Neely, Ariana N.

e17134 Background: Despite being the most prevalent malignancy among men, prostate cancer (PC) lacks FDA-approved primary prevention therapies. Current options, such as 5-alpha reductase inhibitors (5-ARIs), offer only modest risk reduction—approximately 23–25%—as shown in the PCPT and REDUCE trials. Emerging preclinical data indicate that GLP-1 receptor agonists (GLP-1RAs) may offer a novel alternative by inhibiting oncogenic pathways and inducing apoptosis in PC cell lines. To investigate this potential, we conducted the first real-world comparative analysis of PC incidence among high-risk men receiving GLP-1RAs versus 5-ARIs. Methods: Using the TriNetX global collaborative network (150M patients), we identified men with elevated PC risk (genetic risk, family history, or high-risk demographics/comorbidities). GLP-1RA users (cohort A) were propensity-score-matched 1:1 with 5-ARI users (cohort B) on demographics, metabolic comorbidities, baseline PSA, BMI and HbA1c. A minimum of 2 month’s prescription was required. The primary endpoint was incident PC. The secondary endpoint was adverse events related to GLP-1RA and 5-ARI. Patients with outcomes before the study inclusion were excluded. Sensitivity and subgroup analyses were performed, adjusting for screening frequency and baseline BMI. Kaplan–Meier curves assessed cumulative incidence, Cox models estimated hazard ratios (HRs, 95% CI), and logistic regression analyzed binary outcomes. Results: After matching, 118,904 high-risk men were identified (59,452 patients per cohort). Cohorts had comparable demographics with a mean age of 48 years, 77% White, 9% Black, and 2% Asian. GLP-1RA users had higher mean A1C (6.3% vs 5.7%) and BMI (38 vs 31), while 5-ARI users had higher mean PSA (3.1 vs 1.3). Median follow-up was 7 years for both cohorts. PC incidence was 2.10% (1,245/59,189) in GLP-1RAs users versus 2.85% (1,689/59,164) in 5-ARI users (NNT 133). GLP-1RAs were associated with a 20% reduction in PC risk (HR: 0.803; CI: 0.746–0.864). Safety outcomes showed that GLP-1RAs were associated with an increased risk of erectile dysfunction and nausea/vomiting. In contrast, GLP-1RAs were associated with lower risks of abdominal pain and constipation. No significant associations were observed for gynecomastia or diarrhea. Conclusions: In this large-scale, head-to-head comparison, GLP-1RAs demonstrated superior efficacy over 5-ARIs, providing a 20% relative risk reduction in PC incidence among high-risk men. Given the global surge in GLP-1RA utilization, these findings suggest a profound public health opportunity: the ability to achieve systemic oncologic protection through existing metabolic therapies. If validated by prospective trials, GLP-1RAs could transition from metabolic blockbusters to a cornerstone of precision oncology and primary cancer prevention.

e16449 Background: Pancreatic cancer (PC) carries a dismal 5-year survival of < 12%, and no FDA-approved agents exist for primary prevention. PC risk is strongly linked to obesity, diabetes, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) directly target obesity-driven inflammatory pathways, reduce metabolic stress, and modulate signaling pathways (PI3K/AKT/mTOR) that drive cancer apoptosis. Based on this biological rationale, we conducted the first large-scale real-world study to evaluate the safety and efficacy of GLP-1RA for primary prevention of PC in high-risk patients. Methods: Leveraging a large real-world database (TriNetX), we identified patients aged 18-90 years with ≥1 PC risk factor (tobacco use, obesity, type 2 diabetes, alcohol use disorder, chronic pancreatitis, first-degree relative with PC, genetic susceptibility to PC) based on ICD-10 codes. Patients were stratified by GLP-1RA exposure into two cohorts: Cohort A (GLP-1RA users with ≥ 2 months of prescriptions) and Cohort B (controls). The primary endpoint was incident PC, and the secondary endpoints were adverse events related to GLP-1RAs. Patients with outcomes before the study window were excluded. Propensity score matching adjusted for confounders. Multivariate logistic regression was used to estimate odds ratios for categorical outcomes, and the Cox proportional hazards model was used to estimate hazard ratios for time-to-event outcomes. Subgroup and sensitivity analyses were employed to validate the strength of our results. Results: Median follow-up was 3,397 days for GLP-1RA users and 2,531 days for controls. Demographics were balanced between cohorts (mean age 42 years; 74% White, 15% Black; 72% female). Among 572,330 high-risk patients (286,165 per cohort), PC incidence was significantly lower among GLP-1RA users (0.05%; 134/286,165) than among non-users (0.13%; 362/286,097), with a 2.6-fold reduction in the absolute incidence of PC among high-risk patients (NNT of 1,255). GLP-1RA use was associated with a 71% reduction in PC incidence (HR 0.289; 95% CI 0.237–0.352). GLP-1RA use was associated with an increased risk of gastrointestinal adverse events, including nausea/vomiting (HR 1.108; 95% CI 1.096–1.121), abdominal pain (HR 1.081; 95% CI 1.066–1.097), diarrhea (HR 1.199; 95% CI 1.182–1.217), and constipation (HR 1.159; 95% CI 1.143–1.176). Conclusions: GLP-1RA use significantly reduced PC incidence by 71% in high-risk patients, the strongest real-world signal yet for a pharmacologic prevention of this lethal malignancy. Although the absolute incidence remained low, the magnitude of the risk reduction underscores the transformative potential of GLP-1RA in preventive oncology. These findings address a critical unmet need in pancreatic oncology. Prospective mechanistic and randomized studies are warranted to validate these associations.