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564 Background: HER2+ ILC is rare (~5% of ILC), with limited data on long-term adjuvant trastuzumab outcomes. We investigated late recurrence and immune landscapes of HER2+ ILC vs invasive ductal carcinoma (IDC) in the phase III NCCTG N9831 trial (NCT00005970) and a real-world cohort. Methods: We evaluated 3304 early-stage HER2+ breast cancer patients (pts) enrolled in N9831 (122 ILC, 3182 IDC). Recurrence-free survival (RFS) and overall survival (OS) were estimated (Kaplan-Meier) and compared using multivariable Cox regression adjusting for age, tumor size, grade, hormone receptor (HR), and nodal status. Findings were validated in a real-world cohort of HER2+ pts (Caris Life Sciences CODEai platform). Immune microenvironments were profiled by WTS deconvolution (Quantiseq). Real-world overall survival was calculated from trastuzumab start to last contact. Results: In N9831, ILC pts were older (median 54 vs 49 y), more ER+ (74.6% vs 51.4%), and had more N3 disease (25.4% vs 12.7%) compared to IDC. ILC pts derived a comparable magnitude of benefit from adjuvant trastuzumab compared to the overall population (HR 0.58 vs 0.67). However, long-term outcomes diverged: while the 5-year RFS was similar (77.1% vs 82.7%), ILC pts experienced a steep decline between years 5-15 (77.1% to 57.7%; ~20% decline) vs IDC (82.7% to 72.7%; ~10% decline) after multivariable Cox analysis (Table). In the real-world early/advanced cohort (n=1328; 26 ILC vs 1302 non-ILC [subset IDC n=595]) treated with trastuzumab-based therapy, ILC pts had worse mOS (33.7 vs 68.6 m, HR 2.01, 95%CI 1.00-4.07, p=0.04) compared to non-ILC. However, there was no statistically significant difference when compared specifically to IDC (HR 1.77, 95% CI 0.87-3.61, p=0.11). ILC had: i) numerically lower tumor mutation burden (TMB)-high (4.2% vs 9.5%, p=0.38); ii) higher infiltration of B cells, Tregs, and M2 macrophages (p<0.05); iii) upregulated MHC class II expression (HLA-DOA, p<0.05); and iv) downregulated proliferative and DNA repair pathways (E2F, G2M, MYC; FDR <0.25) compared to non-ILC. Conclusions: HER2+ ILC carries late recurrence risk despite initial trastuzumab benefit. The unique immune landscape (Treg/M2 macrophage enrichment and lower proliferative signatures) distinguishes HER2+ ILC from IDC, highlighting the need for tailored strategies. Long-term RFS and OS in HER2-positive ILC vs IDC (N9831 trial). Population N 5-year% (95% CI) 10-year% (95% CI) 15-year% (95% CI) ILC 122 RFS 77.13% (69.9, 85.1) OS 84.04% (77.7, 90.9) RFS 70.57% (62.7, 79.4) OS 76.0% (68.7, 84.2) RFS 57.67% (44.2, 75.1) OS 65.22% (56.6, 75.2) IDC 3182 RFS 82.71% (81.4, 84.1) OS 90.18% (89.1, 91.2) RFS 77.45% (75.9, 78.9) OS 81.81% (80.4, 83.2) RFS 72.68% (70.77, 74.6) OS 76.68% (75, 78.4)

590 Background: The landmark FAST-Forward trial demonstrated that ultra-hypofractionated whole-breast irradiation with 26 Gy in 5 fractions over 1 week was non-inferior to 40 Gy in 15 fractions for local control (HR 0.67, 95% CI 0.38–1.16), with similar normal tissue effects at 5 years. In response, major international guidelines incorporated 26 Gy in 5 fractions as a standard approach or recommended option for selected patients. Despite robust randomized evidence and guideline endorsement, U.S. real-world adoption patterns and equity of uptake across patient populations remain incompletely characterized. This study evaluated national trends in 5-fraction breast radiotherapy and sociodemographic differences from 2020 to 2023. Methods: The National Cancer Database radiotherapy fractionation fields were used to identify radiotherapy (RT) courses with evaluable fraction counts, and a binary indicator for 5-fraction RT (yes/no) was created. Temporal trends by diagnosis year (2020–2023) were assessed, and associations between 5-fraction RT and sociodemographic factors (primary insurance, urban or rural status, neighborhood income quartile, and race) were examined using chi-square testing. Results: Among 536,783 RT courses with complete data from 2020 to 2023, use of 5-fraction RT increased substantially over time: 4.3% in 2020, 8.1% in 2021, 12.7% in 2022, and 17.4% in 2023, resulting in an overall adoption rate of 10.7% (p < 0.001). In the subset eligible for fractionation (5, 15–16, 25–28 fractions; N = 31,448), 5-fraction RT accounted for 11.7% and differed significantly by insurance type (p < 0.001): Medicare 17.4%, Private 7.6%, Medicaid 5.9%, and Uninsured 6.9%. Geographic variation was notable (p < 0.001), ranging from 7.3% in mid-size metropolitan areas (250,000–1 million population) to 17.7%–18.1% in more remote or non-adjacent areas; large metropolitan areas (≥1 million) had 12.8% uptake. Neighborhood income showed a gradient (p < 0.001): 10.1% in the lowest quartile compared to 12.5% in the highest. Race was also associated with uptake (p < 0.001), with lower use among Black patients compared to White patients (9.4% vs 12.2%). Conclusions: In routine U.S. practice, adoption of 5-fraction breast RT increased rapidly from 2020 to 2023, with the most pronounced growth after 2021, reflecting the swift translation of trial evidence into clinical practice. However, uptake varies by insurance, geography, income, and race, indicating that diffusion is not uniform. Given the potential benefits of ultra-hypofractionation in reducing treatment burden and supporting timely completion, targeted implementation strategies, such as provider education, reimbursement alignment, and facility-level operational support, may be necessary to ensure equitable access as 5-fraction regimens become more widely adopted and potentially become the standard of care.

6028 Background: RET alterations are targetable oncogenic drivers in multiple solid tumors and TCs. Pralsetinib is an oral, potent, selective RET inhibitor granted accelerated approval by the FDA for adults and children aged ≥12 y with advanced/metastatic RET fusion-positive TC who require systemic therapy and are radioactive iodine-refractory, based on ARROW trial (NCT03037385) results. Accelerated approval for medullary TC (MTC) was withdrawn by the sponsor in 2023 due to recruitment challenges in the confirmatory trial. We report final efficacy and safety in ARROW patients with RET -altered TC and MTC. Methods: Phase 2 ARROW patients were enrolled from 84 sites in 13 countries. Primary end points were overall response rate (ORR; per RECIST v1.1) and safety. Progression-free survival (PFS), overall survival (OS), and safety were assessed in patients with advanced/metastatic TC and MTC who received ≥1 dose of pralsetinib (Efficacy Population [EP]). ORR and duration of response (DOR) were assessed in the Measurable Disease Population (MDP). Results: At the May 20, 2024, data lock, 28 patients with RET -altered TC and prior systemic treatment and 145 patients with RET -altered MTC received pralsetinib 400 mg/d (median treatment duration: 24.7 mo [TC]; and 35.4 mo [MTC]). In the TC and MTC groups, median age was 58 and 57 y; 39% and 64% were male; median (range) prior lines of treatment was 2 (1, 9) and 1 (1, 6). 53.8% of MTC patients had prior systemic treatment. In TC and MTC patients, ORRs (95% CI) were 91.7% (73.0, 99.0) and 68.2% (59.5, 76.0) (Table). Treatment-related adverse events (TRAEs) occurred in 27 (96%) TC and 142 (98%) MTC patients; 68% and 67% had grade ≥3. TRAEs in ≥35% of TC and MTC patients were increased AST (50% and 38%) and ALT (43% and 30%), decreased white blood cell count (39% and 30%), and anemia (39% each). Death due to a TRAE occurred in 1 TC patient (liver injury) and 1 MTC patient (pneumonia). Safety was consistent with prior reports. Conclusions: The final analysis of ARROW confirms that pralsetinib yields clinically meaningful and durable responses in patients with RET -altered TC and MTC with a manageable safety profile consistent with prior reports. Clinical trial information: NCT03037385 . Efficacy summary. All MTC MTCPrior Cabozantinib/Vandetanib MTC Treatment-Naïve TCPrior Systemic Treatment MDP, n 132 60 62 24 ORR, % (95% CI) 68.2(59.5, 76.0) 56.7(43.2, 69.4) 79.0(66.8, 88.3) 91.7(73.0, 99.0) Complete response, n (%) 12 (9.1) 2 (3.3) 7 (11.3) 4 (16.7) Partial response, n (%) 78 (59.1) 32 (53.3) 42 (67.7) 18 (75.0) DOR, median, mo (95% CI) 39.6(29.4, NE) 21.7(15.1, 34.8) NR(36.8, NE) NR(16.0, NE) DOR follow-up, median, mo (95% CI) 45.7(41.0, 48.4) 48.9(36.9, 58.7) 45.1(40.4, 47.8) 35.4(26.9, 40.0) EP, n 145 67 67 28 OS, median, mo (95% CI) NR(54.6, NE) 42.2(31.2, NE) NR(NE, NE) NR(25.4, NE) PFS, median, mo (95% CI) 37.2(27.5, 55.5) 24.9(19.9, 35.0) 55.3(36.8, NE) NR(14.7, NE) NE, not evaluable; NR, not reached.

560 Background: Patients (pts) with early stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) remain at both short and long term risk of recurrence. While clinico-pathological and gene-based biomarkers provide insight into early and late recurrence risk, additional prognostic tools are needed. We previously developed (Saha et al. Clin Cancer Res , 2025) a new breast MRI image-based artificial intelligence prognostic tool (TumorSight Risk) composed of both radiographic and clinical information. Here we sought to validate this tool in an independent cohort. Methods: In this multi-center, blinded, prospective/retrospective validation study, we sought to validate the 5-year recurrence-free survival (RFS) according to pre-defined risk scores (0-100) and categories (“high” or “low”) via pre-specified cutoff (≥47) for pts with HR+/HER2- BC. Kaplan-Meier and Cox regression analyses were then used to assess the unadjusted and adjusted association between risk category/score and the 5-year RFS. Results: 2,129 pts with HR+/HER2- BC diagnosed between January 1, 2010, and December 31, 2024, who underwent breast MRI prior to surgery (no neoadjuvant therapy) were included from four institutions. Median age was 57 years, 16% were Black, 15% had grade 3 disease, 93% were clinical T1 or T2, and 85%/15% were clinical N0/N1. At a median follow up of 6.24 years, the unadjusted hazard ratio (HR) for RFS comparing low (n=1808) and high risk (n=321) pts was 2.71 (95% CI = 1.95 – 3.76, p = 3x10 -9 ). The estimated 5 year RFS rate according to risk score (low and high) was 95.5% (95% CI: 94.63 – 96.3%) and 89.6% (95% CI = 86.4 – 92.6%) while the 10 year RFS estimates were 88.9% (95% CI = 86.5 - 90.9%) and 69.6% (95% CI = 59.1 – 77.9%). Univariate subgroup analysis demonstrated that the risk score was prognostic by age (< 50 vs. ≥50 years), pathologic nodal status, grade, and surgery type, regardless of chemo-, endocrine, or radiation therapy administration. The observed continuous risk score was strongly associated with risk of recurrence, with a 22% increase in relative risk per 10-unit change in risk score (0-100), translating to a 2.4% (95% CI = 1.2 – 4.5%) and 25.5% (95% CI = 15.4 – 40.4%) risk of recurrence at 5-years for pts at the lowest (0-9) versus highest (90-100) risk score. The prognostic association between risk score and RFS remained after adjusting for pathologic T- and N-stage, grade, age, race, and treatment (p = 0.002). Conclusions: TumorSight Risk is a new image-based biomarker for HR+/HER2- BC that provides prognostic information independent of standard clinico-pathological parameters. Given the ready availability of breast MRI in most pts with BC, TumorSight Risk may be a convenient tool for estimating risk for recurrence.

5543 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Emerging evidence suggests that these agents may have potential anti-tumor activity as GLP-1 signaling may influence pathways involved in cell proliferation and inflammation. Endometrial cancer is the most common gynecologic malignancy, and obesity represents a well-established, modifiable risk factor that may adversely affect oncologic outcomes through chronic inflammation and metabolic dysregulation. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with endometrial cancer and comorbid obesity. Methods: A retrospective cohort study was conducted using the TriNetX Global Collaborative Network, covering January 2000 to December 2025, encompassing data from 168 global healthcare organizations. Patients aged 18 and above with endometrial cancer and comorbid obesity were identified and then stratified into two groups based on treatment with GLP1 agonists or not. The two groups were then propensity-matched based on age, ethnicity, medical comorbidities, and stage of cancer. Outcomes were assessed for five years from treatment initiation and included overall mortality, myocardial infarction (MI), ischemic stroke; development of peritoneal, lymph node, and visceral metastases; sepsis, pancreatitis, and ED visits. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models. Results: After propensity matching, 6352 patients were included in each cohort with balanced baseline characteristics. Our analysis found that patients with endometrial cancer and comorbid obesity who received GLP-1 agonists had a significantly lower risk of overall mortality (Hazard Ratio [HR]: 0.45, 95% CI: 0.39-0.51, p-value <0.001), development of peritoneal metastases (Risk Difference [RD]: -2.16%, 95% CI: -2.74% to -1.58%, p-value <0.001), nodal metastases (RD: -0.41%, 95% CI: -0.72% to -0.09%, p-value =0.01), visceral metastases (RD: -3.76%, 95% CI: -4.60% to -2.93%, p-value =0.01), and sepsis with and without shock (RD: -1.42%, 95% CI: -2.14% to -0.70%, p-value <0.001) compared to patients who did not receive GLP-1 agonists. There was no statistically significant difference in the rates of MI, ischemic stroke, ED visits, and pancreatitis between the two cohorts. Conclusions: In this large real-world analysis, patients with endometrial cancer and comorbid obesity who received GLP-1 agonists had lower rates of overall mortality; peritoneal, lymph node, and visceral metastases, and sepsis with or without shock. Additional longitudinal cohort studies are imperative to explore the associations between these agents and inform clinical practice guidelines in this patient population.

536 Background: Folate receptor alpha (FRα) is overexpressed in ~80% of triple-negative breast cancers (TNBC). We previously demonstrated that patients (pts) with breast cancer naturally mount immune responses to FRα. In prior Phase I and II studies, a GM-CSF-adjuvanted FRα peptide vaccine (FRPV) was safe and induced durable FRα-specific T-cell immunity in 83–90% of pts with breast and ovarian cancer. Methods: Eligible pts were women ≥18 years with TNBC (ER/PR ≤10%) with 1+ of the following: stage ≥T1c disease, node-positivity, or residual disease after neoadjuvant chemotherapy. Pts were randomized 2:1 to receive FRPV or placebo (GM-CSF alone) every 28 days for cycles 2-7 and then every six months for 7 booster doses, with cycle 1 consisting of cyclophosphamide 50mg orally twice daily for days 1-7 and 15-21 (in both arms). Randomization was stratified by chemotherapy setting (adjuvant only vs neoadjuvant) and stage (I/II vs III). FRα expression was evaluated by immunohistochemistry. The study was designed to detect (at 30 months after the last pt enrolled) a disease-free survival (DFS) difference of 14% assuming a 3.5-year DFS rate of 70% in the control group and with 78% power. Results: 280 pts were enrolled (median age 52). The majority had stage I or II tumors (n = 219, 78%). There were numerically more node-positive tumors in the vaccine arm, 78 (41%) vs 27 (32%), p = 0.15. Median follow-up was 3.5 years, and 33 (FRPV: 25, placebo: 8) DFS events were observed; 3.5-year DFS rate was 88% with FRPV and 90% with placebo (HR 1.42, 95% CI 0.64–3.15; p = 0.39). Overall survival (OS) also did not differ by arm (HR 2.48, 95% CI 0.55–11.20; p = 0.22). Among node-positive pts (n = 105), DFS did not differ between arms (HR 0.95, 95% CI 0.34–2.66; p = 0.92). However, a numerical DFS event rate improvement (14% for vaccine vs. 26% for placebo) was observed in 61 patients with stage III disease (HR 0.51, 95% CI 0.16–1.68; p = 0.26). DFS did not differ by chemotherapy setting or by receipt of anthracycline, capecitabine, and/or an immune checkpoint inhibitor. FRPV was well tolerated, with predominantly grade 1–2 adverse events (AEs) and no vaccine-related grade ≥4 AEs. FRα expression was available from tumor in 230 pts, with 72% expressing > 0. Overall, DFS was not significantly associated with FRα expression (0 vs > 0; HR 0.55, 95% CI 0.21–1.44; p = 0.21), and no significant differences in DFS by FRα expression were observed between treatment arms. Conclusions: FRPV following oral cyclophosphamide was safe, with no vaccine-related high-grade AEs. While no significant improvement in DFS or OS was observed overall, a numeric trend toward improved DFS was observed in pts with stage III TNBC. This finding is hypothesis-generating and supports further evaluation of FRα-targeted vaccination in higher-risk TNBC. Immune correlative analyses are ongoing to better define vaccine immunogenicity and its relationship to clinical outcomes. Clinical trial information: W81XWH-15-1-0293.

545 Background: ILC is characterized by loss of E-cadherin expression, with distinct biological and clinical features, and is often perceived to be less sensitive to chemotherapy compared with IDC. Oncologists and pts may face a treatment dilemma regarding the benefits of adjuvant chemotherapy in pts with lower biologic risk but higher anatomic risk (N2/N3), stage III ILC. In this study, we sought to compare the benefit of adjuvant chemotherapy in pN2/N3 ILC compared with IDC. Methods: We used the National Cancer Database (NCDB) to identify adults with primary, non-metastatic, ER-positive/HER2-negative invasive breast cancer diagnosed between 2010 and 2022 who underwent upfront surgery. Patients receiving neoadjuvant systemic therapy were excluded. Analyses were limited to pathologic stage I–III disease with known nodal involvement (N2–N3) and tumor category (T1–4). Propensity score matching (1:3, caliper 0.2; using R 4.5.1) was performed to balance age, sex, race, insurance status, grade, pathologic stage, nodal category, tumor category, Charlson-Deyo comorbidity score, and year of diagnosis. Overall survival (OS) was assessed using Kaplan–Meier methods and Cox proportional hazards models used to estimate hazard ratios (SPSS v28). Results: After propensity matching, we analyzed 28,115 pts with pN2/N3 disease (ILC 9,603 and IDC 18,512). Upstaging from cN0 to pN2/3 was higher for ILC than IDC (20.3% vs 13.3%, p<0.001). ILC pts were more likely to undergo mastectomy compared to IDC (80.2% vs 71.2%, p<0.001). Receipt of adjuvant chemotherapy for pN2/N3 disease was similar between IDC and ILC (78.0% vs 78.4%, p=0.37), as was use of adjuvant radiation and endocrine therapy. Among patients receiving chemotherapy, treatment was associated with a 65% reduction in death in ILC (HR 0.35, 95% CI 0.32–0.38, p<0.001) and a 73% reduction in IDC (HR 0.27, 95% CI 0.26–0.29, p<0.001), compared with no chemotherapy. 5-year OS among chemotherapy-treated patients was lower for ILC compared with IDC (HR 1.4, 95% CI 1.33-1.49; p<0.001, Table 1). In contrast, no OS difference was observed between ILC and IDC among patients who did not receive chemotherapy (HR 1.03, 95% CI 0.96-1.11; p=0.38). Chemotherapy was associated with higher 5-year OS in both IDC (87.7% vs 58.9%) and ILC (84.3% vs 59.2%). Conclusions: Adjuvant chemotherapy was associated with a substantial improvement in 5-year OS among patients with pN2/N3 disease in both IDC and ILC. Pts with ILC and extensive nodal involvement benefit from adjuvant chemotherapy. 5-year survival of IDC and ILC. IDC (18,512) ILC (9,603) No Chemotherapy (4,078) Adjuvant Chemotherapy (14,434) No Chemotherapy (2,071) Adjuvant Chemotherapy (7,532) pN2 (18,669) 62.8% 90.1% 64.4% 87.6% pN3 (9,446) 48.3% 82.2% 51.4% 79.4% pN2/pN3 Combined (28,115) 58.9% 87.7% 59.2% 84.3% P <0.001, log rank.

525 Background: Adjuvant endocrine therapy (ET) decreases breast cancer (BC) recurrence and improves overall survival (OS) for patients (pts) with estrogen receptor positive (ER+) BC. Omission of adjuvant ET and nonadherence are major issues contributing to worse clinical outcomes. Recent data suggest that the number of pts who omit adjuvant ET may be increasing in Europe [1]. These data have yet to be evaluated in the U.S. We previously reported data from the National Cancer Database (NCDB) that ET omission was more likely in pts with ER+/HER2+ disease who achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) [2]. Herein we report an updated analysis with a larger cohort designed to examine trends in ET omission over time and the impact on OS in a group of pts at high risk of recurrence. Methods: The NCDB was queried from 2010-2022 for pts with stage I-III ER+BC treated with NAC and surgery. pCR was defined as ypT0, ypN0. Use of adjuvant ET and the impact of adjuvant ET omission on OS in pts with and without pCR were assessed separately based on HER2 status. Adjuvant ET initiation by 1 year was summarized using the cumulative incidence estimate to account for the competing risk of death. OS was analyzed with ET as a time-dependent covariate using multivariable Cox proportional hazards regression. Results: We identified 130,438 pts with ER+BC (78,778 ER+/HER2-, 51,660 ER+/HER2+) who received NAC. Median follow-up was 5 years. Overall, pCR was achieved in 10.0% of ER+/HER2- and 35.9% of ER+/HER2+. On multivariable analysis, ET omission was significantly associated with worse OS in pts with residual disease (RD) [ER+/HER2- (HR 1.80 p<0.001) ER+/HER2+ (HR 1.66 p<0.001] and in those with a pCR [ER+/HER2- (HR 1.38 p=0.002) ER+/HER2+ (HR 1.42 p<0.001)]. Between 2010-2017, adjuvant ET omission was stable, with approximately 10.0% of pts not having initiated ET by 1 year after surgery. The proportion of pts omitting ET overall increased thereafter to 12.9% in 2018, rising to 24.4% in 2022. A sharp increase in ET omission was observed 2021-2022 in ER+/HER2- BC who achieved pCR, with 42.4% omitting ET compared to 25.1% for 2018-2020 and 18.8% for 2010-2017 (p<0.001). Adjuvant ET omission showed more modest but significant increases for other subgroups (p<0.001): ER+/HER2- with RD (8.5% 2010-2017, 12.3% 2018-2020, 18.7% 2021-2022), ER+/HER2+ with pCR (15.1% 2010-2017, 14.0% 2018-2020, 24.4% 2021-2022), and ER+/HER2+ with RD (9.5% 2010-2017, 12.5% 2018-2020, 22.2% 2021-2022). Conclusions: In ER+BC treated with NAC, omission of ET is increasing over time and associated with a higher risk of death, regardless of HER2, RD, or pCR status. These findings have substantial public health implications as they may result in a reversal of the 4-decade improvements in breast cancer mortality. Additional intervention is critical to improve adherence to guidelines. [1] Verreck et al. Breast 2025 [2] Choong et al. SABCS 2022.

522 Background: Tumor-associated macrophages (TAMs) drive immune evasion and chemotherapy resistance in breast cancer through tumor microenvironment reprogramming. We developed a composite TAM score integrating transcriptional programs with spatial IHC polarization markers to stratify recurrence risk and enrich macrophage-modulating trials, hypothesizing it would improve prognostic accuracy in treatment-naïve disease and predict neoadjuvant chemotherapy (NACT) response. Methods: TAM score was derived from scRNA-seq atlases (n=4), filtering survival-associated genes in METABRIC/TCGA (n=2,509), and weighting IHC markers CD163/CD206 normalized to CD68/CSF1R via Cox coefficients. Validation: treatment-naïve invasive carcinomas (n=83; follow-up 57 months; 24 events). Primary endpoint: recurrence-free survival (RFS); multivariable Cox adjusted for age, tumor size, nodal status, grade, subtype, treatment. Predictive utility assessed in matched primary/post-NACT residual tumors (n=45) correlating TAM dynamics with RCB. Results: High TAM score (≥median) independently predicted worse RFS (HR 3.8, 95% CI 1.6-9.1, p<0.05) and outperformed CD163/CD68 alone (HR 2.1, p<0.05); 5-year RFS was 68% vs 91% (TAM-high vs TAM-low). Prognostic value persisted in node-negative (HR 4.2, p=0.02) and luminal B (HR 3.5, p=0.01) subsets. In the NACT cohort, baseline TAM score inversely correlated with pCR (12% vs 38%, p=0.04). Among residual disease (RCB-II/III, n=34), persistent TAM-high post-NACT identified 3-year RFS 52% vs 85% in TAM-low/normalized cases (HR 4.1, p=0.01), independent of RCB; CD163+/CD206+ expansion occurred in 76% of RCB-III vs 29% of RCB-I (p=0.008). Conclusions: This TAM score predicts recurrence from pre-treatment tissue and identifies macrophage-driven resistance persisting post-NACT, nominating TAM-high residual disease for macrophage-modulating trials. Translational evidence supports this: CSF1R inhibition reduced immunosuppressive TAMs, increased M1-like programs, decreased PD-L1/PD-L2, and enhanced anti-PD-1 efficacy preclinically with ex vivo confirmation. Early-phase data (rebastinib plus chemotherapy in HER2-negative metastatic disease) demonstrate feasibility, supporting prioritization of TAM-high patients with residual disease for trials combining TAM modulation with checkpoint therapy. TAM score performance in treatment-naïve and NACT cohorts. Endpoint TAM-High TAM-Low HR scores (95% CI) p-value Treatment Naïve cohort 5 year RFS (Overall) 68% 91% 3.8 (1.6-9.1) <0.05 RFS (node-negative) 4.0 0.02 RFS (luminal B)-- 3.5 0.01 CD163/CD68 alone 2.1 <0.05 NACT Cohort (n=45) Baseline pCR rate 12% 38%- 0.04 3-year RFS(RCB-II/III n=34) 52% 85% 4.1 0.01 CD163+/CD206+ expansion 76% (RCB-III) 29%(RCB-I)- 0.008

5079 Background: Treatment sequencing in metastatic castration-resistant prostate cancer (mCRPC) after ADT and ARPI exposure varies in practice. While 177 Lu-PSMA use is expanding in routine practice, real world head to head comparisons with docetaxel in ARPI-exposed mCRPC are limited, particularly for short-term outcomes and treatment related acute care utilization. Methods: Using TriNetX, adults > 18 years of age with metastatic prostate cancer and prior ARPI exposure who initiated 177 Lu-PSMA or docetaxel were identified (index = first administration). Cohorts were balanced with 1:1 propensity score matching (PSM) on demographics and baseline comorbidities. Outcomes from day 1–180 post-index included all-cause mortality (primary), hospitalization, acute kidney injury (AKI; ICD-10 N17), and thromboembolic/ischemic events (ICD-10 I21/I26/I63/I82). For each outcome, patients with prior documentation of that outcome were excluded. Outcomes are reported as risks and risk ratios (RR) with 95% confidence intervals. Results: Before matching, 563 patients initiated 177 Lu-PSMA-617 and 8,749 initiated docetaxel; after 1:1 PSM, 497 patients per cohort were analyzed. At 180 days, all-cause mortality was 7.3% (36/494) with 177 Lu-PSMA-617 versus 12.2% (60/491) with docetaxel (RR 0.60, 95% CI 0.40–0.88). Hospitalization occurred in 7.2% (21/290) versus 21.1% (52/247) (RR 0.34, 95% CI 0.21–0.55). In a separate matched renal-safety analysis (480 per cohort), AKI occurred in 2.8% (11/390) versus 9.0% (36/399) (RR 0.31, 95% CI 0.16–0.60). Thromboembolic/ischemic events were 3.8% (15/394) versus 6.4% (26/404) (RR 0.59, 95% CI 0.32–1.10). Conclusions: In ARPI-exposed mCRPC, 177 Lu-PSMA was associated with lower 180-day mortality risk and substantially fewer hospitalizations than docetaxel, with a lower risk of AKI. These findings highlight a potential short-term effectiveness and acute-care utilization advantage of 177 Lu-PSMA in routine practice and support further prospective evaluation. Key 180-day outcomes after matching. Outcome 177 Lu-PSMA Docetaxel Effect estimate (180 days) All-cause mortality 36/494 (7.3%) 60/491 (12.2%) RR 0.596 (0.402-0.884) Hospitalization 21/290 (7.2%) 52/247 (21.1%) RR 0.344 (0.213-0.554); Acute kidney injury (AKI)* 11/390 (2.8%) 36/399 (9.0%) RR 0.312 (0.163-0.595) Thromboembolic/ischemic† 15/394 (3.8%) 26/404 (6.4%) RR 0.592 (0.318-1.100) *AKI analysis used a separate matched run (480 per cohort). †Composite of I21, I26, I63, I82.