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484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.

224 Background: Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes ( PKM, SLC2A1 , SLC16A1 , and CAV1 ) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank P -values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites, KRAS , CMS, and treatment. Results: PKM gene expression was associated with cet treatment outcomes with PKM- low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H, P < 0.0001, LRT P = 0.011; median OS: 45.9 vs 31.2 vs 20.9 months, P < 0.0001, LRT P = 0.12). Low SLC2A1 was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months, P = 0.02, LRT P < 0.0001). Similar results were observed in bev-treated pts where low SLC2A1 expressing tumors had longer OS (37.4 vs 26.1 vs 29 months, P = 0.037, LRT P = 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months, P = 0.076). CAV1 low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months, P = 0.0048, LRT P = 0.013), while no significant associations were found in bev-treated (interaction LRT P = 0.0009). No significant results were observed for SLC16A1 . Conclusions: The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by SLC2A1 ) and PKM2 (encoded by PKM ) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of SLC2A1 and PKM was associated with improved survival and increased benefit from cet treatment in our cohort. Low CAV1 expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.

566 Background: Immune checkpoint inhibitors (ICIs) have become the preferred treatment for unresectable hepatocellular carcinoma (HCC). Conflicting data exist regarding the prognostic value of immune-related adverse events (irAEs) in these patients. We aimed to explore potential the association between irAEs and prognosis in HCC patients treated with ICIs. Methods: We searched PubMed, Scopus, Web of Science, and CENTRAL databases for articles published from inception to June 2024 using keywords including ICI, HCC, and irAEs. Two reviewers independently screened studies for eligibility and relevant data. A random effects model was used for statistical analysis, and subgroup analysis was performed by the grade of irAEs. Results: Of 3,028 studies, 25 (n=4,116 patients) met criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n=10 studies). About half (49.5%) of patients experienced irAEs. irAEs were associated with increased objective response rate (ORR) (pooled OR: 1.72; 95% CI: 1.36 – 2.19, I 2 =39%), higher complete response rate (pooled OR: 1.45; 95% CI: 1.21-1.74, I 2 =74%), and longer progression-free survival (PFS) (pooled HR: 0.66; 95% CI: 0.52-0.84, I 2 =71%). Although irAEs were associated with longer overall survival, this difference was not statistically significant (pooled HR: 0.83; 95% CI: 0.62 – 1.11, I 2 =73%). Subgroup analysis showed a survival benefit for patients with grade 1-2 irAEs (pooled HR: 0.50; 95% CI: 0.36-0.67, I 2 =0%) but not for those with grade 3-4 irAEs (pooled HR: 0.95; 95% CI: 0.24-3.72, I 2 =84%). Conclusions: The development of irAEs is associated with a favorable prognosis in HCC, including improved PFS and higher ORR. A survival benefit was noted in patients with mild irAEs, but not in those with severe irAEs. Future studies are needed to determine if a differential survival benefit relates to the continuation vs. discontinuation of ICI therapy.

269 Background: Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts. Methods: We evaluated the impact of the tumor gene expression of sirtuin genes ( SIRT1 -7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test. Results: Of the seven genes analyzed, SIRT3 high was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74], P < 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83], P = 0.002) overall. Treatment-gene interaction testing found significant interactions for SIRT1 and SIRT5 with PFS ( P values: 0.021 and 0.016, respectively) and OS ( P values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed SIRT1 high associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89], P = 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89], P = 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99], P = 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93], P = 0.23) in bev-treated pts. SIRT5 high showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91], P = 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83], P = 0.013) in cet-treated pts, with no similar associations in bev-treated pts. Conclusions: Our results highlight a potential role for SIRT3 as prognostic and, SIRT1 and SIRT5 as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in SIRT1 high and SIRT5 high tumors. However, previous reports suggest an opposite role of SIRT5 that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of SIRT5 with cetuximab activity and establish the potential of targeting SIRT1/5 in CRC.

254 Background: SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking. Methods: Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into SLFN11 -high and -low groups based on the median SLFN11 gene expression levels. Survival outcomes were compared between SLFN11 -high and SLFN11 -low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS). Results: In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank p = 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39, p = 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank p = 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16, p = 0.19) compared to SLFN11 -high patients. In patients treated with FOLFOX-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank p = 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05, p = 0.12) and OS (31.1 vs 26.1 months, log-rank p = 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08, p = 0.16) compared to SLFN11 -high patients. No significant interaction was observed between treatment and SLFN11 expression in terms of PFS ( p = 0.69) and OS ( p = 0.44). In the Caris CODEai cohort, a better OS in SLFN11 -low patients than in SLFN11 -high patients was observed in irinotecan-treated patients ( N = 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00, p = 0.048). However, no significant difference in OS between SLFN11 -low and SLFN11-high was observed in oxaliplatin-treated patients ( N = 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06, p = 0.56). Conclusions: Low SLFN11 expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.

532 Background: HCC accounts for 80% of primary liver cancers, and worldwide, is the third common cause of cancer-related death. Two FDA approved 1st line systemic treatment options include atezo/bev and durva ± treme. Herein we report outcomes of these regimens in the 1st line setting via a real-world, multi-institutional retrospective cohort study. Methods: We reviewed clinical outcomes of patients (pts) who initiated 1st line atezo/bev or durva ± treme for unresectable HCC between March 2017 and February 2024, across 5 institutions (Mayo Clinic, University of Alabama, Cedars-Sinai Medical Center, University Hospitals Seidman Cancer Center and University of Michigan). Time to treatment failure (TTF) and overall survival (OS) were analyzed using the Kaplan-Meier method. Best (objective) response was tabulated. Multivariable analyses were performed using Cox models and logistic regression for time-to-event and binary outcomes, respectively, while adjusting for age, sex, race, HCC etiology, Child-Pugh class, and ALBI grade. Results: A total of 433 HCC pts were included; atezo/bev (336), durva ± treme (97). Median age at the start of therapy was 68 years; 77% were male, 82% were Caucasian. Etiologies of HCC were viral hepatitis (38%), MASLD (20%), alcohol (10%), non-viral multifactorial (10%), or unknown (22%). Pts receiving durva ± treme were less likely to have cirrhosis (11% vs. 28%, p<0.01) but similar in terms of macrovascular invasion (63% vs. 58%, p=0.35) compared to pts receiving atezo/bev. Reasons for treatment discontinuation were similar between the two groups, with the most common being disease progression - atezo/bev (56%) and durva ± treme (47%). The differences in clinical outcomes were not statistically significantly and remained consistent after multivariable adjustment. (Table, atezo/bev as the reference group). Outcomes were significantly different between Child-Pugh classes (CP: A,B,C) respectively, OS: 19.0 m, 6.4 m, 1.9 m (p<0.001); TTF: 6.1 m, 2.7 m, 1.3 m (p<0.001). Conclusions: In this real-world retrospective cohort study of unresectable HCC, the differences in overall survival, objective response, and time to treatment failure were not statistically significant between atezo/bev and durva ± treme in the 1st line setting. Outcome Atezo/bev Durva±treme Univariate p-value Multivariable adjusted hazard ratio (95% CI) Multivariable adjusted odds ratio (95% CI) Overall Survival, Median (month) 14.0 14.6 0.77 0.78 (0.54-1.14) --- Time to Treatment Failure, Median (month) 4.9 4.1 0.71 0.95 (0.72-1.26) --- Objective response, % 26.3% 21.1% 0.31 --- 0.78 (0.43-1.39)

573 Background: Immunotherapy has shown great efficacy in hepatocellular carcinoma (HCC). No clear consensus exists on when to stop the immune checkpoint inhibitor (ICI) after complete response (CR), and clinical course after stopping ICI remains unknown. Methods: We identified 138 HCC patients who received ICI at Cedars-Sinai Medical Center and Mayo Clinic Rochester from 2016-2023. Modified Response Evaluation Criteria In Solid Tumors (mRECIST) was used to assess treatment response. We further described the clinical course of patients who achieved CR after ICI discontinuation, including cancer recurrence, subsequent treatment, liver transplantation (LT) listing and outcomes. Results: The median age at ICI initiation was 68 years; 79% were male; 55.9% were white; 51.5% were BCLC stage C. 9.4% CRs, 25.4% partial responses, 39.9% stable diseases, and 25.4% progressive disease. Hepatitis C etiology was associated with higher likelihood of CR (P=0.005). Among 13 patients who achieved CR, 10 stopped ICI (60% for LT evaluation, 40% for toxicity). After stopping ICI, 40% had recurrence (Table). 3 patients underwent local therapy for recurrent HCC within Milan criteria and 1 patient restarted ICI for recurrence beyond Milan criteria. Among CR patients, 9 patients underwent LT evaluation after stopping ICI and 7 patients were waitlisted. After listing, 3 dropouts were observed, due to recurrent HCC beyond Milan criteria, sepsis leading to death, and personal preference. 4 patients underwent LT. 2 patients underwent local therapy before LT for recurrent HCC (Table). All transplanted patients had the last dose of ICI more than 1 year before LT (12, 21, 24, and 29 months). On explanted livers, 2 patients had no residual viable tumor and 2 patients had residual HCC within Milan criteria. 1 patient developed acute cellular rejection and was treated with immunosuppressants and maintained stable graft function. None had graft loss or evidence of HCC recurrence in the follow-up period at 8, 20, 28, and 51 months. Conclusions: Immunotherapy demonstrated excellent effects on a subset of HCC patients, including 9.4% who achieved CR. After stopping ICI, 40% had cancer recurrence but 3 out of 4 were within Milan criteria. 4 underwent successful LTs (2.9%) with excellent post LT outcome. Larger prospective data is needed to establish a protocol for ICI use, especially to determine the optimal timing for ICI discontinuation after CR. BCLC at ICI initiation ICI cycles before stopping, ICI Recurrence after last ICI (days) Within Milan at recurrence Treatment(s) received after recurrence and outcomes OS (days) Patient 1 B 7, Nivolumab 730 No Nivolumab. Died from GI bleeding 1065 Patient 2 B 64, Atezo/Bev 149 Yes TACE with CR, followed by LT without recurrence. 1203 Patient 3 A 8, Nivolumab 1393 Yes Y90 with CR. No recurrence. 1984 Patient 4 C NA, Pembrolizumab 407 Yes TACE and MWA with CR, followed by LT without recurrence. 1722

285 Background: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC) outside of mismatch repair (MMR) deficient/microsatellite instability-high (MSI-H) tumors. Most CRC cases are MMR proficient /microsatellite stable and demonstrate resistance to ICIs, attributed to the tumor microenvironment. Colony Stimulating Factor 1 Receptor (CSF1R), a regulator of tumor-associated macrophages, has emerged as a potential target due to its association with poor prognosis in CRC. Methods: Data from 433 metastatic CRC (mCRC) patients in the CALGB/SWOG 80405 trial were analyzed. CSF1R RNA was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced. Patients were divided into tertiles of CSF1R expression (high, medium, low). Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted based on liver metastases, treatment type (Bevacizumab, Cetuximab, FOLFOX, FOLFIRI), and MSI status. Results: Low CSF1R expression (CSF1R-L) was associated with significantly better survival outcomes. Median PFS was 12.9 months for CSF1R-L, compared to 11.2 and 9.2 months for CSF1R-M and CSF1R-H (p = 0.003). Median OS was 35.8 months for CSF1R-L versus 32.5 and 24.4 months for CSF1R-M and CSF1R-H (p = 0.00086). Stratification by liver metastases showed that CSF1R-L remained a strong prognostic factor only in patients with liver metastases. There were no significant survival differences based on CSF1R expression in bevacizumab-treated patients. However, in cetuximab-treated patients, CSF1R-L tumors had significantly longer PFS (12.9 vs 8.8 months, p = 0.037) and OS (35.8 vs 21.4 months, p = 0.002) than CSF1R-H tumors. Similarly, in FOLFOX-treated patients, CSF1R-L tumors showed longer PFS and OS (p = 0.018 and p = 0.013, respectively), and in FOLFIRI-treated patients, OS was significantly longer for CSF1R-L tumors (42.2 vs 24.7 months, p = 0.022) than CSF1R-H tumors. Conclusions: Our data suggests that CSF1R expression may serve as a prognostic biomarker in CRC, with lower expression potentially linked to improved survival, particularly in patients with liver metastases. These findings warrant further investigation of CSF1R as a possible prognostic and predictive biomarker, as well as a potential therapeutic target in CRC. Clinical trial information: NCT00265850 .

Abstract Background: The trajectory of metastatic castration-sensitive prostate cancer varies based on disease presentation and biology. While proteomic profiling studies of primary prostate tissue have linked protein expression with metastatic progression and prognosis, few studies have explored biological changes after treatment and their associations with response. Therefore, we conducted proteomic profiling of patients with oligometastatic castration-sensitive prostate cancer (omCSPC) treated with stereotactic ablative radiotherapy (SABR) or observation in the ORIOLE phase 2 randomized clinical trial (RCT). Methods Plasma from omCSPC patients in the ORIOLE trial was collected at baseline (day 1), day 90, and day 180. Protein abundance was quantified using the Olink Explore Assay. Differential expression from baseline to day 90 or 180 in each treatment arm was analyzed using a 2-sided t-test with Benjamini-Hochberg correction. Changes in protein expression at day 90 and 180 were compared with a Pearson correlation. Pathway enrichment was performed via gene set enrichment analysis (GSEA) using Reactome, KEGG, and Hallmark gene sets. Associations with progression-free survival (PFS) were analyzed using Kaplan-Meier and log-rank tests. Results In total, 1,472 proteins were assayed across 130 samples from 46 patients over 3 time points. Significant changes in expression post-SABR were noted at day 90 and 180 compared to baseline (using adjusted p-value cutoff of 0.05). At day 90, four proteins (FCRL1, CD22, TCL1A, FCER2) were downregulated; at day 180, only FCRL1, a Fc receptor-like gene family preferentially expressed in B cells, remained downregulated. No significant expression changes were found in the observation arm. Differential expression of proteins during follow-up were associated with PFS. In particular, LTO1, a maturation factor of ABCE1 important for ribosomal biogenesis and translation, was overexpressed at both day 90 and 180 post-SABR, and overexpression was associated with improved PFS at day 90 (median 24.5 mo vs 6 mo; p=0.017) and day 180 (median 33 mo vs 6 mo; p=0.043). These associations were absent in the observation arm. For proteins differentially expressed in the SABR arm at day 90, several signaling pathways were significantly enriched for patients with prolonged PFS, including positive enrichment of unfolded protein response (UPR) (p=0.008) and IL-4/IL-13 (p=0.009). At 180 days, several pathways were enriched for patients with prolonged PFS including negative enrichment of CTLA4 inhibitory signaling (p=0.005) and CD28 co-stimulation (p=0.008). Conclusion Proteomic analysis in omCSPC patients from the ORIOLE trial reveals significant expression changes at days 90 and 180 after SABR. B-cell signaling proteins were selectively downregulated in the SABR arm, and pathways associated with protein translation and immune response were enriched post-SABR for patients with prolonged PFS. Further research will explore connections to genomic and transcriptomic changes, with additional validation needed. Citation Format: Jarey H. Wang, Amol Shetty, Yang Song, Noura Radwan, Soha Bazyar, Xiaolei Shi, Theodore L. DeWeese, Daniel Y. Song, Ryan M. Phillips, Matthew P. Deek, Philip Sutera, Ana P. Kiess, Phuoc T. Tran. Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B031.