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Purpose Radioligand therapy (RLT) with [ 177 Lu] Lu-PSMA-617 has shown significant benefits in metastatic castration-resistant prostate cancer (mCRPC), including prolonged overall survival (OS) and progression-free survival (PFS), as well as improved quality of life. For patients previously treated with [ 177 Lu]Lu-PSMA-617 who subsequently experience disease progression, retreatment with [ 177 Lu] Lu-PSMA-617 has emerged as a potential approach, yet data on the outcomes of RLT retreatment remains limited. This study aimed to assess the efficacy and safety of retreatment RLT in mCRPC. Methods Clinical and imaging data of patients who underwent at least two cycles of [ 177 Lu] Lu-PSMA-617, followed by a second course of treatment with [ 177 Lu] Lu-PSMA-617 between March 2018 and December 2024, were retrospectively reviewed. Endpoints included biochemical response, imaging response, toxicity, PSA-PFS, rPFS, and OS. Radiologic and biochemical responses were evaluated using RECIST 1.1 criteria and PSA levels, respectively. Results A total of 589 patients underwent [ 177 Lu] Lu-PSMA-617 RLT, of whom 20 (3.4%, 20/589) received RLT retreatment. The median age was 71.3 years (range: 63.7–95.2), and the median follow-up was 73.3 months (95% CI, 35.7–77.2 months) after the initial treatment and 21.7 months (95% CI, 16.9–26.0 months) after retreatment. The initial treatment involved a median of 4.5 cycles (range: 2–6). Following the first course of RLT, 15 patients (75%, 15/20) had exhibited a >50% decline in PSA levels, including 9 who achieved a >90% decrease. Additionally, 12 patients (60%, 12/20) had demonstrated a complete or partial imaging response, while 3 (15%, 3/20) patients had stable disease, and 5 (25%, 5/20) patients had progressive radiologic disease. Patients received a median of 4 retreatment cycles (range, 1–6), and the median interval between initial RLT and retreatment RLT was 33.1 months (IQR, 16.2–48.9 months; range, 10.7–58.8 months). A PSA decline of ≥50% was observed in 9 out of 20 patients (45%, 9/20). An imaging response was observed in 10 patients (50%, 10/20), with 4 achieving a complete response and 6 achieving a partial response, whereas 10 patients (50%, 10/20) showed progression. The median PSA-PFS was 9.8 months (95% CI, 4.1–17.9 months), and the median rPFS was 8.2 months (95% CI, 3.3–17.9 months). Eight deaths occurred during follow-up. The estimated Kaplan Meier OS rates were 83.6% at 12 months (95% CI, 57.3%–94.4%) and 53.7% at 24 months (95% CI, 28.3%–73.7%). Grade 2 renal toxicity was observed in one patient (5%, 1/20). Three patients (15%, 3/20) developed Grade 2 anemia. Notably, no grade 3 or grade 4 adverse events were observed during either treatment period. Conclusion In our cohort, retreatment with [¹ 77 Lu]Lu-PSMA-617 RLT was associated with biochemical and imaging responses in some patients, with observed survival outcomes that support further investigation. However, given the retrospective single-arm design and small sample size, large prospective studies are needed to more rigorously evaluate the safety, efficacy, and optimal patient selection for retreatment RLT.

Background The optimal management of biochemical recurrence (BCR) after radical prostatectomy (RP) remains controversial, particularly in the absence of clinical or radiographic evidence of disease. Salvage radiotherapy (SRT) remains standard of care, but it is unclear whether SRT benefits patients when modern imaging with a multiparametric magnetic resonance imaging (mpMRI) and prostate‐specific membrane antigen‐positron emission tomography/computed tomography (PSMA‐PET/CT) are negative for local recurrence. Retrospective data comparing SRT to observation for such patients is fraught with selection bias, underscoring the need for a prospective randomised controlled trial. Study Design and Methods The Biochemical Recurrence Irradiation or Observation (BRIO) is a randomised study under the DIVINE trial framework (NCT06378866) enrolling men with BCR (prostate‐specific antigen [PSA] level ≥0.2, up to 1.5 ng/mL) after RP with no radiographic evidence of recurrence on mpMRI and PSMA‐PET/CT. Major inclusion criteria include age ≥18 years, biochemically recurrent prostate cancer after RP with a PSA level between 0.2 and 1.5 ng/mL, and no local or metastatic recurrence on imaging. A total of 312 patients will be enrolled. Participants are randomised 1:1 to standard‐of‐care SRT followed by surveillance (Group A), or initial observation with subsequent image‐guided therapy at radiographic progression (Group B). Based on historical analysis, a total of 30 metastasis events provides 80% power to detect a significant improvement (hazard ratio 0.5 corresponding to a 5‐year metastasis‐free proportion of 80.7% in the control group and 89.8% in the experimental group with one‐sided type I error rate of 0.15). All participants undergo baseline blood collection to measure prostate cancer‐extracellular vesicles and cell‐free DNA for biomarker development. Participants are followed in a 16‐week cycle with serial PSA measurements, repeat imaging if PSA doubles, safety assessment, and patient‐reported outcomes. Endpoints The primary endpoint is distant recurrence‐free survival at 5‐years using a 12‐month landmark to mitigate bias arising from differing assessment schedules for patients receiving optional 6 months of androgen deprivation therapy. Key secondary outcomes include time to hormone therapy, quality of life measures, adverse effects, and novel blood and urine biomarkers. Conclusion The BRIO study will clarify the clinical benefit of immediate SRT vs observation with image‐guided intervention in mpMRI and PET‐negative BCR after RP.

Background and Objective: Radiographic progression in prostate cancer (PCa) can occur even when prostate-specific antigen (PSA) levels are undetectable. We aimed to determine the frequency and characteristics of radiographic disease progression (rDP) on PSMA PET/CT in patients with undetectable PSA, referred to as PSA zero rDP. Methods: We analyzed the Mayo Clinic PSMA PET Prostate Cancer Registry to identify patients with rDP on PSMA PET/CT despite undetectable PSA levels. Disease progression was confirmed via biopsy or treatment response. The cohort included patients with non-metastatic and metastatic hormone-sensitive disease, as well as those with castration-resistant prostate cancer at the time of imaging. Overall survival (OS) was estimated using the Kaplan–Meier method. Group comparisons were performed with the log-rank test. Univariate Cox regression was used to identify factors associated with poor OS. Key findings and Limitations: Among 2141 patients imaged between 2021 and 2023, 257 (12%) had PSA zero rDP. Sixty-one percent had initially localized disease; 39% had de novo metastatic disease. Median (IQR) time from diagnosis to PSA zero rDP was 51.9 (18.4–115.5) months. A total of 184 patients (72%) progressed to castration-resistant PCa. Sites of rDP included bone (57%), visceral (15%), lymph node (18%), and local recurrence (10%). During median follow-up of 8.1 (3.5–11.9) months, 5% of patients died. Only visceral metastases were significantly associated with poorer OS (p < 0.0001). Conclusions and Clinical Implications: Prostate cancer patients frequently develop metastatic disease with undetectable PSA values. Our findings suggest the use of periodic advanced imaging techniques, irrespective of PSA value, for more prompt detection and early management of disease progress.

Abstract OBJECTIVE To demonstrate that Prostate-specific membrane antigen (PSMA) PET imaging, though primarily used in prostate cancer surveillance, can reveal PSMA uptake in non-prostatic tumors due to neovascular PSMA expression. BACKGROUND PSMA PET imaging is increasingly used for staging and monitoring prostate cancer. However, PSMA uptake is not exclusive to prostate carcinoma and may be observed in non-prostatic malignancies, including glioblastoma, due to neovascular expression. CASE REPORT We present a 67-year-old gentleman with metastatic prostate carcinoma, diagnosed in 2014 and treated with neoadjuvant Lupron, prostatectomy, and salvage radiation. In 2019, he developed nodal recurrence in retroperitoneal and bilateral iliac chain nodes, treated with lymphadenopathy, six cycles of Taxotere-based chemotherapy, and consolidative proton beam radiation (56.25 Gy/25 fractions). He later developed progression to the right proximal humerus and left coracoid process, treated with stereotactic body radiation therapy (25Gy/5 fractions). Follow-up PSMA PET/CT revealed no systemic abnormalities but showed a new PSMA-avid lesion in the right medial temporal lobe. Brain MRI confirmed a 3.5 x 1.7 x 2.5 cm ring-enhancing, intra-axial lesion with edema. The patient was asymptomatic. PSA was undetectable on abiraterone/prednisone and leuprolide. He underwent right frontotemporal craniotomy and resection. Pathology confirmed Glioblastoma, IDH-wildtype, CNS WHO Grade 4 with focal epithelioid features and positive MGMT promoter methylation. He received standard-of-care treatment with radiation, temozolomide, and TTF device. Surveillance PSMA PET and MRI showed no residual brain avidity or progression. Discussion: PSMA is a type II transmembrane glycoprotein expressed by prostatic and various non-prostatic tissues. In healthy brain parenchyma, PSMA expression is typically absent but is overexpressed in neovasculature of high-grade gliomas, including glioblastoma, IDH-wildtype, allowing for radiotracer uptake, as seen in this case. CONCLUSION This case illustrates the potential role of PSMA as a diagnostic tool, as it allows for easy identification of glioblastoma neovasculature, as demonstrated in our case report.

Background: Longitudinal genomic profiling through serial circulating tumor DNA (ctDNA) testing offers a noninvasive method to monitor clonal evolution in advanced prostate cancer. This study evaluated the frequency and nature of newly emergent and potentially actionable genomic alterations detected through serial testing in a real-world setting. Methods: We conducted a retrospective analysis of advanced prostate cancer patients who underwent multiple Guardant360 ctDNA tests between October 2020 and March 2023. The study focused on identifying new genomic alterations absent in the initial test, with particular attention to alterations relevant for on-label therapies, therapies approved in other oncologic indications (i.e., off-label), or a clinical trial. Results: Among 479 patients with at least two ctDNA tests, the median interval between the first and second evaluable tests was 207 days. New and potentially actionable alterations emerged in 57.8% of patients, including potential targets for on-label therapies (16.7%), off-label therapies (16.5%), and clinical trials (55.7%). Tumor mutational burden (TMB) increased from “low” to “high” in 11% of patients, although none had microsatellite instability or mismatch repair deficiency. In a Mayo Clinic subset, ten patients received olaparib based on treatment-emergent alterations, but none achieved a prostate-specific antigen (PSA) response. Two patients who transitioned from low to high TMB received pembrolizumab, both with progressive disease as best response. Conclusions: In a large real-world cohort, serial ctDNA testing frequently identified new alterations that were not detected at baseline and are potentially actionable therapeutic targets, highlighting the value of serial genomic profiling for capturing clonal dynamics. Additional research is needed to better establish a framework for retesting and to clarify how these results should influence subsequent treatment decisions.

Aims Schistosomiasis remains endemic in various parts of the world, and insights into pathogen immunobiology are mainly based on experimental models, while studies on human tissues are limited. Methods We explored the role of immune checkpoint pathway by evaluating the immunohistochemical expression of programmed death-ligand 1 (PD-L1) in a retrospective cohort of patients with bilharzial cystitis. Inflammation severity by conventional histology and staining intensity by immunohistochemistry were assigned three-tier scores (0/1+/2+), and a cut-off for staining percentage was set at 5%. Results 38 biopsies from 31 patients were considered adequate for evaluation, and positive staining was detected in 80.6% of patients (34 biopsies). High expressors (22.6%) showed strong positive membranous staining (score 2+) with high staining density (more than 5% of inflammatory cells). Low expressors (58.1%) showed mild/moderate staining (score 1+) predominantly in less than 5% of the cells (91.6%) or expressed restricted cytoplasmic staining (6/31). All high expressors showed severe inflammation (score 2+) (p<0.001), and viable ova were only observed in these cases. Calcified ova were associated with mild/moderate inflammation or absent/minimal inflammation, correlating with low expressors or non-expressors (19.4%), respectively. Conclusion Schistosomal granuloma exhibits upregulated PD-L1 expression proportional to inflammation severity and pathogen viability, highlighting a critical immune checkpoint engagement in disease pathology.

e17168 Background: Prostate cancer is the most prevalent cancer and the second leading cancer related death in men in the USA. Radical prostatectomy represents the mainstay treatment for patients with localized prostate cancer. Management of metastatic disease requires multidisciplinary practice and innovative approach for individualized favorable outcomes. Treatment sequencing in patients with advanced prostate cancer has been reported to impact patient’s response to subsequent treatment as well as overall survival outcomes. Here in, we thought to investigate the impact of prior chemotherapy treatment on PSA response rates to 177Lut PSMA. Methods: We conduct a single center retrospective study including 164 patients diagnosed with advanced prostate cancer and treated with 177Lut PSMA for metastatic hormone resistant prostate cancer. 92 patients received 177Lut PSMA as a salvage treatment late after chemotherapy (group A), and we compared them with 70 patients received 177Lut PSMA early in an adjuvant fashion within 3 months after chemotherapy (group B). Favorable PSA response was defined by 50% or more reduction in PSA value after complete treatment with 177Lut PSMA. Results: Approximately 43 % of patients in (group B) received their 177Lut PSMA within six months. The average number of chemo cycles received by patients of (group B) is between 3 to 6 cycles. Median patients’ age (IQR) 63 years (57.75 - 68), median (IQR) number of cycles of 177Lut PSMA 5 (5 - 6). Statistical analyses were performed to determine any differences in post lut PSA response in both groups of patients. Approximately 49 % of patients in (group A) had favorable PSA response versus 44 % of patients in (group B) (p-value 0.3853). Conclusions: The use of 177Lut-PSMA in the post-chemotherapy setting demonstrated similar outcomes whether administered early or late. These findings suggest that the timing of treatment may not significantly impact its effectiveness, but further research is needed to confirm these results and explore potential optimizations for patient care.

e17081 Background: Prostate cancer is the most common cancer in men. In early localized disease, surgery represents the mainstay treatment. However, management of metastatic and advanced stages requires multidisciplinary approach. The prognosis in metastatic prostate cancer has improved recently due to advanced pharmaceutical and interventional methods of treatment with modern diagnostic methods. In our study, we aim to investigate the impact of concomitant treatment with 2nd generation hormonal therapy and 177Lut PSMA on PSA response in patients with metastatic CRPC Methods: In a retrospective observation study including 91male patients with metastatic CRPC treated with 177Lut PSMA, we divided our cohort into 2 groups depending on whether they had 2nd generation hormonal therapy alongside their treatment with 177Lut PSMA. 43 patients received 177Lut PSMA (group A). While the other 48 patients (group B) had 2 nd generation hormone therapy with 177Lut PSMA. Primary endpoint was PSA response after they complete their therapy. Favorable PSA response was defined by PSA reduction more than 50% from baseline PSA before treatment Results: Statistical analysis identified 91 male patients, median (IQR) age of 61.5 years (56,67.75). Median (IQR) Gleason score 8 (7 - 9). Pre-177Lut PSMA PSA had a median of 2 (0.255 - 99), post-177Lut PSMA had a median of 0.15 (0.1 - 2.7). Median (IQR) 177Lut PSMA 6 (5 - 6). There was no significant change in PSA response in patients who received 177Lut PSMA alone versus 177Lut PSMA with concomitant 2 nd generation hormonal therapy. Of that, 54.17% of group B had favorable PSA response compared to 48.84% of group A (P value 0.6115). In multivariable analysis, concomitant treatment with 2nd generation hormone therapy and 177Lut PSMA has no impact on PSA response rates. Conclusions: This data suggests that concomitant treatment with 2nd generation therapy and 177Lut PSMA did not demonstrate superior PSA response than treatment with 177Lut PSMA alone. This data contributes to the current literature and serve in patients counseling. Further studies are warranted.

Abstract Addressing the limited responsiveness to immune checkpoint blockade (ICB) in human cancers remains a critical challenge. Efforts over the past two decades have primarily focused on enhancing CD8 T cell function and preventing their exhaustion. However, less attention has been given to understanding the molecular mechanisms that contribute to the immunosuppressive tumor microenvironment (TME), which impedes CD8 T cell infiltration and fosters ICB resistance. The TME in ICB-resistant tumors is characterized by Transforming Growth Factor beta (TGF-β) cytokine signaling, leading to a fibrotic extracellular matrix (ECM) and the accumulation of immunosuppressive fibroblasts and myeloid cells. These features hinder CD8 T cell penetration, thereby promoting immune escape. The immune checkpoint molecule B7-H3, overexpressed in ICB-resistant cancers, has been linked to impaired CD8 T cell infiltration and poor prognosis. However, the molecular mechanisms governing B7-H3 function remain poorly understood. We investigated the relationship between B7-H3 gene expression and ICB response using transcriptomic data from two randomized phase 3 trials (IMvigor010 and IMvigor210). Bulk RNAseq data, tissue staining, and spectral flow cytometry were used to characterize the TME composition of B7-H3 high and low tumors. Multi-omic profiling of tumor cell lines with manipulated B7-H3 expression was performed to identify downstream targets of B7-H3. Syngeneic mouse tumor models were used to assess the impact of B7-H3 on tumor growth and antitumor immunity. High B7-H3 expression was associated with shorter overall survival in both IMvigor010 (HR=0.48, 95% CI: 0.33-0.70, p&lt;0.0001) and IMvigor210 trials (HR=0.68, 95% CI: 0.51-0.92, p=0.01). In ICB-refractory cancers, B7-H3 expression correlated with high levels of fibroblasts, collagen deposits, and M2 macrophages. Gene set enrichment analysis revealed a positive association between B7-H3 and TGF-β signaling. Genetic deletion of B7-H3 in tumor cells reduced the surface expression of MMP14, a metalloprotease that activates TGF-β. Pan-cancer analysis identified MMP14 as the gene most correlated with B7-H3 (Pearson r=0.69, p&lt;0.0001). TGF-β activation was reduced by 70% in B7-H3 knockout cells compared to wild-type. Loss of B7-H3 led to MMP14 accumulation in lysosomes, resulting in its degradation. We generated a B7-H3 inhibitor, 5D10, which promotes MMP14 degradation and inhibits TGF-β activation. In humanized B7-H3 mouse models, 5D10 significantly reduced TGF-β activation, enhancing CD8 T cell infiltration and impairing tumor growth. Our research identifies B7-H3 as a driver of immune exclusion and ICB resistance. We describe a novel, receptor-independent mechanism where B7-H3 promotes TGF-β activation via stabilization of MMP14. Targeting B7-H3 represents a strategy to modulate the TME, transforming immune-excluded tumors into immune-inflamed states that may respond better to ICB. Citation Format: Fabrice Lucien, Roxane Lavoie, Jack Korleski, Yohan Kim, Bharath Wootla, Liguo Wang, Ava Farrell, Kelly Harper, Martine Charbonneau, Claire Dubois, Igor Frank, Sounak Gupta, John Cheville, Jacob Orme, Stephen Boorjian, Parash Shah, Eugene Kwon, Sean Park, Haidong Dong. The immune checkpoint molecule B7-H3 is a driver of tumor immune exclusion by mediating TGF-β activation [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B034.