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776 Background: Surgery is the only potentially curative option for PC. However, only a minority of patients (pts) undergo resection with current perioperative (periop)-chemotherapy (CT). In the absence of phase III trials, selection between mFOLFIRINOX and gemcitabine/nab-paclitaxel (gem-nab) is based on limited evidence. We assessed whether NGS–based tumor profiling can guide tailoring of CT. Methods: pts with resected PC (resectable, borderline resectable, and downstaged locally advanced) that underwent Tempus xT, xF (DNA), and/or xR (RNA) testing were selected (89% tissue, 11% blood). Most samples (73%) were collected post-CT. Samples were stratified by KRAS status into KRAS -mutated ( KRAS mut) and KRAS wild-type ( KRAS wt). PD-L1 IHC was reported as tumor proportion score (TPS). Primary endpoint was median overall survival (mOS) defined from CT initiation to death with censoring of pts alive at the last follow-up or at a study cutoff of 5 years. Secondary endpoint was molecular profiling by KRAS status. Pearson chi-square and Wilcoxon rank-sum tests were used for descriptive comparisons; univariate Cox regression and log-rank tests (p<0.05) for survival. Results: We included 1,325 pts (median age 66 years [IQR 59–72]) with resected PC [stage II (15%), stage III (12%) and stage I (10%), unknown (62%)]. 95% had adenocarcinoma. Pts received neoadjuvant (50%), neoadjuvant plus adjuvant (26%), neoadjuvant with indeterminate adjuvant allocation (13%) or adjuvant CT (11%). First-line periop-CT was mFOLFIRINOX in 73% and gem-nab in 27% (median duration 4.3 months (mo) [range, 2.6–6.7]). KRAS mutations were present in 75% (G12X 91%: G12D 44%, G12V 34%, G12R 21%, G12C <1%). mOS was 26.7 mo (95%CI, 22.4-35.7) in the total cohort; KRAS mut pts showed a clinically meaningful worse mOS compared to KRAS wt [24.1 vs 35.7 mo; HR 1.61 (95%CI, 0.98 - 2.63); p=0.06]. In the KRAS G12D pts, mFOLFIRINOX showed a trend towards longer mOS compared to gem-nab [17.79 vs 14.53 mo; HR 0.75, (95% CI, 0.56 - 1); p=0.050]; no significant differences were observed in other KRAS subgroups. Compared to KRAS wt, KRAS mut pts were enriched for TP53 (76% vs 22%; p<0.001), SMAD4 (28% vs 5.8%; p<0.001), CDKN2A (33% vs 8.5%; p<0.001), MTAP deletions (7.7% vs 1.2%; p<0.001), and chromatin-regulator alterations ( ARID1A 7.8% vs 1.2%; p<0.001; KMT2C 2.5% vs 0.6%; p=0.034). KRAS wt pts were enriched for BRAF V600E (1.5% vs 0%; p<0.001). PD-L1 TPS ≥1% was more frequent in KRAS mut compared to KRAS wt (11.0% vs 8.1%; p=0.033). Conclusions: KRAS status does not predict benefit from mFOLFIRINOX vs gem-nab in resected PC. Interestingly, resected PC showed a higher prevalence of KRAS wt compared to the metastatic setting. KRAS status is associated with distinct profiles of potentially targetable co-alterations. These findings may suggest the integration of genomic profiling in clinical trials to develop biomarker-driven tailored strategies in the early stage.

761 Background: Glycogen Synthase Kinase-3β (GSK-3β) is a known therapeutic target in cancer including pancreatic adenocarcinoma (PDAC). The combination of elraglusib (9-ING-41), a novel GSK-3 inhibitor, and gemcitabine/nab-paclitaxel (GnP) is being evaluated as first-line therapy for patients with metastatic PDAC (mPDAC). We previously reported topline results indicating that the 1801 Part 3B phase 2 trial (NCT03678883) met its primary endpoint, showing a clinically meaningful survival benefit in patients treated with elraglusib/GnP compared to GnP alone. Here, we examined whether gene mutations correlated with clinical outcomes in mPDAC patients enrolled in this randomized phase 2 trial. Methods: For mutational analysis, archival tumor and/or plasma samples were obtained from 53 (GnP group) and 117 (elraglusib/GnP group) patients with previously untreated mPDAC. Cell-free DNA and/or tumor-extracted DNA were analyzed using the next generation sequencing. The comparison of the response rates was performed with the use of Chi-square tests. Kaplan-Meier survival curves were compared by log-rank (Mantel-Cox) tests. Results: Mutational analysis identified frequently mutated genes (detectable in ≥25% of patients): KRAS (141/170, 83%), TP53 (121/170, 71%), and CDKN2A (56/170, 33%). Mutations in KRAS, TP53, or CDKN2A genes did not correlate with objective response rate. Based on 81% of the recorded death events in the elraglusib/GnP group and 91% in the GnP group (topline data April, 2025), KRAS and TP53 gene mutations were associated with worse overall survival (OS) in patients treated with elraglusib/GnP (p<0.05) but not in GnP-treated patients. The rate of triple (KRAS+TP53+CDKN2A) mutations was significantly higher in the patients with OS<2 months as compared to the patients with OS>2 months in the elraglusib/GnP group (p<0.05) but not in the GnP group. Conclusions: Our preliminary results identified KRAS and TP53 gene mutations as potential predictive biomarkers of clinical outcome in elraglusib/GnP-treated mPDAC patients. Updated OS data and mutational analysis will be included in the final presentation. Clinical trial information: NCT03678883 .

741 Background: IP strategies directly target the peritoneal compartment in PDAC, where systemic chemotherapy alone demonstrates poor efficacy. Approaches include HIPEC, normothermic intraperitoneal paclitaxel (NIPEC/IP-PTX) given with systemic therapy, and PIPAC. This systematic review synthesizes evidence on feasibility, perioperative safety, and clinical outcomes of IP therapy in PDAC. Methods: We conducted a systematic search in PubMed, Embase, Scopus, and Cochrane databases for studies published through August 2025. Eligible studies included prospective or retrospective studies evaluating HIPEC, NIPEC/IP-PTX, or PIPAC with extractable safety or oncologic outcomes. Outcomes included feasibility, 30-day mortality, perioperative complications, locoregional recurrence (LRR) in the adjuvant setting, overall survival (OS) from peritoneal metastasis (PM) diagnosis or first IP therapy, conversion-to-resection, and histologic/radiologic response. Results: Sixteen studies met criteria, including 7 on HIPEC, 5 on NIPEC/IP-PTX, and 4 on PIPAC. In the adjuvant setting, 2 HIPEC studies demonstrated high feasibility (>85%), 0–5% 30-day mortality, and complication rates comparable to pancreatectomy. A randomized trial reported significantly lower LRR with adjuvant gemcitabine HIPEC. Median OS in treated arms was ~17–18 months, with 1-year OS ~63%. In the cytoreductive surgery (CRS) plus HIPEC setting for isolated peritoneal metastases, patients achieved CC-0/1 cytoreduction in most cases, with median OS ~24–41 months and 1-, 2-, and 3-year OS ranging 60–91%, 33–66%, and 39–59%, respectively. Thirty-day mortality was 0–4.3%, and major morbidity 20–43%. For NIPEC/IP-PTX, multicenter and single-institution cohorts consistently reported median OS ~14–16 months, 1-year OS ~60%, and conversion-to-resection rates of 17–24%. Ascites control and feasibility were reproducible, and device-related adverse events were generally manageable. PIPAC programs established oxaliplatin at 120 mg/m² as the recommended dose, with ~50–60% histologic regression by PRGS and disease stabilization in 50–60% after 1–2 cycles. Median OS in PDAC subsets was ~9–13 months, with low major toxicity, though early discontinuation was frequent in progressive disease. Conclusions: Intraperitoneal therapies for PDAC are feasible and show promising biologic and clinical signals. Adjuvant HIPEC reduces locoregional recurrence without excess mortality; CRS plus HIPEC can achieve multi-year survival in selected patients with isolated PM metastases; NIPEC/IP-PTX offers reproducible survival and conversion-to-resection; and PIPAC provides histologic regression with acceptable safety.

733 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have advanced the treatment of type 2 diabetes mellitus (T2DM) yet their association with cancer risk remains subject of ongoing research. While case reports and pharmacovigilance data have linked GLP-1RA’s to pancreatitis, large randomized trials and observational studies have not consistently shown an increased risk of pancreatic cancer. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aim to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using ICD-10 codes within TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified, and the 5-year incidence of pancreatic cancer between GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) users and non-users was compared from 2015-2025. In the subsequent analysis, we restricted the cohort to adults with CP and T2DM and repeated the comparison. Patients with prior diagnosis of pancreatic cancer were excluded from both analyses. All cohorts were propensity score matched (PSM) on age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Results: We identified 95,391 with CP, including 3,139 GLP-1 RA users and 92,252 non-users. After PSM, GLP-1 RA use was associated with a lower incidence of pancreatic cancer (0.6% vs. 1.5%, OR 0.39 [0.22, 0.67]). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower incidence of pancreatic cancer (0.7% vs. 1.6%, OR 0.44 [0.25, 0.75]). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP and in those with CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential protective effect of GLP-1RA use in this high risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

707 Background: Due to insufficient data, therapy for unresectable, locally advanced pancreatic adenocarcinoma (LAPAC) is based on trials in metastatic disease, and outcomes remain poor. TTFields disrupt cancer cell division using alternating low-frequency electric fields delivered externally by a portable device. In the phase 3 PANOVA-3 trial (NCT03377491), TTFields with gemcitabine/nab-paclitaxel (GnP) significantly improved overall survival (OS; HR 0.82) and pain-free survival (HR 0.74) vs GnP in patients with unresectable LAPAC. Methods: In PANOVA-3, patients with newly diagnosed LAPAC were randomized 1:1 to receive GnP with or without concomitant TTFields. Kaplan-Meier methodology was used for time-to-event analyses. Response evaluations were based on RECIST V1.1. OS, pain-free survival, and safety were analyzed post-hoc in subgroups based on sex (male, female), age ( < 65, ≥65 years), and BMI (<25, ≥25 kg/m 2 for efficacy; ≤20, 20–25, 25–30, ≥30 kg/m 2 for safety). Differences between treatment arms were compared using the log-rank test. Results: Efficacy outcomes are shown in the table. TTFields significantly extended pain-free survival in females and patients ≥65 years. Device-related adverse events (AEs) were comparable between sexes, older and younger patients, and across BMI ranges. Some device-related skin adverse events occurred more frequently in females (e.g. dermatitis, 33.1% vs 22.7%; rash 21.8% vs 13.5%, females vs males, respectively); others occurred more often in males (e.g. maculo-papular rash, 9.8% vs 14.2%; erythema, 9% vs 12.1%, females vs males, respectively). Dermatitis and pruritus had a higher incidence in the BMI ≥30 kg/m 2 subgroup (38.5%), whereas patients with BMI <30 kg/m 2 did not show noticeable differences in device-related AEs. Skin irritation (11.5% vs 5.5%) and skin reactions (8.5% vs 2.8%) were more common in patients ≥65 years than patients <65 years. Conclusions: Median OS and pain-free survival in these post-hoc subgroup analyses are generally consistent with the overall analysis, supporting use of TTFields with GnP in unresectable LAPAC. No new safety concerns were noted; observations were consistent with the general PANOVA-3 population. Clinical trial information: NCT03377491 . Survival outcomes for the subgroup analyses. Median OS, months TTFields + GnP GnP P value Age<65 years≥65 years 18.6 (n=113)15.4 (n=172) 16.0 (n=114)12.9 (n=172) 0.2060.061 SexFemaleMale 16.8 (n=138)15.7 (n=147) 14.5 (n=161)13.4 (n=125) 0.1140.145 BMI<25≥25 16.7 (n=166)16.2 (n=117) 14.2 (n=174)14.5 (n=108) 0.1550.105 Median pain-free survival, months Age<65 years≥65 years 16.5 (n=113)13.1 (n=172) 9.2 (n=114)8.3 (n=172) 0.4070.035 SexFemaleMale 16.5 (n=138)15.2 (n=147) 8.3 (n=161)9.3 (n=125) 0.0260.478 BMI<25≥25 16.6 (n=166)14.7 (n=117) 9.1 (n=174)8.3 (n=108) 0.1170.088

679 Background: DNA-damaging agents improve outcomes in metastatic pancreatic cancer (mPC) with homologous recombination repair (HRR) deficiency, albeit use is limited to 6-9% of patients (pts) with BRCA1/2 or PALB2 mutations. We hypothesized that BRCA/PALB2 wildtype mPC may exhibit platinum sensitivity driven by altered HRR gene expression. We correlated HRR gene RNA profiles with real-world overall survival (rwOS) following first-line (1L) platinum therapy (PT). Methods: Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database was used to identify mPC pts with wildtype somatic BRCA1/2 and PALB2 who had Tempus xT DNA and xR RNA testing. RNA-seq data were normalized to correct for assay/batch effects, quantified as transcripts per million (TPM) and reported as log2(TPM+1) for 17 HRR genes and GATA6 . Pts were classified as high and low expressors based on the top and bottom quartile gene expression. Pts were grouped as PT-treated (received 1L PT) or PT-naïve (never received PT). Real world overall survival (rwOS) was calculated from 1L start to death or loss to follow up. Risk set adjustment was applied to mitigate immortal time bias. Median rwOS was estimated using Kaplan-Meier and univariate Cox models. A multivariate Cox Proportional (CoxPh) model included PT use, RAS status, and expression of genes (as continuous variables). Results: Among 1,068 pts, the median age was 66 years and 609 (57%) received 1L PT. In low RAD51 expressors, PT-treated pts (n=136) had significantly longer rwOS than PT-naïve (n=112): 11.4 months (95% CI, 7.8–13.8) vs 8 months (95% CI, 5.5–9.0); p=0.028. In contrast, in high RAD51 expressors, rwOS was similar between PT-treated (n=150) and PT-naïve (n=97): 7.9 vs 6.9 months (p=0.236). High GATA6 expression was also associated with improved rwOS in PT-treated pts vs PT-naïve: 13.5 vs. 9.3 months; p=0.011. In multivariate analysis, increased GATA6 expression remained a positive predictor of rwOS (HR 0.82; 95% CI, 0.76–0.88; p<0.001), and high RAD51 expression was associated with shorter rwOS with PT (HR 1.18; 95% CI, 1.01–1.39; p=0.043). Conclusions: In BRCA/PALB2 wt mPC, transcriptomic profiling identified low RAD51 and high GATA6 expression as predictors for improved rwOS when treated with PT. Integrating these biomarkers may improve development of DNA-damaging therapies beyond canonically defined HRD. Hazard ratios of mPC mortality by selected HRR genes estimated by multivariate CoxPh models. HR 95% CI p value 1L PT (vs PT-naïve) 0.87 0.75, 1.00 0.054 BRCA1 1.15 0.98, 1.35 0.079 BRCA2 0.89 0.77, 1.04 0.14 GATA6 0.82 0.76, 0.88 <0.001 NBN 0.97 0.81, 1.15 0.7 RAD51 1.18 1.01, 1.39 0.043 RECQL4 0.94 0.84, 1.04 0.2 Any RAS mutation 1.43 1.14, 1.81 0.002

653 Background: Elraglusib (9-ING-41), a novel small molecule inhibitor of GSK-3ß, has a multimodal mechanism of action that enhances chemotherapy cytotoxicity and regulates anti-tumor immune cell response. Elraglusib was evaluated in a randomized, open-label, phase 2 study (NCT03678883) comparing elraglusib/GnP vs GnP in previously untreated mPDAC. Methods: Pts were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP. Primary endpoint was mOS, with 1-yr OS rate estimates summarizing clinical benefit throughout the study. Secondary endpoints were ORR, mPFS, and TEAEs/TRAEs. Pre-dose cytokines, mutational analysis, and immunophenotyping were correlated with outcomes. An oral presentation at ASCO 2025 discussed preliminary data. Results: As of 27 April 2025, the primary analysis set included 155 pts in the elraglusib/GnP arm and 78 pts in the GnP arm, with 52.8% males and 57.5% ECOG PS 1. The 1-yr OS rate was 44.1% with elraglusib/GnP vs 22.3% with GnP; the mOS was 10.1 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.62; p=0.01) with approximately 79% events recorded (25.8% of pts on elraglusib/GnP and 10.3% on GnP were censored with the majority at >12 mo OS). Improved OS with elraglusib/GnP was consistent across all randomized pts and subgroups regardless of liver metastases, ECOG status, or baseline CA 19-9 levels. Most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment (66.5% pts vs 0 with GnP). Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 52.3% (vs 30.8%) and anemia 25.2% (vs 29.5%). No differences in sepsis/febrile neutropenia rates were between arms. RAS , TP53 and CDKN2A co-mutations were associated with worse OS in the elraglusib/GnP arm only (p<0.05). Elevation in pre-dose cytokines including CXCL2 correlated with improved OS in the elraglusib/GnP arm. Additionally, increased CD8+ T cells, granzyme B, and NK cells and reduced MDSCs were observed in elraglusib-treated tumors. Conclusions: A significant benefit for 1-yr OS and mOS and a favorable trend for ORR were observed with the addition of elraglusib to GnP. The mOS was lower in the GnP arm vs historical studies, likely due to early deaths in the first 2 months, but aligns with mOS estimates in the real-world analysis with broad heterogeneous population. Our study included 19.7% pts with albumin <3.0 g/dL and >25% with CA 19.9 levels > 8,000 U/mL. Immune correlates support elraglusib’s immune-modulatory role. Final efficacy data cut-off in Dec 2025 and correlative studies will be presented. Clinical trial information: NCT03678883 . Outcome Elraglusib/GnPN=155 GnPN=78 Primary endpoint: mOS (mo)HR=0.62; log-rank p=0.01 10.1 7.2 Events, n (%) 115 (74.2) 70 (89.7) Primary endpoint: 1-yr OS (%) 44.1 22.3 18-month OS (%) 20.5 4.4 24-month OS (%) 13.2 0 mPFS (mo)HR=0.9; p=NS 5.6 5.1 Events, n (%) 136 (87.7) 75 (96.2) ORR, n (%) 44 (28.4) 17 (21.8)

64 Background: The incidence of eoCRC (diagnosed at age <50) is increasing. We have previously shown higher rates of severe anxiety and depression in this group compared to adults diagnosed at age ≥50 (average-onset CRC, aoCRC). We assessed the impact of ePROM collection coupled with a CC-based supportive care intervention on symptom burden in patients with eoCRC. Methods: The Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic trial conducted at Mayo Clinic Rochester and within the Mayo Clinic Health System (in Minnesota and Wisconsin) between 2019 and 2023. Enrolled patients serially reported the severity of six SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Symptom scores were interpreted as none to mild (0-3), moderate (4-6), or severe (7-10). Those with moderate symptoms were offered symptom management education and self-management materials, while those with severe symptoms were offered the option to work with a symptom care manager. In this post hoc analysis we examined the effects of the intervention on change in symptom scores among those with eoCRC, and using the Kaplan-Meier method, the median time to improvement to a mild/moderate level in those with a severe symptom, comparing eoCRC with aoCRC. Results: Among 4,422 patients with CRC, 887 had eoCRC. Forty-six percent of patients were female ( p =0.61), and a greater proportion of eoCRC patients were of a non-white race (11.6% vs 4.7%), lived in an urban setting (65.6% vs 50.5%), had a Bachelor’s degree or higher (36.8% vs 24.4%), were employed (78.5% vs 36.7%), on a non-government insurance plan (83.4% vs 35.3%), single (19.7% vs 11.2%) or married (74.2% vs 67.9%), and had metastatic disease (54.8% vs 46.1%, p <0.0001 for all). Compared to a pre-intervention baseline, the mean change in symptom scores for eoCRC patients following the intervention demonstrated improvements in anxiety (-0.238), depression (-0.134), and fatigue (-0.146, p <0.05 for all). Time to symptom improvement from severe to mild/moderate was longer for anxiety and depression in eoCRC patients compared to aoCRC patients (Table 1). Conclusions: Collection of ePROMs coupled with a CC-based intervention led to improvements in anxiety, depression, and fatigue among eoCRC patients, although time to symptom improvement was longer among eoCRC patients compared to aoCRC patients. Time to improvement of severe symptom (months), median (95% CI). eoCRC aoCRC p -value Sleep 4.2 (3.1-5.8) 3.8 (2.7-5.4) 0.4 Pain 4.1 (3.0-7.5) 3.2 (2.3-5.0) 0.5 Physical function impairment 3.1 (1.9-6.3) 2.8 (2.2-4.2) 0.5 Anxiety 4.3 (3.4-9.1) 2.6 (2.0-3.5) 0.009 Depression 4.3 (2.6-7.5) 2.6 (2.1-3.5) 0.04 Fatigue 4.3 (3.7-9.5) 3.4 (2.7-4.2) 0.06

635 Background: [ 212 Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Here, we report the results of a prospective, open-label, Phase I/IIa trial (NCT05636618), assessing safety, tolerability, pharmacokinetics, and preliminary efficacy of [ 212 Pb]VMT-a-NET in patients with advanced neuroendocrine tumors (NETs). Methods: Adults with well-differentiated unresectable or metastatic SSTR2-expressing NETs, who are peptide receptor radionuclide therapy (PRRT) naïve, and who progressed on at least one prior line of systemic therapy, are eligible. Participants can receive up to four cycles of [ 212 Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Results: As of 16-Aug-2025 (data cut-off [DCO]) a total of 48 participants were enrolled into cohorts 1 and 2 and received at least one dose of [ 212 Pb]VMT-a-NET (n=2 in Cohort 1, and n=46 in Cohort 2 at a dose level of 92.5 MBq and 185 MBq, respectively). Among all participants treated with at least one dose of [ 212 Pb]VMT-a-NET (n=48), no DLTs, no grade 4 or 5 adverse events (AEs), and no treatment-related discontinuations, were observed. Median follow-up time was 28 weeks (range: 6-93). Nine participants were followed for DLT observation (n=2 in cohort 1 and n=7 in cohort 2).Seven of these patients were with no progression as of the DCO. Three out of the seven participants enrolled at the dose level of 185 MBq achieved a confirmed partial response (PR). Median follow-up time for participants included in the efficacy group was 72 weeks (range: 6-93). Cohort 3, at a dose level of 222 MBq, has recently been opened for enrollment. At the DCO, 4 participants were enrolled in this cohort. Updated safety outcome for all participants along with updated efficacy findings for participants in Cohort 1 and 2 with sufficient maturity, will be presented during the congress. Conclusions: [ 212 Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose levels of 92.5 MBq and 185 MBq. The study is ongoing with Cohort 3 (222 MBq) currently open for enrollment. Clinical trial information: NCT05636618 .

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .