor 1
• Cabazitaxel or radium-223 (for bone-predominant disease) are alternatives 1

Prior Docetaxel/Prior Novel Hormone Therapy:

• Cabazitaxel is Category 1 preferred 1
• 177Lu-PSMA-617 for PSMA-positive disease (HR 0.62 for OS; P<0.001) 1
• Olaparib for BRCA1/2 alterations 1

Monitoring Requirements During Darolutamide Therapy

• Serial PSA every 3-6 months 3
• Conventional imaging every 6-12 months 3
• Baseline and periodic monitoring of testosterone (<50 ng/dL), LDH, hemoglobin, alkaline phosphatase, and thyroid function 3
• Blood pressure monitoring for hypertension 3, 2
• Continue concurrent ADT (LHRH agonist/antagonist) to maintain castrate testosterone levels 1, 3

Comparative Tolerability in mCRPC

• The ODENZA trial compared darolutamide vs enzalutamide in mCRPC patients, showing no significant preference (49% vs 40%, p=0.92) 8
• Darolutamide demonstrated clinically meaningful benefit in episodic memory (effect size 0.5 for new information acquisition) and less fatigue (2.7 vs 3.3 on Brief Fatigue Inventory) compared to enzalutamide 8
• Darolutamide has a favorable safety profile with lower rates of CNS adverse events, seizures, and falls compared to other AR inhibitors 1, 3, 4

Common Pitfalls to Avoid

• Do not use darolutamide without confirming castrate testosterone levels (<50 ng/dL) 3
• Do not switch from one AR inhibitor to another in mCRPC after progression on a novel hormone therapy—cross-resistance makes this ineffective 1
• Do not discontinue ADT when starting darolutamide; concurrent ADT must be maintained 1, 3
• Do not administer darolutamide without food—bioavailability increases 2.0- to 2.5-fold with food 2