Pre-Surgical Tirzepatide-Assisted Weight Loss in Overweight and Obese Men With Intermediate Risk Prostate Cancer: A Pilot Feasibility Study

Primary Objectives: To determine the feasibility of a tirzepatide-assisted weight loss program prior to radical prostatectomy in a group of men diagnosed with intermediate risk prostate cancer, defined based on the following process measures: Enrollment (completion of 30 patient accrual within 2 years) Retention (completion of the study through the day of surgery, with ≥90% defined as successful) Adherence (the percentage of completed study sessions and clinic visits, with ≥70% considered successful). Secondary Objectives: 1. Determine differences in plasma and tumor sphingolipids following tirzepatide-based intervention 2. Determine differences in markers of insulin and insulin signaling following tirzepatide-based intervention 3. Determine differences in prostate, plasma and periprostatic fat inflammatory signaling following tirzepatide-based intervention 4. Determine differences in tumor proliferation following tirzepatide-based intervention, including when stratified by obesity- and prostate cancer-associated SNPs and GLP-1 expression. 5. Determine differences in ASCVD risk factors following tirzepatide-based intervention. 6. Determine differences in other markers of cardiovascular risk. 7. Determine changes in body scan as measured by DEXA scan after tirzepatide-based intervention 8. Determine change in body weight following tirzepatide-based intervention. 9. Determine changes in gut microbiome alpha and beta diversity following tirzepatide-based intervention. 10. Determine rates of biochemical recurrence, receipt of salvage radiation therapy, and receipt of androgen deprivation therapy, stratified by prostatectomy pathology, after tirzepatidebased intervention Correlative Outcomes Cardiovascular, Surgical, and Patient-Related Outcomes Outcome Measure Outcome Measure Difference in plasma sphingolipids Change in plasma sphingolipid signature from baseline to pre-surgery within patients Difference in ASCVD risk factor score Change in the Metabolic Syndrome Severity Score (MetSSS)32 Difference in insulin signaling Compare change in fasting insulin, IGFBP-3, IGF-1 and C-peptide within patients Difference other markers of cardiovascular disease risk Between-group difference hsCRP, YKL-40, ICAM-1, E-selectin, leptin, and lipoproteins (e.g. LDL, LP(a)) Difference in tumor and periprostatic fat inflammatory markers Tumor and peri-prostatic fat inflammatory mRNA levels (CXCL12, CXCL1, CCR7 and IL-6, TNF-α) Change is DEXA-defined body composition measures Change in body fat percent, appendicular lean mass index, and other indices Compare tumor ki67 and other relevant proteins stratified by tumor GLP-1 receptor expression and Decipher score Spearman correlation of tumor ki67 change with GLP-1 receptor density (based on IHC). Analyses stratified by Decipher and other groups, as well. Change in body weight Change in the absolute body weight Determine differences in tumor proliferation stratified by germline obesity- and prostate cancer-associated germline SNPs Stratified analysis of ki67 expression based on germline genotype at rs12529, rs6161, rs523349, and rs1047303. Determine changes in the gut microbiome with use of GLP-1 assisted weigh loss Established measures of alpha and beta diversity of microbial species