Background
Phase III, double-blind, placebo-controlled RCT. 1509 patients with nmCRPC (castration-resistant, M0 by conventional CT and bone scan), PSA doubling time ≤10 months, PSA ≥2 ng/mL, on ongoing ADT.
Interventions and follow up
Arm A: Darolutamide 600mg twice daily orally + ongoing ADT
Arm B: Placebo + ongoing ADT
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 17.9 mo (MFS primary); 29.0 mo (OS update)
Arm B: Placebo + ongoing ADT
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 17.9 mo (MFS primary); 29.0 mo (OS update)
Results
MFS: 40.4 vs 18.4 mo, HR 0.41, P<.001
OS: 49.7 vs 36.5 mo, HR 0.69, P=.003
Time to pain progression: HR 0.65
Time to cytotoxic chemotherapy: HR 0.43
OS: 49.7 vs 36.5 mo, HR 0.69, P=.003
Time to pain progression: HR 0.65
Time to cytotoxic chemotherapy: HR 0.43
Adverse events
Overall grade ≥3 AEs: 24.7% vs 19.5% — near-placebo levels
Constitutional / cardiovascular: Fatigue 15.8% vs 11.4%; hypertension 3.2% vs 2.2%
Musculoskeletal / neurologic: Falls 4.2% vs 3.5%; no increased fracture risk vs placebo; seizure 0.2% vs 0%; CNS AEs similar to placebo, consistent with limited blood-brain barrier penetration
Treatment discontinuation due to AEs: 8.9% vs 8.7%
Constitutional / cardiovascular: Fatigue 15.8% vs 11.4%; hypertension 3.2% vs 2.2%
Musculoskeletal / neurologic: Falls 4.2% vs 3.5%; no increased fracture risk vs placebo; seizure 0.2% vs 0%; CNS AEs similar to placebo, consistent with limited blood-brain barrier penetration
Treatment discontinuation due to AEs: 8.9% vs 8.7%
Conclusions
Darolutamide significantly prolonged MFS and OS in nmCRPC with an exceptionally favorable toxicity profile, with grade ≥3 AE rates approaching placebo. The unique chemical structure of darolutamide limits CNS penetration, accounting for its differentiated tolerability versus enzalutamide and apalutamide.
Key Limitations
Key Limitations: M0 status was defined by conventional imaging without PSMA PET — many enrolled patients had undetected micrometastatic disease. Open-label darolutamide was offered to placebo patients at metastasis development, which may attenuate the final OS hazard ratio. Median OS follow-up of 29 months was relatively short compared to median OS values of ~50 months. OS benefit was confirmed despite substantial crossover, strengthening confidence in the OS result.
Clinical Context
ARAMIS established darolutamide as the nmCRPC ARPI with the most favorable toxicity profile, preferred for patients at seizure risk, cognitive impairment risk, frequent falls, or on polypharmacy (minimal CYP2C8 induction). ARASENS extended darolutamide into mHSPC (with docetaxel + ADT). FDA approved darolutamide for nmCRPC in 2019 and for mHSPC in 2022. ESMO-MCBS score for OS endpoint: 4.
References