How does Darolutamide work?

How Darolutamide Works

Darolutamide is a potent androgen receptor (AR) inhibitor that competitively blocks androgen binding to the AR, prevents AR nuclear translocation, and inhibits AR-mediated transcription of genes that drive prostate cancer cell proliferation. 1

Mechanism of Action at the Molecular Level

• Darolutamide competitively inhibits androgen binding to the androgen receptor, preventing testosterone and dihydrotestosterone from activating the receptor 1
• The drug blocks AR nuclear translocation, keeping the receptor from entering the cell nucleus where it would normally activate cancer-promoting genes 1
• Darolutamide prevents AR-mediated transcription, stopping the production of proteins that drive prostate cancer cell growth and survival 1
• A major active metabolite called ketodarolutamide exhibits similar in vitro activity to darolutamide, effectively doubling the therapeutic effect 1
• Darolutamide also functions as a progesterone receptor (PR) antagonist in vitro, though at approximately 1% of its AR activity 1

Unique Structural Advantages

• Darolutamide has a structurally unique chemical structure distinctly different from other AR antagonists like enzalutamide and apalutamide, which provides potential efficacy and safety advantages 2, 3
• The drug targets both wild-type AR and mutated ligand binding domain variants, including F877L, H875Y/T878A, F877L/T878A, and T878G AR mutants that can transform enzalutamide into a partial agonist 3
• This structural uniqueness allows darolutamide to maintain activity in enzalutamide-resistant castration-resistant prostate cancer, as demonstrated in preclinical models 3

Clinical Effects on Prostate Cancer

• Darolutamide decreased prostate cancer cell proliferation in vitro and reduced tumor volume in mouse xenograft models 1
• In non-metastatic CRPC patients receiving 600 mg twice daily, 24.2% achieved undetectable PSA levels at 12 months compared to 0.4% with placebo 1
• In metastatic hormone-sensitive prostate cancer patients receiving darolutamide with docetaxel, 60.2% achieved undetectable PSA levels at 12 months compared to 26.1% with placebo plus docetaxel 1
• PSA reduction plateaus at the 600 mg twice daily dose, establishing this as the optimal therapeutic dose 1

Pharmacodynamic Considerations

• Darolutamide reaches steady-state plasma concentrations 2-5 days after repeated dosing with food, with approximately 2-fold accumulation 1
• The effective half-life is approximately 20 hours for both darolutamide and its active metabolite ketodarolutamide, allowing for twice-daily dosing 1
• Bioavailability increases 2.0- to 2.5-fold when administered with food, which is why the drug must be taken with meals 1
• Protein binding is 92% for darolutamide and 99.8% for ketodarolutamide, with serum albumin as the main binding protein 1

Important Clinical Caveats

• Darolutamide does not significantly prolong the QTc interval (no mean increase >20 ms detected), making it safer for patients with cardiac concerns 1
• The drug must be continued with concurrent androgen deprivation therapy (ADT) to maintain castrate testosterone levels, as it does not suppress testosterone production itself 4, 5
• When used as monotherapy without ADT, darolutamide causes testosterone levels to increase (median increase of 44.3 ng/dL at week 24), demonstrating its pure AR antagonist mechanism without hormonal suppression 6