Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, Bristol Myers Squibb, BioMarin, Endo Pharmaceuticals, EMD Serono, Novo Nordisk, Pfizer, Tolmar Pharmaceuticals. Research Investigator; Self; Alexion, Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics, Sangamo Therapeutics. D. Boldt-Houle: Employee; Self; Tolmar Pharmaceuticals, Inc. S.N. Atkinson: Employee; Self; Tolmar Pharmaceuticals, Inc. Background: Childhood obesity is associated with an increased risk of central precocious puberty (CPP).1 Thus, data on whether weight status affects the treatment of children with CPP would be valuable to help clinicians ensure correct management. We present secondary analyses of hormone and height velocity (HV) data from the pivotal trial of the first small-volume, long-acting, subcutaneously administered gonadotropin-releasing hormone agonists (GnRHa) for CPP, with the goal of assessing if the study drug adequately suppresses hormones in overweight and obese children. Methods: 62 children with treatment-naïve CPP received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals over the 48-week study period. The BMI percentile for children was calculated based on the Center for Disease Control growth charts, accounting for height, weight, age, and gender. Luteinizing hormone (LH) concentrations were assessed using a validated central Cobas ECLIA assay with a lower limit of detection of 0.100 IU/L. Estradiol (E2) concentrations were assessed using liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS) with a lower limit of detection of 10 pg/mL. HV was calculated as the change in height between visits/((number of weeks between visits)/52). Results: Mean GnRH-stimulated LH concentrations at screening, week 24, and week 48 were 24.5, 2.1, and 2.5 IU/L in non-overweight children, 10.5, 3.2, and 2.2 IU/L in overweight children, and 31.5, 4.8, and 1.9 IU/L in obese children, respectively. In these same groups, mean E2 concentrations at screening, week 24, and week 48 were 28.2, 10.5, and 10.3 pg/mL in non-overweight children, 17.8, 10.4, and 10.4 pg/mL in overweight children, and 25.9, 11.0, and 11.1 pg/mL in obese children, respectively. Mean HV at week 4, week 24, and week 48 was 10.2, 5.6, and 5.7 cm/year in non-overweight children, 7.7, 5.5, and 6.2 cm/year in overweight children, and 8.2, 4.9, and 6.6 cm/year in obese children, respectively. Conclusions: Subcutaneous leuprolide acetate effectively treated all overweight children without any requirement for weight-based dosing. This is consistent with results from previous studies of GnRHa efficacy in obese and normal-weight children with CPP.2 Clinicians should consider providing counseling and interventions that support healthy diets and lifestyles to children with above-normal BMI and their caregivers. References Cited 1.Liu G, Guo J, Zhang X, Lu Y, Miao J, Xue H. Obesity is a risk factor for central precocious puberty: a case-control study. BMC Pediatr. 2021;21(1):509.2. Chen M, Eugster EA. Central precocious puberty: update on diagnosis and treatment. Paediatr Drugs. 2015;17(4):273-281. Presentation: Thursday, June 15, 2023

351 Background: Associations between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients have been reported; however, how many of these major adverse CV events (MACE) are caused by ADT itself has been debated. One risk factor for increased CV risk is a prior history of CV events; an analysis found that each new CV event increased the probability of a future event. This study aims to evaluate the incidence of MACE after ADT initiation for patients with and without a prior medical history of MACE. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate MACE incidence after ADT initiation in patients with and without MACE history. Exclusion criteria included lack of ADT initiation date or myocardial infarction (MI)/stroke within 6 months prior to ADT initiation. MACE was defined as MI, stroke, and death from any cause. Kaplan-Meier event-free survival curves were constructed, and Cox regression was used to compare the MACE hazard rates between patients with and without a personal history of MACE. Multivariate Cox regression adjusted for agonists vs antagonist, increasing age per year, BMI (<18.5 vs ≥18.5 kg/m2), race (White vs Black), family MACE history, ethnicity (Hispanic vs non-Hispanic), urology vs oncology setting, history of hypertension, and history of hypercholesterolemia. Results: Overall, MACE incidence was 3.9% and 19.6% for the cohort at one year and four years after ADT initiation, respectively. MACE risk following ADT initiation was higher for patients with history of prior MACE (unadjusted: (HR=2.76, 95% CI [2.49, 3.06], p<0.001); adjusted: HR=2.29, 95% CI [1.93, 2.71], p<0.001). When MACE was divided into component events, the risks of myocardial infarction and stroke were higher for patients with a prior MACE history compared to those without (8 vs. 1% and 8 vs. 2%, respectively), and the risk of any-cause death was similar (13 vs. 14%). Conclusions: MACE incidence in PCa patients in the first year of ADT was consistent with previous publications.(3). When MACE risk was analyzed in detail, ADT patients with a personal history of stroke or myocardial infarction (MI) had a 4- and 8-fold greater risk of a subsequent stroke and MI, respectively, compared to those without a history of stroke or MI. Given the large sample size (~45,000 PCa patients) of this data set over the recent past decade, these results likely reasonably reflect the real world. Urologists and oncologists should work with cardiologists, cardio-oncologists, and primary care practitioners to ensure the highest quality CV care is delivered.

348 Background: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) may experience major adverse cardiovascular events (MACE). It is unclear how much of MACE is caused by ADT itself. High cholesterol has been associated with lower MACE risk in older men, not on statin therapy. This study evaluates MACE risk after ADT initiation for patients with and without hypercholesterolemia using real-world data. Methods: US electronic medical records (2010-2020) of PCa patients (n=45,059) receiving LHRH agonist/antagonist injections were analyzed to calculate the risk of MACE since ADT initiation in patients with and without hypercholesterolemia. Hypercholesterolemia was defined as having taken hypercholesterolemia medication or diagnosis with hypercholesterolemia prior to the first MACE event after ADT start. Exclusion criteria included lack of ADT initiation date or MACE within six months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause. Kaplan-Meier event-free survival curves and cox regression were used to compare MACE risk between patients with and without hypercholesterolemia. Results: The dataset contained 178,388 LHRH injection entries and 7,681 MACE. MACE risk was only 1.8% lower (19.0% vs 20.8%) after 4 years for patients with hypercholesterolemia compared to those without (across 10 years, unadjusted: HR=0.88, 95% CI [0.83, 0.92] and adjusted: HR=0.85, 95% CI [0.77, 0.94]). Conclusions: Patients with hypercholesterolemia appear to have slightly lower MACE rates. This may be due to the use of statins, which can reduce the incidence of CV events in a general population. Our analysis of data over the most recent decade from ~45,000 PCa patients is likely an accurate reflection of the real world. Clinicians should monitor PCa patients with underlying CV risk factors and help educate them on lifestyle changes that could impact treatment outcomes.

TPS608 Background: In US clinical practice, GnRH agonists are widely used to suppress ovarian function in pre/perimenopausal patients with breast cancer that is moderate-to high-risk for recurrence. Despite extensive use of leuprolide acetate (LA) for ovarian suppression, regulatory approval for this indication has not been established in the US. Additionally, existing three month formulations may not reliably provide ovarian suppression, as demonstrated by escapes in estradiol (E2). An extended-release LA product with a 3-month dosing period specifically developed for ovarian suppression in patients with breast cancer could fill this unmet need. TOL2506 is a 3-month, extended-release formulation of 30 mg of LA. This combination of active drug and in situ polymeric extended release technology is expected to deliver higher exposure to drug than the currently available 3-month (22.5 mg) formulations of LA marketed for advanced prostate cancer and potentially reduce escapes in E2 over the dosing period. Methods: TOL2506A (OVELIA) is a phase 3, single arm, open-label study evaluating the effectiveness of TOL2506 to suppress ovarian function in premenopausal women with HR+, HER2-negative breast cancer. Approximately 250 subjects will be enrolled, with 30% aged 40 years or younger. Subjects must be premenopausal women, age 18-49, with a diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER > 1% and/or, PR > 1%, HER2-negative per ASCO CAP guidelines), who are candidates for ovarian suppression with endocrine therapy. For subjects receiving chemotherapy, premenopausal status will be determined, and confirmed by central lab hormone testing, prior to initiating chemotherapy. Male subjects with HR+, HER2-negative breast cancer may also be eligible, but will be evaluated for safety analyses only. Eligible subjects will enter the 48 week treatment period in 2 groups: those receiving tamoxifen concurrently with TOL2506 or those who initiate therapy with an aromatase inhibitor (AI; letrozole, anastrozole, or exemestane) beginning 6 weeks after the first administration of TOL2506, if E2 < 20 pg/mL has been achieved. After Week 12, subjects will be allowed to switch from receiving an AI to receiving tamoxifen or from tamoxifen to AI at the Investigator’s discretion. Subjects will receive 4 doses of TOL2506 every 12 weeks over the 48 week study duration. Achievement of ovarian suppression will be defined as ≥ 90% of subjects with luteinizing hormone (LH) levels < 4 IU/L at Week 6. Secondary endpoints include suppression of LH, E2 (< 20 pg/mL for tamoxifen cohort and < 2.72 pg/mL for AI cohort) and absence of menses at weeks 6, 12, 24, 36, and 48. Clinical trial information: NCT04906395.

46 Background: Recent literature has suggested an association between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients.1,2 The 1-year incidence of major adverse cardiovascular events (MACE) in patients ≥45 years old was 1.4%,3 whereas a recent study of PCa patients on ADT reported MACE in 2.9% of patients treated with an LHRH antagonist (relugolix) and 6.2% of patients treated with an LHRH agonist (leuprolide acetate) over 48 weeks.4 Thus, MACE risk is an important consideration for PCa patients on ADT. This study aims to evaluate MACE risk after ADT initiation with LHRH agonists vs. LHRH antagonists using real-world data. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate the rate of MACE-free survival after ADT initiation by drug class. The database contained 178,388 LHRH agonist and antagonist injection entries and 965 documented MACE events. Exclusion criteria included taking more than one class of ADT and MACE within 6 months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause based on a recent study in this field.4 Kaplan-Meier event-free survival curves were constructed to compare the risk of MACE between patients on agonist vs. antagonist. Statistical significance between survival curves was evaluated by log-rank test. Results: Overall MACE risk for all patients was 1.0% at one year. MACE risk was significantly higher for patients treated with LHRH antagonist compared to agonists in the first seven years after ADT initiation. Conclusions: Risk of MACE was lower than previously reported. Although this may potentially be due to underreporting, our analysis of data over 10 years from >45,000 PCa patients is likely an accurate reflection of the real world. A recent study using large real-world dataset with >50,000 PCa patients over approximately 2 years showed no difference in CV risk following treatment with GnRH agonists and antagonists.5 However, in our analyses MACE risk was lower in patients treated with LHRH agonists vs. antagonists in the first seven years after ADT initiation. Further, we plan to evaluate baseline comorbidities and demographics for imbalances. Future studies evaluating the impact of ADT class and comorbidities on MACE risk for PCa patients during ADT may be helpful to identify CV predictors. 1Ng C-F, et al. Scientific Reports. 2020. 2Zhao J, et al. PLoS One. 2014. 3Miao B, et al. J of the American Heart Association. 2020. 4Shore ND, et al. New England Journal of Medicine. 2020. 5George G, et al. Int J Cancer. 2021.

44 Background: The association between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients is controversial.1-2 Major adverse cardiovascular events (MACE) occurred in 3-6% of patients in a 48-week ADT trial,2 but meta-analysis from a 2011 study found no association between ADT and increased risk of CV death.1 Body mass index (BMI) is a potential risk factor; Lee et al. found a lower risk of MACE in patients with high BMI than those with a normal weight, and patients with low BMI had a higher risk of all-cause mortality.3 This study evaluates the association between BMI and MACE risk in PCa patients on ADT using real-world data. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=36,249) receiving LHRH agonist/antagonist injections were conducted to calculate the risk of MACE since ADT initiation for the following BMI groups: <18.5, 18.5 to <25, 25 to <30, 30 to <35, and >35. BMI groups were based on the standard weight status associated with each BMI range (underweight, normal or healthy weight, overweight, obese, and severely obese, respectively).4 The database contained 178,388 LHRH agonist/antagonist injection entries and 965 documented MACE events. Exclusion criteria included lack of ADT initiation date, lack of BMI data, and MACE within 6 months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause based on a recent study in this field.2 Kaplan-Meier event-free survival curves were constructed to compare the risk of MACE between BMI groups. Statistical significance between survival curves was evaluated by log-rank test. Results: Differences in MACE incidence between BMI groups were not significant. (Table). Conclusions: MACE risk was similar across BMI subgroups after ADT initiation. This is consistent with the literature that higher BMIs do not confer additional CV/MACE risk as might be expected (a lower risk of MACE in patients with high BMI than those with normal weight).3 This 10-year analysis in >35,000 patients is likely reflective of the real world, but further study is recommended to evaluate whether BMI should be considered a predisposing risk factor for CV disease in PCa patients undergoing ADT. As the association between ADT and increased CV risk in PCa patients is controversial, future studies evaluating the role of co-morbidities on MACE risk for PCa patients during ADT may be helpful to identify other CV predictors.[Table: see text]

Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). The JAK inhibitor Ruxolitinib can reduce constitutional symptoms but it does not substantially improve bone marrow fibrosis. Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. Here, we show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis and splenomegaly, and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, we show that TP-3654 treatment significantly inhibits mTORC1, MYC and TGF-β signaling in Jak2V617F mutant hematopoietic cells and diminishes the expression of fibrotic markers in the bone marrow. Collectively, our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF.