Darolutamide Mechanism of Action
Darolutamide is an androgen receptor (AR) antagonist that competitively inhibits androgen binding to the AR, blocks AR nuclear translocation, and prevents AR-mediated transcription. 1, 2
Molecular Mechanism
Darolutamide works through three distinct steps in blocking androgen receptor signaling 2:
Competitive inhibition of androgen binding: Darolutamide competes with testosterone and dihydrotestosterone for binding sites on the androgen receptor, preventing these hormones from activating the receptor 2
Blockade of AR nuclear translocation: Even if the androgen receptor is activated, darolutamide prevents it from moving into the cell nucleus where it would normally activate gene transcription 2
Prevention of AR-mediated transcription: Darolutamide stops the androgen receptor from turning on genes that promote prostate cancer cell growth and survival 2
Active Metabolite
Darolutamide has a major active metabolite called ketodarolutamide that exhibits similar in vitro activity to the parent compound 2
Ketodarolutamide achieves total plasma exposure that is 1.7-fold higher compared to darolutamide itself, contributing significantly to the overall therapeutic effect 2
Additional Receptor Activity
- Darolutamide also functions as a progesterone receptor (PR) antagonist in vitro, though this activity is approximately 1% compared to its AR activity 2
Functional Outcomes
The molecular mechanism translates to measurable anti-tumor effects 2:
Decreased prostate cancer cell proliferation in vitro studies 2
Reduced tumor volume in mouse xenograft models of prostate cancer 2
PSA suppression: In clinical trials, 24.2% of nmCRPC patients achieved undetectable PSA levels at 12 months (versus 0.4% with placebo), and 60.2% of mHSPC patients achieved undetectable PSA levels at 12 months when combined with docetaxel (versus 26.1% with placebo plus docetaxel) 2
Structural Uniqueness
- Darolutamide is described as a structurally unique androgen receptor antagonist, distinguishing it from other second-generation AR inhibitors like enzalutamide and apalutamide 3, 4
Important Clinical Distinction
Darolutamide does not suppress testosterone production itself and must be continued with concurrent androgen deprivation therapy (ADT) to maintain castrate testosterone levels 5
However, when used as monotherapy in hormone-sensitive disease, darolutamide causes serum testosterone levels to increase (median increase of 44.3 ng/dL at week 24) while still achieving profound PSA suppression through potent AR blockade 6