Nubeqa
darolutamide
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant conducted general toxicology studies to evaluate the effects of daily oral administration of darolutamide in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Why that species
Rat metabolite profile comparable to human; dog differs but keto-darolutamide has the same activity
“In terms of pharmacokinetics, the qualitative metabolite profiles of darolutamide in rats as well as the overall biotransformation pathways seem to be quite comparable to the profiles obtained in human plasma. However, the metabolite profiles of darolutamide between dogs and human are different.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Dogs received twice daily oral darolutamide at doses of 25, 75 or 200 mg/kg/dose (50, 150 or 400 mg/kg/day; n=4/sex/group [main], 2/sex/group [recovery for VH and HD only]).”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The Applicant conducted general toxicology studies to evaluate the effects of daily oral administration of darolutamide in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies with 4- and 8-week recovery
“Study title/ Study number : ODM-201-39-week oral (gavage) toxicity study in the Beagle dog followed by an 8-week treatment-free period/Study number AB19526.”
Route in tox
Oral gavage (twice daily)
“Study title/ number: ODM-201-26-week oral (gavage) toxicity study in the wistar rat followed by a 4-week treatment-free period/Study number AB14461”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames and in vivo rat micronucleus/comet; clastogenic in vitro in human lymphocytes; overall no genotoxic risk
“Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. However, darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in an in vivo combined bone marrow micronucleus assay and comet assay in the liver and duodenum of the rat.”
Carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Reproductive & developmental
No dedicated studies; male reproductive organ atrophy in repeat-dose studies, fertility may be impaired
“No embryo-fetal development toxicology studies were conducted or warranted to support this NDA submission, as the proposed indication does not include females.”
Safety pharmacology
Low-potency hERG blocker (IC50 >1 µM); IV vasodilation in anaesthetized dogs; no ECG changes in repeat-dose dogs; low CNS risk
“In vitro, darolutamide, (S,R)-darolutamide, (S,S)-darolutamide and keto-darolutamide were low-potency hERG channel blockers (IC50 > 1 µM).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Nubeqa don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Male reproductive organ atrophy at ≥100 mg/kg/day rat and ≥50 mg/kg/day dog (~0.6–1x human AUC); GI, mammary, adrenal, thyroid (FDA multi-discipline review, p. 29)
NOAEL / key findings
Male reproductive organ atrophy at ≥100 mg/kg/day rat and ≥50 mg/kg/day dog (~0.6–1x human AUC); GI, mammary, adrenal, thyroid
“Toxicities in male reproductive organs occurred at doses ≥ 100 mg/kg/day in male rats (0.6 times the human exposure based on AUC) and ≥ 50 mg/kg/day in dogs (1 times the human exposure based on AUC).”
Risksopen answer page →
Immune & cytokine safety
Increased thymus weight in male rats and dogs, possibly reduced thymic involution; no immunotoxicity studies
“The corresponding microscopic findings included reduction of secretion in the prostate gland, vacuolation of the epididymal epithelium and a possible reduction in the normal involution of the thymus.”
Biodistribution & persistence
Wide distribution; low brain penetration (brain/plasma <0.05); reversible melanin binding; low blood-testis penetration
“In mice, darolutamide and keto-darolutamide and in rats total radioactivity exhibited low penetration into brain (brain/plasma ratio of AUC(0-24) < 0.05).”
Modality-specific risk
Male reproductive toxicity and impaired fertility from anti-androgen activity
“Darolutamide may impair fertility in males of reproductive potential based on mechanism of action and findings in animals.”