PURPOSE: Metastatic castration resistant prostate cancer with low baseline prostate specific antigen represents an early stage in the natural history of castration resistant prostate cancer progression (low volume disease), low prostate specific antigen producing disease or disease that is less dependent on androgen receptor biology (high volume disease). We analyzed outcomes in men with low prostate specific antigen and a high disease burden who received the oral androgen receptor inhibitor enzalutamide in the PREVAIL (Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients with Progressive Metastatic Prostate Cancer) study. MATERIALS AND METHODS: In this exploratory analysis low baseline prostate specific antigen was defined as less than 10 ng/ml. Post hoc analyses included radiographic progression-free and overall survival in the once daily enzalutamide and placebo arms. Patients were stratified post hoc by high volume disease, defined as more than 4 bone metastases and/or visceral disease, and low volume disease, defined as 4 or fewer bone metastases with no visceral disease. RESULTS: Of 1,717 patients enrolled in PREVAIL 242 (14.1%) had low baseline prostate specific antigen, including 110 with high volume disease. Enzalutamide decreased the risk of radiographic progression relative to placebo in patients with low baseline prostate specific antigen (HR 0.20, 95% CI 0.10-0.42). This decrease was irrespective of tumor burden (high volume disease HR 0.17, 95% CI 0.06-0.51 and low volume disease HR 0.25, 95% CI 0.09-0.70). Median overall survival was not reached in patients with low baseline prostate specific antigen in either treatment arm. CONCLUSIONS: Chemotherapy naïve men with metastatic castration resistant prostate cancer and low baseline prostate specific antigen irrespective of disease burden may benefit from enzalutamide. This indicates that targeting the androgen receptor signaling pathway is a therapeutic option in similar patients.