What is darolutamide?

Darolutamide: A Second-Generation Androgen Receptor Inhibitor

Darolutamide is a structurally unique androgen receptor (AR) inhibitor that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription, used primarily in the treatment of prostate cancer. 1

Mechanism of Action

Darolutamide works by:

• Competitively inhibiting androgen binding to the androgen receptor
• Preventing AR nuclear translocation
• Blocking AR-mediated transcription
• Acting as a weak progesterone receptor antagonist (approximately 1% activity compared to AR) 1

Its major metabolite, ketodarolutamide, exhibits similar activity to the parent compound. Darolutamide has been shown to decrease prostate cancer cell proliferation in vitro and reduce tumor volume in mouse xenograft models. 1

Clinical Applications

Darolutamide is FDA-approved for:

1. Non-metastatic Castration-Resistant Prostate Cancer (nmCRPC)

   • Approved in July 2019 for patients with nmCRPC and PSA doubling time ≤10 months 2
   • In the ARAMIS trial, darolutamide significantly improved metastasis-free survival compared to placebo (40.4 vs 18.4 months; HR 0.41) 3
   • Category 1, preferred option per NCCN guidelines for nmCRPC with PSADT ≤10 months 2

2. Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

   • Used in combination with docetaxel 2
   • The ARASENS trial evaluated darolutamide plus standard ADT and docetaxel versus placebo plus ADT and docetaxel in previously untreated men with mHSPC 2

Pharmacokinetics

Key pharmacokinetic properties include:

• Oral administration at 600 mg twice daily
• Peak plasma concentration reached approximately 4 hours after administration
• Absolute bioavailability of approximately 30% under fasted conditions
• Bioavailability increases 2.0-2.5 fold when taken with food
• Protein binding of 92% (primarily to serum albumin)
• Effective half-life of approximately 20 hours
• Steady-state reached within 2-5 days of repeated dosing 1

Side Effect Profile

Darolutamide has a favorable side effect profile compared to other second-generation antiandrogens:

• Most common side effects include:

  • Fatigue (12.1% vs 8.7% with placebo)
  • Pain in extremities (5.8% vs 3.2%)
  • Rash (2.9% vs 0.9%) 4

• Notable advantages:

  • Minimal penetration of the blood-brain barrier, resulting in fewer CNS-related side effects
  • Particularly favorable for patients with history of seizures, brain injury, or fall risk
  • Relatively lower cardiovascular risk profile compared to enzalutamide 4
  • Similar incidence of fractures compared to placebo (4.2% vs 3.6%) 4

Comparative Advantages

Darolutamide offers several advantages over other second-generation antiandrogens:

1. CNS Safety Profile: Unlike enzalutamide, darolutamide shows minimal blood-brain barrier penetration, resulting in fewer CNS-related adverse events 4

2. Cardiovascular Safety: While enzalutamide has been associated with major adverse cardiovascular events (5% vs 3% with placebo), darolutamide appears to have a relatively lower cardiovascular risk profile 4

3. Unique Chemical Structure: Darolutamide has a structurally distinct design compared to other androgen receptor inhibitors like enzalutamide and apalutamide 5

Monitoring and Management

Patients taking darolutamide should:

• Continue androgen deprivation therapy (ADT) as prescribed
• Have regular liver function tests
• Monitor for signs of heart problems
• Report any unusual symptoms promptly to healthcare providers 4

Emerging Research

Recent studies are exploring darolutamide's potential in:

• Monotherapy without ADT in hormone-sensitive prostate cancer 6
• Treatment of metastatic castration-resistant prostate cancer 7, 8
• Combination with docetaxel for previously untreated mCRPC 8

In summary, darolutamide represents an important addition to the armamentarium against prostate cancer, with efficacy comparable to other second-generation antiandrogens but with a potentially more favorable side effect profile, particularly regarding CNS and cardiovascular effects.