Nubeqa: genotox, carcinogenicity and repro: done or skipped?

“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.”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“No embryo-fetal development toxicology studies were conducted or warranted to support this NDA submission, as the proposed indication does not include females.”

“In vitro, darolutamide, (S,R)-darolutamide, (S,S)-darolutamide and keto-darolutamide were low-potency hERG channel blockers (IC50 > 1 µM).”

“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”

“Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes.”

“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.”

“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”

“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”

“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).”