The changes include: Updates were made to fulfill requirements for a Post Authorization Safety Study as defined by EMA: o The sample size calculation was refined to include the incidence rate of seizure (2.8 per 100 person-years). o The description of the study design was expanded to include potential limitations of the study design, data sources and analytical methods. o A statement on the source population was added to state that the patients were drawn from various sources including hospitals, private practices and community-based organizations. o The expected age range of the patient population was added. o A statement was added that patients with alcoholism were allowed into the study assuming eligibility criteria were met. o An appendix outlining the countries planned for participation in the study was added. o An appendix outlining the study milestones was added. ● The suspected seizure event visit window was updated to accommodate logistical challenges that could arise due to hospitalization of patients or transportation challenges in rural areas where modes of transportation could be limited. ● The anti-seizure drug pregabalin was re-categorized as an acceptable drug unlikely to cause interaction with enzalutamide after the team re-examined the potential for drug-drug interaction with pregabalin and enzalutamide. The re-categorization was based on the determination that pregabalin undergoes very little metabolism, is excreted in the urine mostly intact as parent and does not inhibit or induce metabolic enzymes in vitro. ● The timing of additional radiographic disease assessments was clarified to ensure a frequency of no more than every 12 weeks to avoid over-exposure to a patient. ● A statement on data interpretation of enzalutamide was added to clarify that no direct comparison was planned but that the results from the study would be interpreted in the context of all available relevant data.

The changes include: The word “Adverse Events” was deleted from the list of data to be collected for screen failures based on the timing of AE collection defined in the protocol. ● Additional nonsubstantial changes were made to add EudraCT information, update contact information and incorporate minor wording changes.

The changes include: The seizure incidence rate was changed from “0.5% to 0.9%” to “< 1%” and “cognitive/memory impairment” was changed from a potential risk to an identified risk. The changes were based on more current experience regarding enzalutamide and seizures as reflected in the updated Investigator’s Brochure. ● Additional nonsubstantial changes were made including an increase in the number of sites participating in the study, addition of a statement outlining the limit of patients enrolled under a specific risk category (i.e., class of medication) to ensure patients with a reasonably balanced set of risk characteristics were enrolled in the study, addition of a statement to allow for destruction of the study drug at the site with the sponsor permission, addition of a statement indicating patients with Alzheimer’s disease are permitted to be enrolled into the study and the incorporation of other minor wording changes.