The expanded DEAR-EXT study provides compelling real-world evidence that darolutamide offers superior clinical outcomes compared to enzalutamide and apalutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). This retrospective analysis of 1,375 patients from US urology practices demonstrates significantly lower discontinuation rates, longer time to metastatic progression, and improved metastasis-free survival with darolutamide treatment.

Clinical Takeaway

Darolutamide demonstrated superior real-world effectiveness compared to other androgen receptor inhibitors (ARIs) for nmCRPC treatment, with 27-31% lower risk of discontinuation and 28-37% lower risk of progression to metastatic disease. The study provides robust evidence supporting darolutamide as a preferred first-line ARI for patients with high-risk nmCRPC.

Target Population

The study included patients with nmCRPC characterized by rising PSA levels despite medical or surgical castration but without visible metastatic disease on conventional imaging. This patient population represents 1-12% of all prostate cancer cases but faces significant risk of progression to metastatic disease, with at least one-third developing bone metastases within 2 years on ADT alone.

Study Design

  • Design: Retrospective chart review of electronic medical records from US urology practices
  • Timeline: Patients who initiated ARIs from August 2019 to March 2023
  • Population: 1,375 patients with nmCRPC
  • Treatment groups:
    • Darolutamide: 565 patients (41%)
    • Enzalutamide: 609 patients (44%)
    • Apalutamide: 201 patients (15%)
  • Analysis methods: Adjusted Cox proportional hazards models, inverse probability of treatment weighting, and sensitivity analyses

Primary Endpoints

  • Time to initial drug discontinuation
  • Time to metastatic castration-resistant prostate cancer (mCRPC)
  • PSA response rates
  • Metastasis-free survival (MFS)
  • Overall survival (OS)
  • Safety and tolerability

Efficacy Outcomes

Drug Discontinuation:

  • Darolutamide vs enzalutamide: 27% lower risk (HR 0.73, 95% CI 0.61-0.88)
  • Darolutamide vs apalutamide: 31% lower risk (HR 0.69, 95% CI 0.54-0.89)

Progression to Metastatic Disease:

  • Darolutamide vs enzalutamide: 37% lower risk (HR 0.63, 95% CI 0.50-0.80)
  • Darolutamide vs apalutamide: 28% lower risk (HR 0.72, 95% CI 0.53-0.98)

Metastasis-Free Survival:

  • Darolutamide vs enzalutamide: 35% lower risk of metastasis or death (HR 0.65, 95% CI 0.53-0.79)
  • Darolutamide vs apalutamide: 28% lower risk of metastasis or death (HR 0.72, 95% CI 0.55-0.93)
  • 24-month MFS rates:
    • Darolutamide: 72.3%
    • Enzalutamide: 59.2%
    • Apalutamide: 63.9%
  • 36-month MFS rates:
    • Darolutamide: 60.2%
    • Enzalutamide: 48.3%
    • Apalutamide: 47.6%

Safety Profile

The study demonstrated that darolutamide was associated with fewer adverse events compared to enzalutamide and apalutamide in the real-world setting. This improved tolerability profile likely contributed to the lower discontinuation rates observed with darolutamide treatment. The safety advantages are particularly important for patients with nmCRPC, who are largely asymptomatic and require treatments that preserve quality of life.

Key Clinical Implications

✔ Superior real-world effectiveness: Darolutamide demonstrates consistently better outcomes across multiple clinically meaningful endpoints

✔ Improved treatment persistence: Lower discontinuation rates suggest better tolerability and patient acceptance

✔ Delayed disease progression: Significantly longer time to metastatic progression translates to preserved quality of life

✔ Robust evidence base: Findings remained consistent across sensitivity analyses, strengthening confidence in results

✔ Treatment selection guidance: Data support darolutamide as a preferred first-line ARI option for patients with high-risk nmCRPC

Bottom Line

The DEAR-EXT study provides compelling real-world evidence that darolutamide offers superior clinical outcomes compared to other approved ARIs for nmCRPC treatment. With significantly lower discontinuation rates, reduced progression risk, and improved metastasis-free survival, darolutamide emerges as the preferred therapeutic option for patients with high-risk nmCRPC. These findings complement the established efficacy from the phase III ARAMIS trial and provide valuable guidance for treatment selection in clinical practice.

Sources:

  • Shore, N.D., George, D.J., Khan, N. et al. Real-world analysis of androgen receptor inhibitors in US patients with nonmetastatic castration-resistant prostate cancer: DEAR-EXT study. Prostate Cancer Prostatic Dis (2026). https://doi.org/10.1038/s41391-026-01099-3