Background: We hypothesized ¹⁸F-DCFPyL (PSMA-based tracer) and/ or ¹⁸F-FDG (glucose metabolism-based tracer) PET/CT might provide different/complementary molecular imaging information in men with mCRPC treated with abiraterone (A) or enzalutamide (E). Methods: In this prospective cohort study (MISTER trial) mCRPC patients (pts) had conventional imaging and both PSMA and FDG PET/CT prior to standard treatment with A or E, repeated after ~10 weeks on treatment. The main objective was to compare changes in PET/CT findings with conventional imaging. Median of PET maximum standardized uptake value (SUVmax) was measured across all PET avid disease sites and change in SUVmax was evaluated in the 5 hottest sites per patient. Review of PET/CT was performed by 3 experts based on consensus. Results: 36 men were enrolled between 2/2017-12/2018, of whom 28 had treatment and followup imaging. To date, 13 cases have been reviewed: mean age 71.2 years, 7 (53.9%) were ECOG=0, median duration since diagnosis of initial cancer 7.5 months and 8 (61.5%) were stage II/III. PSMA detected more skeletal metastases, positive nodes and non-skeletal, non-nodal metastases in 5/5/3 (39%/39%/23%) men, while FDG detected more non-skeletal, non-nodal metastases in 1 man. Following treatment, new lesions were seen in 3 men on both PSMA and FDG, 3 with PSMA only, and 1 with FDG only. 12 men had baseline FDG-avid disease with median SUVmax 6.5 pre-treatment and 3.8 following therapy (all men had lower SUVmax post-treatment). All 13 men had PSMA-avid disease with median SUVmax 17.6 at baseline and 18.7 post-therapy. Following treatment, 8/12 men (67%) had SUV declines ≥30% (2 had new lesions), 4 had declines of 0-30% (2 had new lesions) using FDG; at followup, 1/13 men had PSMA SUVmax declines ≥30% or more, 6 had declines of 0-30% (2 had new lesions), 5 had SUV increases of 0-30% (4 had new lesions) and 1 had >30% increase. Conclusions: In early analyses, PSMA identified more disease burden in mCRPC pts and was more avid than FDG. SUVmax for FDG declined following treatment in all men, while PSMA changes were heterogeneous. Potential prognostic value of early PSMA and FDG imaging changes on clinical outcomes will be correlated with conventional imaging along with review of remaining cases. Clinical trial information: NCT02813226