How Nubeqa (Darolutamide) Works
Darolutamide is an androgen receptor (AR) inhibitor that works by competitively blocking androgen binding to the AR, preventing AR nuclear translocation, and inhibiting AR-mediated transcription—thereby blocking the cellular signaling that drives prostate cancer growth. 1
Mechanism of Action
Darolutamide functions through three distinct molecular steps that disrupt androgen signaling in prostate cancer cells:
Competitive inhibition of androgen binding: Darolutamide competes with testosterone and dihydrotestosterone (DHT) for binding sites on the androgen receptor, preventing these hormones from activating the receptor 1
Blockade of AR nuclear translocation: Once bound to the receptor, darolutamide prevents the AR from moving into the cell nucleus where it would normally activate gene transcription 1
Inhibition of AR-mediated transcription: Even if the AR reaches the nucleus, darolutamide blocks its ability to bind to DNA and activate genes that promote prostate cancer cell proliferation 1
Active Metabolite and Additional Activity
Darolutamide has a major active metabolite called ketodarolutamide that exhibits similar AR inhibitory activity to the parent compound, contributing to its overall therapeutic effect 1
The drug also functions as a progesterone receptor (PR) antagonist in vitro, though this activity is approximately 1% compared to its AR activity 1
Functional Outcomes in Prostate Cancer
The molecular mechanism translates to measurable anti-tumor effects:
Decreased prostate cancer cell proliferation in laboratory studies, demonstrating direct cytotoxic effects on cancer cells 1
Tumor volume reduction in mouse xenograft models of prostate cancer, confirming in vivo efficacy 1
PSA suppression reaching undetectable levels in 24.2% of non-metastatic CRPC patients at 12 months (vs 0.4% with placebo) and 60.2% of metastatic hormone-sensitive patients at 12 months when combined with docetaxel (vs 26.1% with placebo plus docetaxel) 1
Critical Distinction from ADT
An essential clinical point: darolutamide does not suppress testosterone production itself—it only blocks testosterone's action at the receptor level. 2 This is why:
Darolutamide must be continued with concurrent androgen deprivation therapy (ADT) to maintain castrate testosterone levels (<50 ng/dL) in castration-resistant disease 2, 3
When used as monotherapy in hormone-sensitive disease, testosterone levels actually increase (median increase of 44.3 ng/dL at week 24) due to loss of negative feedback, though the AR blockade prevents this testosterone from stimulating cancer growth 4
Structural and Safety Advantages
Darolutamide is structurally distinct from other AR inhibitors (enzalutamide, apalutamide), which contributes to its favorable safety profile 5, 6
It does not significantly prolong the QTc interval, making it safer for patients with cardiac concerns 2
The drug demonstrates lower rates of central nervous system effects (seizures, cognitive impairment), falls, and fractures compared to other AR inhibitors in the class 5