1. INTRODUCTION 1.1 STUDY O BJECTIVES 1.1.1 Primary Objective Determine if PSA-TRICOM combined with enzalutamide will increase time to progression (as defined by Prostate Cancer Clinical Trials Working Group 2 criteria) in chemotherapy- naïve metastatic castration resistant prostate cancer patients compared to enzalutamide alone. 1.1.2 Secondary Objectives Determine if PSA-TRICOM combined with enzalutamide will increase overall survival in chemotherapy-naïve metastatic castration resistant prostate cancer patients compared to enzalutamide alone. Determine if PSA-TRICOM combined with enzalutamide will delay PSA progression in chemotherapy-naïve metastatic castration resistant prostate cancer patients compared to enzalutamide alone 1.1.3 Exploratory Objectives Evaluate the immune response in patients treated with both the combination of PSA- TRICOM and enzalutamide compared to enzalutamide alone. Immune response evaluation will include CD4 cells, CD 8 cells, PSA-specific T-cells, natural killer cells, Regulatory T- cells, Regulatory T-cell function, cytokines, anti-glycan antibodies, naïve thymic emigrants. Associate immunologic outcomes with clinical outcomes. 11 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 1.2 BACKGROUND AND RATIONALE 1.2.1 Enzalutamide Enzalutamide is a modern update of the original androgen receptor antagonists (ARAs), the last of which was developed over 2 decades ago for the treatment of prostate cancer. Since then, the prevailing focus shifted to chemotherapy and chemotherapy combinations [1]. In addition to binding to the androgen receptor with greater affinity than standard ARAs, enzalutamide prevents downstream effects including nuclear translocation, DNA binding, and signaling to co- activators [2]. Furthermore, enzalutamide has not demonstrated any agonist properties unlike previous ARAs which showed agonist properties in approximately 15%-20% of patients [3, 4]). (Figure 1) The U.S. Food and Drug Administration (FDA) approved enzalutamide for metastatic prostate cancer in docetaxel-refractory patients in August, 2012 and in 2014 for docetaxel naive patients [5-7]. Figure 1.