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The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure.To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC.The UPWARD study (A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer Patients Treated With Enzalutamide) is an international, multicenter (73 sites in 20 countries), single-arm, open-label safety study in institutional practice. Data were collected from September 25, 2013, to February 1, 2016. Patients had at least 1 risk factor for seizure at baseline, including medications that lower seizure threshold, history of stroke, or history of seizure. Exclusion criteria included seizure (assessed by neurologic examination and history) requiring antiseizure medication within the past 12 months.Treatment with oral enzalutamide, 160 mg/d.The primary end point was the proportion of evaluable patients with 1 or more independently confirmed seizures during the 4-month study period; evaluable patients were defined as those who had 3 months or more of treatment or 1 or more confirmed seizures during this treatment period.Of 423 patients with mCRPC receiving enzalutamide, 366 were evaluated. At baseline, risk factors for seizure included medications that lowered seizure threshold (242 of 423 patients [57.2%]), history of brain injury (112 [26.5%]), and history of cerebrovascular accident or transient ischemic attack (94 [22.2%]). Four of the 366 evaluable patients (1.1%) had at least 1 confirmed seizure within 4 months of enzalutamide initiation, and 3 (0.8%) additional patients experienced a seizure within 4 months following the 4-month study period. The incidence of confirmed seizure was 2.6 per 100 patient-years (7 seizures). Of the 423 patients receiving enzalutamide, 357 (84.4%) experienced at least 1 treatment-emergent adverse event (an adverse event temporally related to the study treatment); 141 (33.3%) had at least 1 serious treatment-emergent adverse event, and 29 (6.9%) had at least 1 drug-related serious adverse event. Thirty-eight deaths (9.0%) were reported during treatment or within 30 days of drug discontinuation; 4 were considered possibly drug related.Incidence of seizure is similar in patients with mCRPC and similar seizure risk factors with or without enzalutamide exposure. The risk profile presented, along with the previously established efficacy of enzalutamide, suggests that enzalutamide can benefit patients with a history of seizures or other predisposing factors, but each patient should be closely monitored for the duration of treatment.