Starting with a reduced dose of enzalutamide alleviates fatigue, cognitive side effects, and depressive symptoms compared with the standard dose. Furthermore, there was no evidence of a loss of efficacy at the reduced dose. Fatigue and cognitive impairment are common side effects linked to poor quality of life in cancer patients. A reduction of these side effects can thus have a positive effect on the patient’s quality of life. We conclude that starting with a reduced dose of enzalutamide in frail patients with prostate cancer is associated with fewer side effects, without any indication of interference with efficacy endpoints.