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]).”
Species: general tox
Rat (26-week) and dog (39-week)
“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.”
Species: DART
Not conducted: indication does not include females
“No embryo-fetal development toxicology studies were conducted or warranted to support this NDA submission, as the proposed indication does not include females.”
Species: carcinogenicity
Not conducted pre-approval; 6-month Tg-rasH2 mouse study required post-authorisation
“In the absence of relevant data to adequately assess the carcinogenicity potential of darolutamide, the applicant will submit results of a 6-month Tg-rasH2 mouse study (see RMP).”
Surrogate used in
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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).”
Genotox: Ames
Negative
“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”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration: positive (clastogenic)
“Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes.”
Genotox: in vivo
Negative: rat bone marrow micronucleus and liver/duodenum comet
“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 model
6-month Tg-rasH2 mouse study, results due post-authorisation
“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”
Carcinogenicity timing
None before the marketing application; 6-month Tg-rasH2 mouse study results due after approval (by 30 June 2022)
“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”
hERG / QT
Weak hERG inhibition: IC50 87.9 µM (darolutamide), 8.0 µM (keto-darolutamide); 34.5% block at 30 µM
“The IC50 values reported for the four test compounds were 87.9, 11.5, 30.2, and 8.0 µM, respectively. Darolutamide blocked the hERG current by 34.5% at the highest dose (30µM).”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Ischemic Heart Disease
- Seizure
- Embryo-Fetal Toxicity
CardiovascularNeurotoxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral gavage) with 8-week recovery
“ODM-201-39-week oral (gavage) toxicity study in the Beagle dog followed by an 8-week treatment-free period/Study number AB19526.”
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.”
DART package
Species: DART
Not conducted: indication does not include females
“No embryo-fetal development toxicology studies were conducted or warranted to support this NDA submission, as the proposed indication does not include females.”
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.”
PPND / ePPND: when
Not conducted: not warranted for a drug to treat male patients with advanced prostate cancer
“Not conducted or warranted to support this NDA submission for a therapeuticintended to treat male patients with advanced prostate cancer”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval; 6-month Tg-rasH2 mouse study required post-authorisation
“In the absence of relevant data to adequately assess the carcinogenicity potential of darolutamide, the applicant will submit results of a 6-month Tg-rasH2 mouse study (see RMP).”
Carcinogenicity model
6-month Tg-rasH2 mouse study, results due post-authorisation
“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”
Carcinogenicity timing
None before the marketing application; 6-month Tg-rasH2 mouse study results due after approval (by 30 June 2022)
“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin stated; male reproductive toxicity at 0.6x (rat) and 1x (dog) human AUC
“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).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models of human prostate cancer: tumor growth inhibition and suppressed PSA rise
“In vivo, darolutamide administration inhibited tumor growth in mouse xenograft models of human prostate cancer and suppressed the relative increase in serum PSA when compared to control group.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: tumour weight unchanged in VCaP studies (PSA decreased); no comparison with other antiandrogens
“The anti-tumour activity in these studies was not compared with any other first or second-generation antiandrogen therapy. In both experiments, no change in the tumour weight was observed but a decrease on the serum PSA level was observed.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a condition
No carcinogenicity studies before approval (advanced cancer); EMA required a 6-month Tg-rasH2 mouse study post-approval
Why: Advanced cancer indication; EMA required Tg-rasH2 results by 30 June 2022 via the RMP · Within the guideline · Serious disease
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”
Safety pharmacologyAccepted with a conditionBeyond the letter
Cardiovascular safety pharmacology limited: non-GLP in vitro studies; anaesthetised dog study without control group or metabolite analysis
Why: QT prolongation risk cannot be excluded; adequate measures included in the SmPC
“It was noted that the two in vitro studies were not conducted in compliance with GLP standard. Furthermore, there was no control group and no analysis related to the effect of the metabolite and one of the diastereomers in the non-conscious dog study.”
“Considering these limitations and the available results from safety pharmacology and toxicology studies, the risk for QT prolongation cannot be excluded in clinic and adequate measures have been included in the SmPC (see also discussion clinical safety).”
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