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Background Antitumor immune responses induced by oncolytic immunotherapy (OI) are often followed by upregulation of programmed death-ligand 1 (PD-L1). As such, the combination of OI with blockade of the programmed cell death protein-1 (PD-1)/PD-L1 axis has demonstrated therapeutic activity in preclinical and clinical trials. The purpose of this study is to understand further the immune-mediated mechanism of interaction between oncolytic viruses and anti-PD-1 therapy. Methods Tumor cells and immune cells (splenocytes) were cultured separately, or in co-culture with vusolimogene oderparepvec, an oncolytic herpes simplex virus expressing the fusogenic gibbon-ape leukemia virus-fusogenic membrane glycoprotein protein (GALV) and granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as RP1. Viral replication, interferon (IFN) responses and PD-L1 expression were analyzed using wild-type, IFNAR1, TNFAR1 and STING knockout splenocytes. In vivo studies evaluated immune cell infiltrates into the tumor following RP1 administration with anti-PD-1 therapy. Results RP1 replication was evident in tumor cells but not splenocytes. This was also accompanied by upregulated IFN expression in cultured splenocytes that was absent in cultured tumor cells. However, when these cell types were co-cultured, splenocytes mediated an interferon response to RP1 via STING that was transmitted to tumor cells in a non-touch-dependent manner. Tumor cells responded to these input signals via upregulation of cell surface major histocompatibility complex-I and PD-L1 through tumor intrinsic JAK-STAT signaling. In vivo, an IFN signature was observed following intratumoral injection of RP1, both in injected and non-injected tumors, which was further increased when combined with anti-PD-1 therapy. Marked upregulation of PD-L1 was observed in tumors injected with RP1 accompanied by the recruitment of CD11b+Ly6G+neutrophils into the tumor microenvironment, which stained positive for PD-L1. Conclusion Overall, the data demonstrate that RP1 remodels the tumor microenvironment through a combination of direct and indirect effects on both tumor and immune cells, resulting in an overall more inflamed phenotype.

Abstract Background Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms associated with prolonged survival and substantial symptom burden. However, patient-reported outcomes across NET subtypes remain poorly characterized, particularly in real-world settings. This study describes baseline health-related quality of life (HRQoL) and care experiences among patients with gastroenteropancreatic and lung NETs, examining differences by tumor site and time since diagnosis. Methods The Neuroendocrine Tumors–Patient Reported Outcomes study is a prospective, multi-institutional US cohort of adults (aged 18 years and older) with incident small intestinal, pancreatic, gastroenteropancreatic, or lung NETs diagnosed from January 2018 through September 2024, identified via a validated electronic medical record–based computable phenotype. Baseline surveys assessed HRQoL, symptoms, care experiences, and clinical characteristics using validated instruments. Descriptive statistics and standardized mean differences compared responses by NET site and time since diagnosis. Results Among 2367 participants (mean age = 57.8 years; 57.3% female), 1974 had gastroenteropancreatic NETs (659 small intestinal NET, 555 pancreatic NET) and 393 had lung NETs. Fatigue (mean = 33.0), insomnia (mean = 32.5), and diarrhea (mean = 25.7) were the most burdensome symptoms. Lung NET patients reported worse dyspnea (standardized mean difference = 0.58, P < .001) and lower physical, role, and global QoL scores than those with gastroenteropancreatic NETs, while pancreatic NET patients reported better functioning. Diarrhea worsened over time, especially in small intestinal NETs. Most rated care highly (75.3%) but cited concerns about treatment side effects (80.4%), costs (60.7%), and travel burden (58.8%). Conclusions This large US cohort reveals persistent symptom burden and HRQoL variation by tumor site and disease duration, underscoring the need for longitudinal HRQoL assessment in NET care.

Abstract INTRODUCTION Guidelines recommend non-surgical biopsy for indeterminate pulmonary lesions > 8 mm. Shape-sensing robotic-assisted bronchoscopy (ssRAB) is growing in use to biopsy small pulmonary nodules; however current literature is limited to single center studies with limited follow-up. This study, PRECIsE, assessed safety and performance of the first ssRAB iteration across multiple sites and nascent users. METHODS Prospective, multicenter, observational study evaluating ssRAB without cone-beam CT guidance in patients with nodules 10–30 mm located in or beyond the sub-segmental airways. Patients were followed for 2 years; the primary endpoint was sensitivity for malignancy with diagnostic yield, and safety as secondary endpoints. Multilevel logistic regression models were used to control for factors associated with sensitivity and diagnostic yield. RESULTS A total of 305 procedures were performed across 6 centers. Median nodule size was 17.0 mm (IQR: 14.0–23.0) with bronchus sign present in 37% of cases. Sensitivity for malignancy through 2 years was 81.3% (95% CI: 75.7, 86.1). Multi-level modelling demonstrated female sex, smaller nodule size, lower lobe location, semi-solid density, and higher body-mass-index were associated with lower sensitivity. Diagnostic yield was 74.1% (95% CI: 68.8, 78.9) according to the ATS/ACCP criteria and 77.5% [95% CI: 72.4, 81.8] according to the intermediate criteria. Multi-level modeling demonstrated a non-significant site/center level effect on ATS/ACCP diagnostic yield (P = .36). Pneumothorax requiring intervention was 1.6% (5/305); bleeding was 1.0% (3/305) with two (2) Nashville grade 2 and one (1) Nashville grade 3 events. CONCLUSIONS The first iteration of ssRAB demonstrated encouraging performance and a strong safety profile among nascent users for the biopsy of small peripheral nodules.

TPS913 Background: A subset of patients with MIBC who receive neoadjuvant therapy (NAT) prior to radical cystectomy (RC) have a pathologic complete response (pCR) at the time of RC. With pCR rates of 22-42% in patients with MIBC following NAT (+/- ICI), whether a subset of patients with good clinical response to NAT can avoid RC is an important unanswered question, especially with the development of more active systemic therapies. HCRN 16-257 evaluated maintenance nivolumab in lieu of cystectomy in patients with MIBC who experienced clinical complete response (cCR) following neoadjuvant GC and nivolumab. The cCR rate was 48%, but 8/33 (24%) patients who elected bladder preservation subsequently underwent cystectomy for local disease recurrence. The RETAIN trial also evaluated omission of local therapy following neoadjuvant therapy with a 2-year bladder preservation rate in patients with ≤T1 disease following NAC of 54% (22/41). Of the 9/25 (36%) patients on that trial developed metastatic disease, 8/9 developed localized disease before metastasizing. These data illustrate the critical role that local therapy plays in patients with MIBC. For this reason, we believe that radiotherapy to the bladder combined with ICI will improve bladder intact event-free survival (BI-EFS). This trial also allows for patients to opt for bladder preservation based on a good clinical response to NAT. Methods: This is a single arm, phase 2 trial (NCT07061964) evaluating risk-adapted bladder preservation therapy for patients with MIBC following NAT. NAT consists of any NCCN guideline concordant therapy for MIBC. Patients with cT2-T4aN0M0 MIBC who complete NAT will be eligible if they have ≤T1 disease on post-NAT TURBT, confirmed by biopsies of prior tumor sites and systematic sampling (left/right lateral walls, dome, posterior wall, trigone). Patients will receive 55 Gray (Gy) in 20 fractions of radiotherapy (RT) to the bladder with 1 year of pembrolizumab. The primary objective is to evaluate whether 3-year BI-EFS is at least 70% in participants with < = T1 (without multifocal CIS) following NAT and RT with 1 year of pembrolizumab. Secondary objectives include local muscle invasive recurrence-free survival, metastasis-free survival (MFS), overall survival (OS), the rate of salvage cystectomy, and evaluation of the frequency and severity of toxicities in participants who receive RT and pembrolizumab. Plasma and urine will be banked for future correlative studies. S2427 was activated in September 2025 with an accrual goal of 111 patients. Clinical trial information: NCT07061964 .

392 Background: Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, exerting both tumor-promoting and tumor-restrictive effects, and in some cases, dual roles. CAFs are heterogeneous and have been implicated in tumor progression, metastasis, and therapeutic resistance. Recent translational evidence suggests the existence of at least two CAF subtypes: CAV1+ CAFs and FAP+FN1+ CAFs. The clinical utility of subclassifying CAFs in prostate cancer remains undefined. In this study, we aimed to examine the correlation of CAF subtypes in localized prostate cancer with Decipher genomic classifier (GC) scores, Grade Group (GG), and the presence of adverse pathological features (APF). Methods: We retrieved de-identified transcriptomic and pathological data from 55,329 radical prostatectomy (RP) samples tested with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) between 2016 and 2024, available through the GRID registry (NCT02609269). A subset of 855 patients (META855 cohort) treated with RP was utilized for outcomes analyses. CAF subtypes were defined based on the expression of key biomarkers (FN1, FAP, and CAV1), normalized to total CAF estimates. Correlation analyses and multivariable Cox regression models were performed to evaluate the association of CAF subtypes with GC scores, GG, APF. Metastasis-free survival (MFS) estimates were generated using Kaplan–Meier methodology. Results: FAP and FN1 normalized expressions were highly correlated (r=0.61) and weakly correlated with CAV1 suggesting that they represent two distinct subtypes of CAF. Samples with high expression (top 25%) of FN1 (FN1+) and FAP (FAP+) were enriched with very high Decipher (> 0.85, VHD) and GG4-5. As such, 37% and 32% of FAP+ were VHD and GG4-5 respectively compared to ~18% for low FAP(low 25%). While for FN+ 33.9% were VHD, and 31.5% GG4-5. Patients with FAP+FN1+, 42.5% and 37.1% were VHD, and had GG4-5. Samples with high CAV1 (CAV1+) were associated with lower rate of VHD (15.5%) or GG4-5 (20.8%) compared to low CAV1 (35.4% for VHD and 24.5% for GG4-5). When evaluating VHD in FAP+FN1+CAV1- subgroup, 58% were VHD compared to 6.4% in FAP-FN1-CAV1+. The 5-year MFS was 78% in FAP+FN1+CAV- compared to 96% in FAP-FN1-CAV1+ (p<0.01). When evaluating the biological implications of FAP+FN1+, we found that FAP and FN1 expression is highly correlated to angiogenesis and EMT pathways, radiation sensitivity signature (PORTOS). Conclusions: FAP+FN1+CAV- is a unique subset of CAFs that is associated with aggressive prostate cancer behavior. Our findings may lay the foundation for future efforts to modulate CAFs in localized prostate cancer with existing therapeutics targeting FAP or FN1.

357 Background: Prostate cancer (PCa) is the most incident cancer in adult males in the United States, and the second highest in the world. CTCAE is the standardized method to grade the severity of treatment-related adverse events (AEs), but are tedious to collect and subject to inter-observer variability. This study aimed to evaluate the performance of LLMs in automatically extracting and grading CTCAE toxicities from clinical notes and patient-reported outcomes of PCa patients from a clinical trial. Methods: A total of 55 patients from NCT02874014 trial, undergoing proton therapy (PT) for localized PCa, were included. The ground truth of CTCAE graded toxicities was obtained from the trial’s results. Clinical notes within 3 days, and the most recent patient questionnaires within 90 days of toxicity assessment were retrieved from the electronic health record. A comprehensive prompt was developed to extract and CTCAE grade toxicities from the retrieved records. LLMs used for this analysis were OpenAI GPT-4o and Gemini 2.0 Flash. Phase 1 evaluated both LLMs' performance against the ground truth. To ensure the metrics reflected the models’ performance based only on the information available in the text provided, cases where both LLMs contradicted the ground truth were manually reviewed. Phase 2 recalculated LLMs' performance metrics using this adapted ground truth. A conservative stepwise ensemble model was developed to leverage the complementary strengths of both LLMs. Results: In the conservative stepwise ensemble model, Gemini 2.0 Flash served as the initial screening platform to identify AEs in step 1. All cases with identified toxicity events were then reviewed and confirmed using OpenAI GPT-4o in step 2. This effectively reduced false positive rates while preserving high sensitivity. The ensemble model achieved strong performance metrics: binary accuracy (0.954), sensitivity (0.961), specificity (0.953), F1 score (0.836), and grade accuracy (0.932). Conclusions: This study demonstrates the feasibility of the use of LLMs for extraction and CTCAE toxicity grading in PCa patients treated with RT. The ensemble model achieved strong performance metrics. Further validation is needed for other cancer diagnosis and treatment modalities. Phase Model Binary Accuracy Precision Sensitivity Specificity F1 Score Grade Accuracy 1 Gemini 0.946 0.672 1.000 0.939 0.804 0.919 1 OpenAI 0.940 0.785 0.637 0.978 0.703 0.895 2 Gemini 0.956 0.735 1.000 0.950 0.848 0.927 2 OpenAI 0.954 0.917 0.679 0.991 0.780 0.903

32 Background: PET-based radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have become the mainstay of prostate cancer imaging; however, high urinary radioactivity from these primarily renally cleared compounds may obscure tumors in the prostate and peri-ureteric regions. We conducted the first intra-patient comparator study to assess the urinary radioactivity of two 18 F-labelled PSMA-PET radiopharmaceuticals, 18 F-piflufolastat and 18 F-flotufolastat. Methods: This multicenter, prospective, intra-patient comparator study (NCT06604442) enrolled men ≥ 18 years with low PSA (≤ 0.5 ng/mL) biochemical recurrence of prostate cancer ≥ 6 months after radical prostatectomy with undetectable PSA post-surgery, scheduled for a standard-of-care (SoC) 18 F-piflufolastat PET. Patients had a SoC PET/CT after IV 18 F-piflufolastat (target dose 333 MBq), and a second PET/CT 1–10 days later after IV 18 F-flotufolastat (target dose 296 MBq), both scans started approximately 60 min after administration and used the same scanner. The primary endpoint was the difference in urinary bladder radioactivity (mean standardized uptake value [SUV mean ]) between 18 F-piflufolastat PET and 18 F-flotufolastat PET. Secondary endpoints included patient and region-level detection rates (DR) for each radiopharmaceutical. Images were interpreted by two blinded central readers, with a third to resolve disagreements, allowing majority read results. Results: Between Oct 2024 and Jun 2025, 55 patients (mean PSA, 0.28 [range 0.09–0.50] ng/mL) were included in the primary efficacy analysis. Median bladder SUV mean was significantly higher with 18 F-piflufolastat (29.0; interquartile range [IQR], 18.9–40.8) than 18 F-flotufolastat (10.9; IQR, 6.0–18.5) with a median difference of 15.1 (IQR, 8.5–27.0; p<0.001 [Wilcoxon signed-rank test]). The patient-level DR was 27.3% (15/55) for 18 F-piflufolastat and 45.5% (25/55) for 18 F-flotufolastat (majority read). Among the 21 patients with very low PSA levels (≤ 0.2 ng/mL), 38.1% had a positive 18 F-piflufolastat scan compared with 52.4% for 18 F-flotufolastat scans (majority read). Regional and sub-regional DRs are shown in the table. Conclusions: In this intra-patient study, 18 F-flotufolastat showed significantly lower urinary radioactivity, and a higher overall DR than 18 F-piflufolastat indicating it may offer improved image assessment in regions close to the bladder. Clinical trial information: NCT06604442 . Region 18 F-Piflufolastat DR* n (%)N=55 18 F-Flotufolastat DR*n (%)N=55 Prostate bed 6 (10.9) 10 (18.2) Vesicourethral anastomosis 1 (1.8) 4 (7.3) Retrovesical 2 (3.6) 2 (3.6) Remnant seminal vesicles/ lateral surgical margin 2 (3.6) 4 (7.3) Pelvic lymph nodes 8 (14.5) 9 (16.4) Majority read. *≥ 1 PET positive lesion.

160 Background: To our knowledge, no tools are available to guide care in oligometastatic prostate cancer (omPC). Here, we leveraged individual patient-level data pooled from 8 randomized trials in the X-Met collaboration to construct CEREBRO, a tool for predicting patient-specific responses to various treatment scenarios. Methods: Patients with omPC from the STOMP, ORIOLE, SABR COMET, EXTEND continuous ADT, EXTEND intermittent ADT, ARTO, RADIOSA, and RAVENS trials were included. 6 patients (1%) with missing data were excluded. Treatment scenarios were defined as active surveillance (AS), metastasis-directed therapy (MDT), systemic therapy (ST), or MDT+ST. To account for varying baseline hazards, Weibull models were fit for overall survival (OS); progression-free survival (PFS); and castration-resistance free survival (CRFS) for patients with hormone-sensitive disease. Endpoint definitions were harmonized per X-Met framework. Results: Of 600 patients included (treatment scenarios: AS=50; MDT=153; ST=172; MDT+ST=225), 405 (67%) had hormone-sensitive omPC. With median follow-up of 38 months, median PFS, CRFS, and OS of all patients were 18, 70, and 84 months. In order of relative contribution, inputs for predicting outcomes were: treatment scenario, stage, prostate-specific antigen annotated by ADT status, metachronous vs synchronous presentation, imaging type, number of metastases, hormone sensitivity, and age. The model for each endpoint showed robust fit, calibration, superiority against the null model (per the likelihood ratio test), and risk stratification (Table). Median PFS times for model-defined low-, intermediate-, and high-risk strata were 46 months, 18 months, and 7 months ( p <0.0001). In addition, the PFS and OS models also showed strong discrimination via c index and a large interval of risk probabilities with additive clinical utility per decision-curve analysis (Table). A public webpage will be made available to facilitate prospective trial stratification, patient counseling for patient-specific outcome predictions for each potential treatment scenario, and forecasts comparing outcomes between treatment scenarios. Conclusions: CEREBRO is a high-performance tool, trained on robust prospective data from 8 randomized trials with routinely collected clinical variables, for predicting risk and treatment outcomes in omPC. Given the uncertainties in optimal timing of MDT and combination with ST, this tool has been built to facilitate current decision making. External validation is planned. Model summary. Endpoint C index (95% CI) Calibration Likelihood ratio p Risk strata p Net clinical utility observed between thresholds PFS 0.72 (0.70-0.75) 1.04 <0.0001 <0.0001 0.2-1.0 CRFS 0.63 (0.60-0.70) 1.01 0.02 0.004 0.2-0.5 OS 0.81 (0.76-0.86) 1.01 <0.0001 <0.0001 0.05-1.0

TPS290 Background: Landmark randomized trials established the survival benefit of adding D to ADT in mCSPC. Building on this foundation, subsequent trials (PEACE-1 and ARASENS) demonstrated further survival improvements when androgen receptor pathway inhibitors (ARPI) were added to the ADT + D backbone. However, the independent contribution of D within the triplet regimen remains unclear given lack of prospective evaluation. Additionally, tumor suppressor gene (TSG) alterations involving TP53, PTEN, and RB1 are frequently observed in PC and are associated with aggressive biology and poor outcomes, providing an opportunity to enhance prognostic accuracy and optimize selection of candidates for treatment intensification. We hypothesize that adding D to ADT plus A will improve survival compared to ADT + A in mCSPC and stratification by TSG status may identify different treatment effects across molecular subgroups. Methods: ASPIRE is an open-label, two-arm, randomized phase 3 study to assess the benefit of D added to ADT plus A for patients with mCSPC. Eligible patients include those with confirmed adenocarcinoma of the prostate with evidence of distant metastatic disease on conventional imaging and are appropriate to receive D. Patients with metachronous low-volume disease or PSMA-PET only disease are excluded. Candidates must have next-generation sequencing (NGS) results from a CLIA-certified tissue test available for TSG status stratification at registration. Eligible patients will receive ADT plus A (240 mg PO daily) +/- D for up to 6 cycles until progression of disease by PCWG3/RECIST version 1.1 criteria. Prior therapy with ADT (with or without ARPI) initiated within 120 days before registration is permitted. The primary endpoint is overall survival (OS). Secondary endpoints include OS by TSG status; radiographic progression-free survival (rPFS); time to castration resistance; symptomatic skeletal event–free survival; time to worsening of disease-related symptoms (NCCN-FACT FPSI-17); safety and tolerability (CTCAE v5.0); PSA90 response at 6 weeks and 6 months; time to PSA progression; and objective response rate in patients with measurable disease. The study will enroll 1200 patients and is currently actively accruing patients. Clinical trial information: NCT06931340 .

TPS276 Background: Metastatic castration-resistant prostate cancer (mCRPC) can evolve into a neuroendocrine-like subtype with aggressive behavior and poor outcomes (1). Nuclear Receptor-Binding SET Domain Protein 2 (NSD2) is overexpressed in prostate cancer and is a driver of both androgen-receptor (AR)-dependent signaling and of neuroendocrine differentiation, where cancer cells lose AR dependence and response to AR pathway inhibitors (ARPIs) (2,3,4). In studies of patient-derived neuroendocrine prostate cancer (NEPC) models, genetic depletion of NSD2 led to restoration of AR expression, reversal of adeno-to-neuroendocrine differentiation, and re-sensitization to ARPI (4). We hypothesize that NSD2 inhibition can reverse resistance to ARPIs in patients with progressive mCRPC, including with neuroendocrine differentiation. KTX-2001 is an oral, potent and selective small molecule inhibitor of NSD2. It is the sponsor’s second NSD2 inhibitor to enter the clinic. The sponsor’s first in class NSD2 inhibitor, KTX-1001, was shown to be tolerable and have preliminary efficacy in patients with relapsed/refractory multiple myeloma (5). Methods: STRIKE-001 (NCT07103018) is a multicenter, open-label phase 1 dose escalation trial of KTX-2001 monotherapy (Part A) and KTX-2001 + darolutamide (Part B). Key inclusion criteria are males age ≥18 years with mCRPC, progression after receiving ARPI, Eastern Cooperative Oncology Group performance score of 0-1, willingness to undergo biopsy if safe and feasible, and life expectancy of ≥6 months. Participants take KTX-2001 by mouth once daily alone (Part A) or with darolutamide 600 mg twice daily (Part B). Dose escalation of KTX-2001 in Parts A and B will follow a 3+3 design and occur in parallel at multiple planned dose levels. Primary objectives are to assess the safety and tolerability, determine MTD, and determine RP2D(s) for further study of KTX-2001 alone and in combination with darolutamide. Secondary objectives include characterization of efficacy and PK parameters for both KTX-2001 monotherapy and in combination with darolutamide. Exploratory objectives include study of pharmacodynamic effects, circulating tumor cells, and cell-free DNA. 1. Conteduca V, Eur J Cancer 2019. 2. Parolia A, Nat Genet 2024. 3. Aytes A, Nat Commun 2018 4. Li J, bioRxiv 2023.07.18.549585 5. Bories P, Blood Vol 144, Suppl 1,2024. Clinical trial information: NCT07103018 .