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Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

This cohort study examines patterns of bone-modifying agent use from 2013 to 2024 among men with metastatic castration-resistant prostate cancer.

57 Background: Cardiovascular disease (CVD) is the leading non-cancer cause of death among men with prostate cancer (PC), particularly during androgen-deprivation therapy. While CVD risk-prediction models are well established in the general population, barriers to integration within oncology workflows remain poorly defined. Guided by the PRISM and RE-AIM frameworks, this study evaluated multilevel determinants influencing adoption, feasibility, and sustainability of CVD risk-assessment tools in PC care. Methods: A national, cross-sectional survey of 45 physicians (medical oncology 49%, urology 38%, radiation oncology 13%) from 18 U.S. states was conducted. Respondents represented early- (27%), mid- (36%), and late-career (38%) clinicians across academic (87%) and community (13%) settings. Quantitative items mapped to PRISM/RE-AIM domains assessed adaptability, cost/resource feasibility, effectiveness, equity, and sustainability; open-ended responses explored contextual barriers and facilitators. Descriptive statistics summarized quantitative data. Results: Physicians reported moderate-to-high readiness to adopt a CVD risk-assessment tool, emphasizing workflow alignment and EHR integration over algorithmic complexity. Table 1 summarizes domain-specific findings. Ninety-three percent of respondents favored lab-independent models that minimize workflow disruption. Conclusions: Pre-implementation analysis highlighted that structural barriers, rather than algorithmic or statistical limitations, remain the primary obstacles to adopting CVD risk-assessment tools in prostate-cancer care. Physicians emphasized the need for EHR-integrated, non-laboratory-based, and time-efficient tools that align with routine oncology workflows and minimize cross-specialty friction. Addressing these practical and organizational determinants may be pivotal to achieving equitable, scalable, and sustainable cardio-oncology implementation across diverse practice settings. PRISM and RE-AIM constructs evaluation results. Construct Likely/Very Likely (%) Interpretation Perceived Effectiveness 87% Broad confidence in clinical utility Equity in Patient Reach 75% Strong perceived equity in reach Equity in Effectiveness 73% Expected to perform consistently across populations Adaptability to Workflow 71% High compatibility with existing clinic workflows Cost/Resource Feasibility 65% Feasible for resource-constrained settings Likelihood of Adoption 60% Moderate readiness for implementation Equity in Adoption 58% Equitable uptake possible despite resource differences Reach to Target Population 57% Moderate likelihood of reaching most patients Sustainability Over Time 51% Moderate long-term feasibility Consistency of Implementation 42% Need for standardized protocols

352 Background: Glucagon-like peptide 1 (GLP1) receptor expression in prostate cancer tissue has raised concerns that GLP1 receptor agonists (GLP1A) may influence tumor growth or progression. We compared prostate cancer severity at diagnosis among patients receiving GLP1A versus other glucose lowering therapies. Methods: A retrospective chart review identified patients who received GLP1A or alternative second-line glucose lowering agents (DPP4/SGLT2 inhibitors) and were subsequently diagnosed with prostate cancer. Patients receiving both drug classes were excluded. Baseline demographics (race, ethnicity, age), comorbidities (diabetes, myocardial infarction, peripheral vascular disease) concomitant medications (insulin, metformin, statins), appointments (within past year) and laboratory values (HbA1c, eGFR) at therapy initiation were recorded. Primary outcomes included Gleason grade group and metastatic presentation within three months of diagnosis. Propensity score matching balanced baseline characteristics between groups. Mann-Whitney U tests compared grade groups. Chi-square tests compared metastatic presentation, reporting odds ratios (OR) with 95% confidence intervals (CI). Multivariable logistic regression identified predictors of grade group (low-grade: 1-2; high-grade: ≥3) and metastatic presentation, reporting OR with 95% CI. A p value <0.05 indicated a significant association. Results: Of 260 propensity-matched patients (GLP1A: 130, comparison: 130), 87% were White and 95% were Non-Hispanic/Non-Latino in each group. Median HbA1c was 7% (IQR: 6.4-8) in GLP1A group versus 7.5% (6.2-8.5) in comparison group. Median eGFR was 75mL/min/1.73m 2 (IQR: 61.5-90.0) in GLP1A group versus 60.0 (52.0-80.5) in comparison group. High-grade disease occurred in 33 (25%) GLP1A patients and 37 (29%) comparison patients. Among patients with available imaging (GLP1A: 40; comparison: 32), metastatic presentation occurred in 7 (18%) GLP1A group and 7 (22%) comparison group patients. No significant differences were observed in grade group (GLP1A median: 2; IQR: 1-2 vs. comparison median: 2; 1-3; p=0.44) or metastatic presentation (OR: 1.32; 95%CI: 0.41-4.25; p=0.64) between groups. In multivariable analysis, higher HbA1c was associated with high-grade disease in GLP1A group (OR: 1.83; 95%CI: 1.07-3.35; p=0.03) while higher eGFR was associated with low-grade disease in the comparison group (0.97; 0.93-0.99; p=0.04). Conclusions: GLP1A use was not associated with prostate cancer grade or metastatic presentation at diagnosis compared to alternative glucose-lowering agents. However, the association between elevated HbA1c and high-grade disease in GLP1A patients suggests a potential impact of poor glycemic control on tumor biology. Prospective studies are needed to elucidate the relationship between metabolic dysregulation and prostate cancer severity.

145 Background: Multiple trials have demonstrated addition of androgen-receptor pathway inhibitors (ARPIs) improve survival in patients with metastatic prostate cancer but there is a need to quantify cardiovascular toxicity. Understanding the nature and extent of ARPI-associated cardiovascular adverse events across disease states and toxicity grades is critical to inform treatment decisions and long-term patient safety. Methods: MEDLINE, and EMBASE were systematically searched from database inception through August 30, 2025, for phase III randomized controlled trials evaluating abiraterone, enzalutamide, apalutamide, darolutamide, orteronel in metastatic prostate cancer. Trials were included if they reported CVS toxicity. Meta-analysis using a random-effects model was performed to assess the difference of all-cause and treatment-emergent cardiovascular adverse events between ARPI+ADT and ADT alone. Summary effects were expressed as relative risk (RR) with associated 95% confidence intervals. Results: A total of 21 trials (45 references) with 25,576 patients (mCSPC: 12,537, mCRPC: 13,039) were included in this meta-analysis. Compared to ADT alone, ARPI+ADT significantly increased the risk of all cause, all grade hypertension in both mCSPC (RR 1.60, 1.22–2.10) and mCRPC (RR 1.61, 1.20–2.16) as well as grade ≥ 3 hypertension (RR 1.71, 1.17–2.48) in mCRPC setting. There was an increased risk of all-cause, all grade acute coronary syndrome (RR 2.21, 1.09–4.49) and AV nodal disease (RR 2.53, 1.18–5.43) with ARPI+ADT compared to ADT alone in mCSPC setting. There was increased risk of all cause, all grade, any cardiac events (RR 1.30, 1.10–1.54) as well as grade ≥ 3 any cardiac events (RR 1.70, 1.20–2.42) in mCRPC setting. Risk of all cause, all grade hot flashes (RR 1.47, 1.16–1.85) was also significantly increased with ARPI+ADT when compared to ADT alone. In terms of treatment-emergent adverse effects, a significant increase was observed only for pulmonary embolism with ARPI+ADT when compared to ADT alone (RR 1.66, 1.06–2.60) in mCRPC setting. Conclusions: Current evidence indicates potentially increased risk of hypertension, venous thromboembolic, and ischemic cardiac events with ARPI therapy in metastatic prostate cancer. Proactive CV risk assessment, particularly in patients with preexisting comorbidities or prolonged ARPI exposure, may optimize outcomes and minimize treatment interruptions. All cause adverse events. Adverse Event Disease State All Grade Grade ≥3 Any Cardiac Event mCSPC 0.81 (0.37–1.76) 0.88 (0.16–4.64) mCRPC 1.30 (1.10–1.54) 1.70 (1.20–2.42) Hypertension mCSPC 1.60 (1.22–2.10) 1.43 (0.82–2.52) mCRPC 1.61 (1.20–2.16) 1.71 (1.17–2.48) ACS mCSPC 2.21 (1.09–4.49) 1.77 (0.86–3.61) mCRPC – – Hot Flashes mCSPC – – mCRPC 1.47 (1.16–1.85) 1.46 (0.21–9.97)

Abstract Background Socioeconomic position (SEP) is a fundamental social determinant of health (SDoH) contributing to observed disparities in cancer and cardiovascular (CV) care among individuals with prostate cancer (PC). Understanding the influence of SEP on CV health is essential for addressing outcome inequities within this population. Methods We conducted a retrospective study utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare to evaluate CV outcomes in patients ≥65 years with PC from 2009 to 2017. We studied the impact of SEP on cardiovascular events (CVEs), cardiovascular mortality (CVm), PC-specific mortality (PCsm), and all-cause mortality. CVE, CVm, and PCsm were analyzed using competing risk models and all-cause mortality with Cox proportional hazards models. A subgroup analysis was performed in Non-Hispanic Black and Non-Hispanic White individuals. Results We included 141 242 patients of whom 76 844 were in high SEP areas (45.6%) and 64 398 in low SEP ones (54.4%). Both groups had a mean age of 72 years; patients in low SEP areas were 67.5% Non-Hispanic White, 34.4% having diabetes, 73.3% hypertension, and 67.7% dyslipidemia versus the high SEP group with 85.6% Non-Hispanic White, 30.4% diabetes, 69.9% hypertension, and 70.7% dyslipidemia. Patients in low SEP areas had higher risks of CVm (subdistribution hazard ratio [sHR] = 1.18, 95% CI = 1.12 to 1.25), PCsm (sHR = 1.12, 95% CI = 1.06 to 1.17), CVE (sHR = 1.07, 95% CI = 1.04 to 1.09), and all-cause mortality (HR 1.16, 95% CI = 1.13 to 1.20). Accentuated results were shown in the Non-Hispanic Black subgroup. Conclusion Adverse SEP plays a significant role in shaping outcomes among older patients with PC, contributing to elevated risks of adverse CV and survival outcomes.

75 Background: The Rx landscape of pts with mCRPC has recently evolved with the approval of lutetium-177-PSMA-617 (Lu-177) and poly(ADP) ribose polymerase inhibitors (PARPi) either as single agents or as combinations with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. However, real-world data on the uptake of these agents are lacking. Herein, we sought to assess the Rx patterns and attrition rates of pts with mCRPC in the era of newly approved therapies. Methods: The de-identified nationwide Flatiron Health Electronic-Health Record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: diagnosis of mCRPC and Rx line (L) information. The data cut-off date was 5/31/2024. Rx patterns in each line of therapies were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 12,333 pts diagnosed with mCRPC between 1/1/2013 and 5/9/2024 met the eligibility criteria and were included. Rx trends are summarized (Table). Of pts receiving 1L Rx, 61% of pts received 2L therapy, and 35% received 3L therapy. Androgen receptor pathway inhibitor (ARPI) was the most common Rx in the 1L setting (73.7%), followed by taxane (10%) and sipuleucel-T (3.8%). In 2L, ARPI was again the most frequent Rx (46.8%), followed by taxane (23.6%). In 3L, taxane became the most frequent Rx (35.4%), followed by ARPI (26.2%) and radium-223 (4.9%). Rx trends per year will be presented in the meeting. Conclusions: In the current era,a high proportion of pts with mCRPC receiving 1L Rx do not receive a subsequent line of Rx (39% of pts do not receive 2L, and 65% do not receive 3L Rx). ARPIs and taxanes remain the most frequently used Rx options in most L of therapy. These findings highlight the need for better tolerated Rx, therapies with a novel mechanism of action, and improved access to care for our pts. Rx trends per year will be presented in the meeting. Rx patterns in pts with mCRPC. Rx 1L, n (%)N = 12,333 2L, n (%)N = 7475 3L, n (%)N = 4316 4L, n (%)N = 2339 5L, n (%)N = 1225 ARPI 9085 (73.7) 3503 (46.8) 1130 (26.2) 356 (15.2) 157 (12.8) PARPi-based therapies 93 (0.8) 185 (2.5) 142 (3.3) 98 (4.2) 47 (3.9) Platinum-based therapy 127 (1) 216 (2.9) 198 (4.6) 148 (6.3) 130 (10.6) Lu-177-based therapies 50 (0.4) 109 (1.5) 169 (3.9) 143 (6.3) 103 (8.4) Radium-223 183 (1.5) 241 (3.2) 213 (4.9) 125 (5.3) 79 (6.4) Sipuleucel-T 474 (3.8) 94 (1.3) 53 (1.2) 18 (0.8) 8 (0.7) Taxane 1240 (10) 1763 (23.6) 1526 (35.4) 935 (40) 393 (32) Pembrolizumab 24 (0.2) 41 (0.5) 36 (0.8) 27 (1.2) 29 (2.4) Other*/not-applicable** 665 (5.4)/392 (3.2) 1000 (13.4)/323 (4.3) 602 (14)/247 (5.7) 320 (13.7)/169 (7.2) 162 (13.3)/117 (9.5) *Includes drugs approved for mCRPC in combination with unapproved agents or clinical trial drugs. **Includes agents not approved for prostate cancer.

95 Background: Most pts with prostate cancer with bone metastasis experience symptomatic skeletal events (SSEs) [PMID: 23884473], leading to increased morbidity and mortality. BMAs have been approved since 2007 and are recommended in mCRPC to prevent SSEs in pts with bone metastases or a high risk of osteoporotic fracture. Herein, we sought to assess the real-world trends of BMA administration in pts with mCRPC. Methods: We used the de-identified nationwide Flatiron Health electronic health record (EHR)-derived database to extract pt-level data. Inclusion criteria: pts with mCRPC with available date of diagnosis of mCRPC and information on receipt of BMA. Pts were categorized into 2 cohorts based on BMA receipt (e.g., bisphosphonates, denosumab, teriparatide, romosozumab) or not. Treatment trends of BMA by year of mCRPC diagnosis were summarized using frequency and percentages. Baseline characteristics at the time of mCRPC diagnosis (age, race-ethnicity, practice type, insurance) were compared between cohorts using the Wilcoxon rank-sum and Chi-squared tests. Results: Of 24,105 pts with metastatic prostate cancer in the dataset, 14,112 with mCRPC were eligible and included. 7,990 (56.6%) received BMA while 6,122 (43.4%) did not. In BMA receipt cohort: median age was 75 (IQR 67 – 81), majority were White (61%), treated in community practice (87%) and had commercial health plan (80%). In BMA non receipt cohort: median age was 75 (IQR 68 – 82), majority were White (61%), treated in a community practice (78%), and had commercial health plan (76%). The use of BMA decreased over time from 56% in 2013 to 46% in 2024 (Table). Statistically significant differences existed between cohorts in race-ethnicity, practice type, and insurance (p < 0.001) and will be presented at the meeting. Conclusions: Despite recommendations to use BMAs in pts with mCRPC and bone metastasis or high risk of osteoporotic fracture, our findings reveal a low utilization rate of BMAs in mCRPC setting with a notable decline over time. This highlights the need to incorporate the use of BMAs in clinical practice and improve access to these agents. Trends by year of mCRPC diagnosis in receipt of the first BMA and frequency and percentage of each agent. Year 2013N = 549 2014N = 1035 2015N = 1223 2016N = 1345 2017N = 1441 2018N = 1346 2019N = 1469 2020N = 1380 2021N = 1352 2022N = 1393 2023N = 1196 2024N = 383 Receipt of BMA, n (%) 316 (56) 674 (65) 792 (65) 837 (62) 886 (61) 766 (57) 816 (56) 766 (56) 692 (51) 713 (51) 556 (46) 176 (46) Denosumab, n (%) 190 (60.1) 450 (66.8) 557 (70.3) 599 (71.6) 606 (68.4) 533 (70) 526 (64.5) 488 (63.7) 410 (59.2) 414 (58.1) 290 (52.2) 94 (53) Zoledronic acid, n (%) 120 (38) 220 (32.6) 228 (28.7) 233 (27.8) 270 (30.5) 225 (29) 281 (34.4) 273 (35.6) 277 (40) 295 (41.4) 258 (46.4) 82 (47) Teriparatide, other bisphosphonates, n (%) 6 (1.9) 4 (0.6) 7 (1) 5 (0.6) 10 (1.1) 8 (1) 9 (1.1) 5 (0.7) 5 (0.7) 4 (0.5) 8 (1.4) 0

90 Background: Poly(ADP) ribose polymerase inhibitors and pembrolizumab are approved for patients with metastatic prostate cancer (mPC) with susceptible genomic alterations based on NGS testing. We recently reported that the rate of NGS testing in mPC remains low at 29.3% in the United States (1). Herein, we investigated the rates of NGS testing at the end of life in a real-world patient population. Methods: This study utilized the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Eligibility: diagnosis of mPC, with information on receipt of NGS testing (blood/tissue) and recorded date of death. The time between each patient’s first NGS testing result date and date of death was measured and categorized into 3 groups: NGS test results delivered more than 3 months (mo) before death, within 3 mo of death, and delivered after death. Frequencies and percentages of these 3 categories were reported, also by the year of death. Results: Out of 24,105 patients with mPC in the database, 3,397 had both a recorded date of death and underwent NGS testing and were eligible and included. The median age was 74 (IQR 67–80), 70% were White non-Hispanic, and 83% were treated in a community-based practice. In these patients, 2,901 (85.4%) NGS results were reported more than 3 mo before death, 457 (13.5%) within 3 mo of death, and 39 (1.1%) after death. From 2015 to 2024, the percentage of patients receiving their result more than 3 mo before death increased from 27% to 91%, while those receiving it within 3 mo before death decreased from 55% to 8.5%, and the percentage of NGS results reported after death declined from 18% to 0.6%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting. Conclusions: Despite the availability of life-prolonging targeted therapies based on NGS testing results for patients with mPC, in ∼14% of patients, the first NGS testing results were reported within 3 mo before death or after death. The lack of timely NGS testing limits patients' access to life-prolonging personalized treatments in earlier settings, resulting in missed opportunities for improved outcomes. 1. Hage Chehade, Swami, JAMA Network Open, 2024.

104 Background: Androgen deprivation therapy (ADT) intensification [ADT + androgen receptor-pathway inhibitor (ARPIs) +/- docetaxel] has been shown to improve survival outcomes in pts with mHSPC and is recommended as standard of care by all major guidelines. However, prior studies have shown underutilization of ADT intensification [PMID: 39191549]. There are limited updated and large-scale studies on the use of ADT intensification, beyond January 2023. In this study, we aimed to assess the treatment patterns of ADT intensification in real-world pts with mHSPC in the US, including data on those treated since January 2023. Methods: This retrospective study utilized the nationwide Flatiron Health Electronic Health Record (EHR) derived de-identified database. Eligibility: Pts diagnosed with mHSPC and availability of treatment information (ADT and/or line of therapy in mHSPC). The data cut-off date was 5/31/2024. Treatment patterns were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Among 24,105 pts with metastatic prostate cancer in the database, a total of 14,084 were eligible and included. The median age at metastatic diagnosis was 72 years (IQR 65 – 79), and 60% were White non-Hispanic. In the overall cohort (1/1/2013–5/15/2024), 56.8% received ADT monotherapy, and 37.7% received ADT intensification. Table summarizes the treatment patterns by year, highlightinga consistent increase in adoption of intensified ADT regimens, and a decline in use of ADT monotherapy. Notably, since January 2023, 76.8% pts with mHSPC received ADT intensification while only 17.3% of pts received ADT monotherapy. Conclusions: To our knowledge, this is the first and largest study to evaluate the current use of ADT intensification. These data indicate a notable improvement in the adoption of level 1 evidence (ADT intensification) in the treatment of pts with mHSPC. These encouraging data emphasize the benefits of continued efforts to promote guideline-concordant care and provide the current treatment landscape to design clinical trials. Treatment patterns by year in pts with mHSPC. Treatment 2013–2017n = 5,263(%) 2018n = 1,313 (%) 2019n = 1,407(%) 2020n = 1,353(%) 2021n = 1,483(%) 2022n = 1,556(%) 2023n = 1,459(%) 2024n = 250(%) ADT monotherapy 4,095 (77.8) 856 (65.2) 819 (58.2) 664 (49) 698 (47.1) 569 (36.6) 291 (20) 5 (2) ADT + ARPI 155 (2.9) 238 (18) 354 (25.1) 452 (33) 555 (37.4) 695 (44.7) 842 (58) 154 (61.6) ADT + Docetaxel 709 (13.5) 156 (12) 175 (12.4) 156 (12) 134 (9.0) 117 (7.5) 78 (5.3) 19 (7.6) Triplet(ADT + ARPI + Docetaxel) 6 (0.1) 2 (0.2) 1 (0.1) 2 (0.1) 9 (0.6) 82 (5.2) 166 (11.1) 53 (21.2) Other therapies 298 (5.7) 61 (4.6) 58 (4.1) 79 (5.8) 87 (5.9) 93 (6) 82 (5.6) 19 (7.6)