# Darolutamide
**Darolutamide** (brand name Nubeqa; research codes ODM-201, BAY 1841788) is an oral androgen receptor inhibitor used to treat prostate cancer, indicated for non-metastatic castration-resistant prostate cancer (nmCRPC) and for metastatic castration-sensitive prostate cancer (mCSPC), in the latter case with or without docetaxel[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf). It was first approved in the United States in 2019 and received a European Union marketing authorization on 27 March 2020; Bayer AG is the marketing authorization holder[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf) • [2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa).
| Key fact | Detail |
|---|---|
| Drug class | Androgen receptor (AR) inhibitor; competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf) |
| Dose | 600 mg (two 300 mg tablets) orally twice daily with food, with a GnRH agonist or antagonist or prior bilateral orchiectomy[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf) |
| Approvals | Initial US approval 2019; EU marketing authorization 27 March 2020 (Bayer AG)[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf) • [2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa) |
| ARAMIS (nmCRPC) | 1,509 men; median metastasis-free survival 40 months with darolutamide versus about 18 months with placebo[2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa) |
| ARASENS (mCSPC) | 1,306 men; about 63% alive at 4 years with darolutamide plus docetaxel and ADT versus 50% with placebo[2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa) |
| Brain penetration | Brain-plasma ratios of 1.9–3.9% in animal models, versus 27% for enzalutamide and 62% for apalutamide[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10517889/) |
| Drug interactions | Low potential for clinically relevant drug-drug interactions; main note is increased exposure of BCRP and probably OATP substrates[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6828636/) |
## Mechanism and chemistry
Darolutamide competitively inhibits androgen binding to the androgen receptor, AR nuclear translocation, and AR-mediated transcription; a major metabolite, ketodarolutamide, showed similar in vitro activity to the parent drug[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf). In nonclinical studies it potently blocked AR signaling and inhibited testosterone-induced nuclear translocation of AR in prostate cancer cells, leading to impaired tumor growth and survival, and it did not increase serum testosterone levels[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6828636/).
The molecule is structurally distinct from other androgen receptor inhibitors and comprises two pharmacologically active diastereomers, (S,R)-darolutamide and (S,S)-darolutamide[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6828636/). Per the FDA label, it is an optically active white to grayish- or yellowish-white crystalline powder with a pKa of 11.75, soluble in tetrahydrofuran but practically insoluble in aqueous medium[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf).
**Low brain penetration.** In rodent studies, darolutamide showed low penetration of the blood-brain barrier, which may explain a lower propensity for central nervous system effects compared with approved AR inhibitors[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6828636/). Mouse studies found brain-plasma ratios after seven days of oral dosing of 1.9–3.9% for darolutamide and 1.9–2.8% for keto-darolutamide, versus 27% for enzalutamide and 62% for apalutamide[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10517889/) • [5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7367726/). In healthy men, darolutamide did not significantly alter cerebral blood flow compared with placebo, whereas enzalutamide produced significant decreases[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10517889/).
## Clinical evidence
**ARAMIS (nmCRPC).** In this randomized (2:1), double-blind, placebo-controlled trial, 1,509 men with non-metastatic castration-resistant prostate cancer received darolutamide 600 mg twice daily or placebo, all continuing androgen deprivation therapy. Darolutamide recipients went a median of 40 months before their disease metastasized, versus roughly 18 months among those receiving placebo[2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa).
**ARASENS (mCSPC with docetaxel).** In a main study of 1,306 men with metastatic hormone-sensitive prostate cancer, both arms received docetaxel and androgen deprivation therapy; around 63% of patients given darolutamide were alive 4 years after starting treatment compared with 50% of those given placebo[2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa).
**ARANOTE (mCSPC without docetaxel).** This double-blind, placebo-controlled phase 3 trial randomized 669 metastatic prostate cancer patients in a 2:1 ratio to darolutamide 600 mg twice daily plus ADT or placebo plus ADT. Darolutamide significantly improved radiographic progression-free survival, reducing the risk of radiologic progression or death by 46% (HR 0.54, 95% CI 0.41–0.71, p<0.0001), with benefits across high- and low-volume disease; at a median follow-up of 24 months, overall survival trended to benefit (HR 0.81, 95% CI 0.59–1.12), and time to mCRPC was delayed (HR 0.40, 95% CI 0.32–0.51)[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC12091038/). In a third EMA-described study of 669 men, after 3 years of treatment the cancer had not worsened in 71% of patients receiving darolutamide versus 58% with placebo[2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa).
## Comparison with apalutamide and enzalutamide
No published head-to-head randomized trials have compared darolutamide with apalutamide or enzalutamide in nmCRPC, so evidence comes from indirect methods[7](https://pubmed.ncbi.nlm.nih.gov/33818140/). A matching-adjusted indirect comparison using individual patient data from ARAMIS (943 darolutamide, 553 placebo) reweighted to match the SPARTAN and PROSPER trial populations found that metastasis-free survival did not differ across the drugs, but darolutamide showed a favorable safety and tolerability profile in prespecified adverse events versus both comparators[7](https://pubmed.ncbi.nlm.nih.gov/33818140/).
A network meta-analysis of the SPARTAN, PROSPER, and ARAMIS trials, covering 4,117 observations, ranked darolutamide first for overall survival benefit relative to androgen deprivation therapy, followed by enzalutamide and apalutamide[8](https://www.nature.com/articles/s41391-021-00395-4). An earlier systematic review and network meta-analysis reached a different ranking on efficacy: for progression-free survival by PSA, apalutamide (HR 0.71, 95% CrI 0.69–0.74) and enzalutamide (HR 0.76, 95% CrI 0.74–0.79) were both significantly more effective than darolutamide, while darolutamide was the likely best option for adverse events including grade 3 or 4 events, grade 5 events, and discontinuation rates[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7572325/).
**Real-world cohort.** A retrospective cohort study of 870 patients with nmCRPC from a US urology practice network (362 on darolutamide, 382 enzalutamide, 126 apalutamide; mean age 78.8 years) found lower risks with darolutamide after adjustment: a composite of treatment discontinuation or progression to metastatic disease (HR 0.66 versus enzalutamide; HR 0.65 versus apalutamide), discontinuation alone (HR 0.73 and 0.61), and progression to mCRPC (HR 0.59 and 0.65)[10](https://pubmed.ncbi.nlm.nih.gov/PMC11350483). The authors concluded the results suggest better tolerability for darolutamide, possibly associated with a clinical effectiveness advantage, and called for comparative studies in the absence of head-to-head trials[10](https://pubmed.ncbi.nlm.nih.gov/PMC11350483).
A matching-adjusted indirect comparison and network meta-analysis of five trials with 4,360 participants found that, compared with placebo, darolutamide led to the lowest hazard of death (HR 0.69, 95% CrI 0.53–0.90) and the lowest odds of serious adverse events (OR 1.32, 95% CrI 1.02–1.70) among the drugs studied, while abiraterone acetate showed the lowest hazard of metastasis and death (HR 0.22, 95% CrI 0.12–0.41)[11](https://pubmed.ncbi.nlm.nih.gov/33830214/).
## Adverse effects and precautions
In ARAMIS, the most common adverse reactions (more than 2% with at least a 2% increase over placebo), including laboratory abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash; serious adverse reactions occurred in 25% of darolutamide patients versus 20% on placebo, and permanent discontinuation due to adverse reactions occurred in 9%[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf). In mCSPC with docetaxel (ARASENS), the most common adverse reactions were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf). The FDA label carries warnings for ischemic heart disease, seizure, and embryo-fetal toxicity[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf). The most common side effects reported in the EU (more than 1 in 10 people) are tiredness, weakness, lethargy, and feeling unwell; with docetaxel they are rash and hypertension[2](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa).
## Drug interactions and dosing in special populations
Darolutamide is a substrate for CYP3A4, several UGTs, P-gp, and BCRP, and at therapeutic concentrations has few inhibitory or inducing interactions with other compounds; increased exposure of BCRP and probably OATP substrates is the main interaction of note[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6828636/). The label advises avoiding combined P-gp and strong or moderate CYP3A inducers, monitoring with combined P-gp and strong CYP3A inhibitors, and avoiding or monitoring BCRP substrates, whose plasma concentrations may rise about five-fold (rosuvastatin)[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10517889/). Rifampicin reduces darolutamide AUC and C-max by 72% and 52%, respectively[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10517889/).
Because the drug is extensively metabolized by oxidation and glucuronidation and excreted in urine and feces, a reduced dose of 300 mg twice daily is recommended for severe renal impairment (eGFR 15–29 mL/min/1.73 m², not on hemodialysis) and for moderate hepatic impairment (Child-Pugh class B)[1](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf) • [12](https://pubmed.ncbi.nlm.nih.gov/37458966/). Its limited solubility and bioavailability increase when taken with food, regardless of fat content[12](https://pubmed.ncbi.nlm.nih.gov/37458966/).
## References
1. [NUBEQA (darolutamide) Full Prescribing Information, FDA (revised 6/2025)](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212099s008lbl.pdf)
2. [Nubeqa, European Medicines Agency, EPAR overview](https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa)
3. [Darolutamide: A Review in Metastatic Hormone-Sensitive Prostate Cancer, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10517889/)
4. [Drug–Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6828636/)
5. [Darolutamide: An Evidence-Based Review of Its Efficacy and Safety in the Treatment of Prostate Cancer, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7367726/)
6. [2025 Canadian Urological Association-Canadian Uro-oncology Group Guideline: Metastatic castration-naive and castration-sensitive prostate cancer (Update), PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12091038/)
7. [Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer, PubMed](https://pubmed.ncbi.nlm.nih.gov/33818140/)
8. [Overall survival and adverse events after treatment with darolutamide vs. apalutamide vs. enzalutamide for high-risk non-metastatic castration-resistant prostate cancer, Prostate Cancer and Prostatic Diseases](https://www.nature.com/articles/s41391-021-00395-4)
9. [Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7572325/)
10. [Androgen Receptor Inhibitors in Patients With Nonmetastatic Castration-Resistant Prostate Cancer, PubMed](https://pubmed.ncbi.nlm.nih.gov/PMC11350483)
11. [Comparison of Treatments for Nonmetastatic Castration-Resistant Prostate Cancer: Matching-Adjusted Indirect Comparison and Network Meta-Analysis, PubMed](https://pubmed.ncbi.nlm.nih.gov/33830214/)
12. [Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide, PubMed](https://pubmed.ncbi.nlm.nih.gov/37458966/)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Cancer chemotherapy and regimens › Hormonal and endocrine therapy*
*Initially written Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
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