Project Summary/Abstract The goal of this research project is to investigate new 3D advanced hyperpolarized (HP) 13C-pyruvate MRI techniques to quantitatively monitor metabolic changes in prostate cancer following stereotactic body radiation therapy (SBRT) and to study HP 13C + multiparametric 1H MRI for detecting residual/progressive cancer following RT, addressing current unmet clinical needs. This research trial is important because RT too often causes excess morbidity without sufficient efficacy and current imaging approaches are inadequate in identifying clinically significant cancer following RT. FDG-PET imaging is significantly limited in prostate cancer since in the localized setting, significant excretion in the bladder precludes the ability to adequately detect signal within the prostate and even in the metastatic setting there is significant heterogeneity of uptake with substantial proportion of non- FDG avid, yet still metabolically active and growing tumors, for reasons related to intra-cellular uptake and trapping of the FDG tracer. While we use PSMA-PET, to identify metastatic prostate cancer, it does not provide the metabolic information on prostate cancer aggressiveness and response to therapy that HP 13C has demonstrated in preclinical and initial human studies at our and other sites. Recent patient studies of this emerging imaging approach at multiple sites world-wide have shown repeatable findings of greatly up-regulated LDH catalyzed pyruvate-to-lactate conversions in cancer using this safe, rapid, fast <5 min, non-radioactive molecular HP 13C MRI. It has demonstrated not only feasibility, but also valuable biomedical information at costs similar or less than PSMA-PET and other PET exams. This project aims to study two groups of patients with multiparametric (mp) 1H MRI with HP 13C-pyruvate MRI (HP 13C mpMRI); 1) Before, 3 months after, and 1 year following SBRT; and 2) patients exhibiting “biochemical failure” indicated by a rising PSA after radiation therapy who are going on to image-guided biopsies prior to selection of further salvage treatment. We strengthened this resubmission by addressing the prior critiques and including new preliminary data applying new improved HP technology. Our multidisciplinary research team has extensive experience in conducting early phase clinical trials and combines the expertise of prostate cancer imaging scientists with physician/scientists and radiation oncologists to advance our preliminary studies to translate and investigate new HP 13C-pyruvate mpMRI techniques for monitoring RT response in order to address important unmet clinical needs in the treatment of prostate cancer patients.