ODM-201 and the CNS: A clinical perspective.

Abstract

275^ Background: ODM-201 is a potent, new generation androgen receptor inhibitor with activity in preclinical in vivo and in vitro studies. ODM-201 shows negligible penetration into the rat brain at pharmacological doses. In the phase I/II study with 134 patients with progressive castration-resistant prostate cancer (CRPC) (the ARADES study) patients with a history, or risk, of a seizure were not excluded. We reviewed the ARADES safety database to assess potential seizure or seizure-related adverse events (AEs). Methods: The following AE terminology was reviewed: seizure, syncope, presyncope, loss of consciousness, depressed level of consciousness, encephalopathy, and transient ischemic attack, hallucinations, vasovagal syndrome, falls and fall-related injuries, nonpathologic fractures, urinary or fecal incontinence, tonic-clonic activity, abnormal EEGs. We further reviewed medical histories and use of anti-seizure medications, as well as medications that could lower the seizure threshold and identified any seizure or seizure like condition as an AE. Results: Twenty one percent of the patients had concomitant medications indicated for epilepsy or other seizure-related disorders. Twelve patients had one or more of the above listed AE. None of the patients experienced seizures or related disorders while receiving ODM-201; one seizure event was reported to occur 27 days after stopping treatment. There were five fall events, one syncope, one presyncope, and four urinary incontinence cases - all interpreted by the investigators as not related to ODM-201 treatment and not leading to treatment discontinuation. Careful evaluation of these cases suggested that these events were unlikely to be related to seizure. Conclusions: ODM-201 has negligible brain entrance in nonclinical models. Treatment with ODM-201 was not linked with CNS-related events in patients in this trial. These preliminary findings suggest minimal CNS safety concerns. Clinical trial information: NTC01317641, NTC01429064.