Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Current FDA-Approved Indications for Darolutamide

The National Comprehensive Cancer Network recommends darolutamide 600 mg twice daily with food for non-metastatic CRPC (M0 CRPC) when PSADT is ≤10 months 1, 2
The ARAMIS trial demonstrated metastasis-free survival of 40.4 vs 18.4 months compared to placebo (HR 0.41; P<0.001) in patients with non-metastatic CRPC (M0 CRPC) 1
Overall survival at 3 years was 83% vs 77% (HR 0.69; P=0.003) in patients with non-metastatic CRPC (M0 CRPC) 1, 2
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 in patients with non-metastatic CRPC (M0 CRPC) 1

Darolutamide is FDA-approved in combination with ADT and docetaxel for mHSPC 3, 4
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 in patients with mHSPC 5, 6, 4
The European Society for Medical Oncology recommends this triplet therapy as first-line treatment for mHSPC, including patients with de novo disease and those who progressed to metastatic disease 5, 7

The National Comprehensive Cancer Network guidelines organize mCRPC treatment based on prior therapeutic exposures rather than lines of therapy 8
For patients with prior novel hormone therapy given for earlier disease states, switching to another androgen receptor inhibitor is rarely effective due to cross-resistance 8
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) 8, 6

For patients with no prior docetaxel and no prior novel hormone therapy, options include abiraterone plus prednisone, enzalutamide, or docetaxel 1, 3
For patients with prior novel hormone therapy and no prior docetaxel, docetaxel is preferred over switching to another AR inhibitor 8
For patients with prior docetaxel and prior novel hormone therapy, cabazitaxel is Category 1 preferred 8, 6

The National Comprehensive Cancer Network recommends serial PSA every 3-6 months and conventional imaging every 6-12 months during darolutamide therapy 2
Baseline and periodic monitoring of testosterone, LDH, hemoglobin, alkaline phosphatase, and thyroid function is recommended during darolutamide therapy 2
Blood pressure monitoring for hypertension is recommended during darolutamide therapy 2
Concurrent ADT should be maintained during darolutamide therapy 1, 3, 2

The National Comprehensive Cancer Network (NCCN) 2023 guidelines designate triplet therapy with ADT, docetaxel, and either darolutamide or abiraterone as Category 1, preferred options for patients with metastatic castration-sensitive prostate cancer, particularly those with high-volume de novo disease who are fit for chemotherapy 9

If a patient has high-volume disease (≥4 bone metastases with spread outside pelvis/vertebral column) and is fit for chemotherapy, adding darolutamide to an existing doublet regimen is strongly supported by evidence and should be offered, according to the NCCN 2023 guidelines 9
For patients not fit for chemotherapy or with significant comorbidities, alternative doublet regimens (ADT + novel hormone therapy without docetaxel) may be more appropriate, as suggested by the NCCN 2023 guidelines 9

The NCCN recommends the use of bone-protective agents, such as denosumab or zoledronic acid, to prevent skeletal-related events in patients with bone metastases 10

Cost and access considerations may limit the availability of darolutamide, though this should not override clinical benefit when feasible, as noted in the Journal of the National Comprehensive Cancer Network 10