Background/Objectives: Radical cystectomy with urinary diversion is the standard treatment for patients with muscle-invasive bladder cancer, which represents a complex, preference-sensitive decision about the diversion options. To facilitate patient-clinician shared decision-making, we developed and evaluated the feasibility and acceptability of the Personal Patient Profile-Bladder Cancer (P3-BC), a web-based decision support system for patients considering urinary diversion options. Materials and Methods: We employed an iterative development approach following an established framework, including qualitative assessments of radical cystectomy patients' (n = 30) needs to inform content development, followed by usability testing with 10 key stakeholders. We then conducted a feasibility study with patients newly diagnosed with bladder cancer undergoing cystectomy. Feasibility was assessed through P3-BC completion rates among patients randomized to the intervention and study retention rates. Acceptability was measured using a program-based 12-item questionnaire integrating the six-item Acceptability E-Scale. Secondary outcomes included decisional conflict, shared decision-making, psychological distress, and decisional regret. Results: Of 114 eligible patients, 24 provided consent (21% consent rate), and 15 were randomized to receive the P3-BC intervention (n = 10) or usual care (n = 5). Retention was 93% at 1 month and 73% at 3 months. Among intervention participants, P3-BC achieved high feasibility (100% accessed the program) and acceptability, with 86% reporting overall satisfaction and 86% reporting ease of use. No statistically significant between-group differences were observed in secondary outcomes. Although the study was not powered to examine group differences, numerical trends suggest improvements in decisional conflict and symptom burden over time, particularly in the intervention group. Conclusions: P3-BC demonstrated feasibility and acceptability as a web-based decision support intervention for patients with bladder cancer considering cystectomy and urinary diversion. Primary barriers to enrollment included treatment burden, limited diagnosis-treatment time, and technology concerns. Findings support progression to an adequately powered randomized controlled trial to evaluate clinical effectiveness.

4591 Background: Circulating tumor DNA (ctDNA) has emerged as a valuable biomarker in urothelial cancer but remains limited by cost and turnaround time. Keratin 19 (KRT19) is a cytoskeletal protein that is highly and specifically expressed in urothelial tumor tissue in The Cancer Genome Atlas (TCGA) urothelial cancer cohort. Based on this tumor specific expression, we hypothesized that circulating KRT19 levels could serve as a rapid, inexpensive measure of disease burden to guide systemic therapy for urothelial cancer. Methods: Two patient cohorts from completed clinical trials were analyzed. HCRN GU16-257, a phase 2 trial of gemcitabine, cisplatin, and nivolumab as organ-sparing treatment for localized muscle-invasive bladder cancer, included 76 patients evaluable for KRT19 with median follow-up of 30 months. HCRN GU14-182, a phase 2 switch maintenance trial of pembrolizumab versus placebo following first-line chemotherapy for metastatic urothelial cancer, included 46 patients evaluable for KRT19 in the pembrolizumab arm with median follow-up of 12.9 months. Serum KRT19 levels were quantified using Olink proteomics technology alongside 91 additional proteins. Cox proportional hazards models assessed associations between KRT19 expression and clinical outcomes, with adjustment for multiple comparisons using false discovery rate correction. Results: In the GU16-257 cohort, among 92 peripheral blood analytes tested at baseline (C1D1), KRT19 demonstrated the strongest association with overall survival. Elevated baseline KRT19 was independently associated with inferior overall survival (HR 2.62, adjusted p=0.016) and metastasis-free survival (HR 3.01, adjusted p=0.001). A decrease in KRT19 from C1D1 to C3D1 was associated with improved overall survival (HR 0.59, unadjusted p=0.024) and metastasis-free survival (HR 0.60, unadjusted p=0.041). In GU14-182, elevated baseline KRT19 was associated with inferior overall survival (HR 2.11, adjusted p=0.034) and progression-free survival (HR 1.57, unadjusted p=0.024). Optimal KRT19 cutpoints enabled significant risk stratification for mortality and disease progression in both cohorts. Analysis of an independent peripheral blood single-cell RNA sequencing cohort from patients with urothelial cancer confirmed epithelial cells as the predominant source of circulating KRT19. Conclusions: KRT19 represents a promising, readily measurable serum biomarker with specificity for urothelial cancer. Both baseline levels and on-treatment changes correlate with disease progression and survival. Further validation of KRT19 as a tool to assess disease burden and guide treatment decisions in urothelial cancer is warranted.

737 Background: Many pts with MIBC are not candidates for radical cystectomy (RC) and/or favor bladder-sparing alternatives. Neoadjuvant chemotherapy (NAC) following TURBT leads to a pathologic complete response (pCR) in a subset of pts, suggesting that RC is not universally required to achieve cure. We previously showed that TURBT followed by cisplatin-based NAC plus PD-1 blockade yielded a stringently defined clinical CR (cCR) in 43% of pts and ~2/3 of such pts omitting upfront RC experienced durable bladder-intact survival (Galsky, Nat Med, 2023). However, ~50% of pts with MIBC are ineligible for cisplatin, and neoadjuvant PD-1 blockade monotherapy can produce pCR rates of 30-40%. HCRN GU 20-444 evaluated TURBT followed by P monotherapy with response-guided bladder-sparing for pts with MIBC. Methods: Eligible pts had cT2-3N0M0 urothelial cancer and were cisplatin-declining or -ineligible. Following maximal TURBT, pts received 2 cycles of P (q6 week dosing) followed by clinical restaging with MRI/CT, urine cytology, and cystoscopy with biopsies. Pts with a cCR omitted definitive local therapy and received up to 7 additional cycles of P. Pts without a cCR received definitive local therapy (RC or chemoradiation). ctDNA was serially evaluated through WGS of tumor and plasma coupled with artificial intelligence-based pattern recognition for ultrasensitive detection of residual disease (TrueMRD, Veracyte). The primary endpoint was cCR rate. Key secondary and exploratory endpoints included 2-year MFS, OS, and ctDNA status. Results: From 7/2022 to 12/2024, 46 pts were enrolled; the median age was 74 (24% were ≥80). cCR was achieved in 43% (95% CI 29%-59%) of pts. Median follow-up was 11 months (range 2.4-33.5). Among pts achieving a cCR, all proceeded without upfront RC, none developed metastatic disease; 1/20 had a delayed cystoprostatectomy due to a new prostate cancer (bladder cancer pT0N0); 2/20 died due to non-cancer causes. Adverse events were consistent with the toxicity profile of P. Cycle 1 (C1) ctDNA was undetectable in 90% and 55% of pts with and without a cCR, respectively (Mann-Whitney P = 0.01). Undetectable C1 ctDNA was associated with improved MFS (HR 11.2, 95% CI 2.2-57, log-rank P = 0.0003) and OS (HR 11.4, 95% CI 1.3-103, P = 0.007). C2 ctDNA was undetectable in 100% pts with a cCR. Among pts without a cCR, undetectable C2 ctDNA was associated with improved MFS (HR 14.8, 95% CI 1.4-2000, P = 0.02). Conclusions: TURBT plus P monotherapy yields promising bladder-intact metastasis-free survival in pts achieving a stringently defined cCR. Pts with C1 or C2 undetectable ctDNA have an extremely low risk of metastatic recurrence, even when omitting RC. ctDNA status after only 6 weeks of P distinguishes outcomes in pts without a cCR. These findings highlight the potential of cCR status coupled with ctDNA to redefine response-guided individualized treatment pathways in MIBC. Clinical trial information: NCT05406713 .

To compare perioperative and survival outcomes of patients undergoing robotic versus open post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testicular cancer. Analyzing data from patients who underwent PC-RPLND at eleven academic centres between 1990 and 2023, we used propensity score matching (PSM) to create a 1:1 (open-RPLND: robotic-RPLND) matched cohort. The primary endpoint was time to relapse. Secondary endpoints included operative time, length of stay, estimated blood loss, and surgical complications. Relapse free survival rates were calculated using the Kaplan-Meier methodology, and Cox proportional hazards model was used to compare perioperative outcomes between robotic vs. open PC-RPLND after adjusting for template and pathology. A total of 134 robotic cases were propensity score matched to 134 open cases. At a median follow-up of 2.2 years, estimated relapse-free survival at 3 years was similar between robotic and open PC-RPLND (92.8

PURPOSE:Serum tumor markers (STMs), including alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG), are currently used in management of patients with germ cell tumors (GCTs). STMs in a substantial proportion of patients are normal or falsely elevated. We evaluated circulating tumor DNA (ctDNA) as a prognostic biomarker in patients with GCTs. PATIENTS AND METHODS:Longitudinal ctDNA testing was performed on a multi-institutional cohort of patients with GCTs using a clinically validated, personalized, tumor-informed 16-plex multiplex PCR-NGS ctDNA assay (Signatera, Natera Inc). ctDNA was evaluated preorchiectomy and during the molecular residual disease (MRD; 1-12 weeks postorchiectomy) and surveillance windows (>12 weeks postorchiectomy, after retroperitoneal lymph node dissection [RPLND], or postchemotherapy). The correlation between ctDNA status and event-free survival (EFS) was assessed. RESULTS:ctDNA testing was performed for 74 patients (324 plasma samples) with clinical stages I to III GCTs. The median age was 34 years (IQR, 27-39), and the median follow-up was 17 months (IQR, 12-25). Disease management postorchiectomy included surveillance in 23% (17/74), RPLND in 7% (5/74), chemotherapy in 41% (30/74), and chemotherapy + RPLND in 29% (22/74) of patients. Preorchiectomy ctDNA was detectable in 14 of 15 patients. During the MRD (N = 42) and surveillance (N = 51) windows, patients who were ctDNA-positive versus ctDNA-negative showed a significantly inferior EFS during MRD (hazard ratio [HR], 5.11 [95% CI, 1.31 to 19.95]; P = .019) and surveillance windows (HR, 12.45 [95% CI, 4.32 to 35.85]; P < .0001). By contrast, elevated versus normal STM was not associated significantly with worse EFS (MRD: HR, 2.97 [95% CI, 0.68 to 13.05]; P = .149. surveillance: HR, 1.74 [95% CI, 0.75 to 4.02]; P = .194). CONCLUSION:Tumor-informed ctDNA analysis shows promise for MRD detection in patients with GCTs. With further study, ctDNA monitoring may be useful in clinical decision making. Larger prospective trials are planned to establish clinical utility.

4573 Background: Enfortumab vedotin plus pembrolizumab (EV+P) is standard first-line treatment for metastatic urothelial cancer (mUC), yet responses vary considerably. Identifying resistance mechanisms may guide patient selection and inform novel therapeutic strategies. Single-cell RNA sequencing (RNA-Seq) across tumor types has revealed dichotomous tumor-associated macrophage (TAM) populations: SPP1+ TAMs exhibit tumor-promoting programs while CXCL9+ TAMs express programs associated with anti-tumor immunity. The CXCL9:SPP1 gene expression ratio (CS ratio) from bulk RNA-Seq captures this balance and correlates with outcomes across solid tumors (Bill et al, Science, 2023). We explored the CS ratio's association with outcomes in mUC patients receiving pembrolizumab monotherapy or EV+P. Methods: We retrospectively analyzed mUC patients who underwent molecular profiling at Caris Life Sciences using NGS (592-gene panel, DNA WES, or RNA WTS). CS ratios were calculated and patients stratified into quartiles (Q1–Q4; Q4=highest ratio). PD-L1 expression was assessed by IHC (22c3, positive (+) CPS ≥ 10%) while TMB-High was defined as ≥ 10 Mut/Mb. TME composition was inferred using quanTIseq. Real-world overall survival (rwOS) was derived from insurance claims and calculated from biopsy to last contact or time on treatment (TOT) using Kaplan-Meier analysis while Hazard ratio (HR) was calculated by Cox proportional hazard method. Mann-Whitney U and χ²/Fisher exact tests were applied with adjustment for multiple comparisons. Results: Among 6,708 mUC patients, 1,299 received pembrolizumab and 561 received EV+P. Lower CS ratios (SPP1+ TAM predominance) were associated with shorter time on treatment and rwOS (Table 1). Low CS ratio was also associated with reduced PD-L1 expression (15.5% vs 66.7%, p < 0.001) and TMB-H prevalence (34.6% vs 52.3%, p = 0.006). Low CS ratio tumors demonstrated reduced immune infiltration except for neutrophil enrichment. Conclusions: Lower CS ratios associate with shorter time on treatment and rwOS with both pembrolizumab and EV+P. To our knowledge, this is the first analysis linking macrophage transcriptional states with EV+P resistance. Further validation of the CS ratio in patients treated with EV + P or P is warranted. CS ratio and associated outcomes with pembrolizumab monotherapy and EV+P. Pembrolizumab Monotherapy EV + P CS Ratio TOT (months) OS (months) TOT (months) OS (months) CS-Q1 2.7 (2.1-3.0) 5.7 (4.4-8.2) 7.6 (6.2-8.8) 17.8 (13.8-19.8) CS-Q2 3.1 (2.2-4.1) 7.2 (5.4-8.8) 6.9 (6.0-8.0) 16.4 (13.2-19.4) CS-Q3 4.5 (3.9-5.6) 13.5 (10.7-16.8) 9.2 (8.1-10.8) 17.2 (14.4-20.3) CS-Q4 6.9 (4.9-8.7) 18.7 (13.1-23.7) 10.6 (9.3-12.2) 21.8 (16.5-28.1) CS-Q4 vs. CS-Q1 HR 0.56, 95% CI 0.47-0.67,p < 0.001 HR 0.53, 95% CI 0.44-0.64,p < 0.001 HR 0.69, 95% CI 0.54-0.87, p = 0.00189 HR 0.62, 95% CI 0.46-0.83, p = 0.00148

We previously reported initial results from a clinical trial testing a strategy in which patients with muscle-invasive bladder cancer (MIBC) achieving a clinical complete response after cystoscopic resection of the bladder tumor plus systemic therapy could forgo removal of their entire bladder (cystectomy). While the results were highly promising, a subset of patients omitting initial cystectomy developed recurrence highlighting the need for biomarkers to refine selection of patients for this approach. We here report long-term follow-up of these patients and investigate whether tumor DNA in the plasma (ctDNA) or urine (utDNA) could inform prognosis and the need for cystectomy. Three-year bladder-intact survival among patients with a complete clinical response following four rounds of systemic therapy was 69%. Metastatic risk was significantly higher for patients with detectable versus undetectable ctDNA presystemic therapy (HR 4.68; 95% CI 1.10-43.35; log-rank P = 0.036). Only 4.5% (1 of 22) of patients with undetectable baseline ctDNA developed metastatic disease. Undetectable ctDNA before or after systemic therapy was associated with extremely low metastatic risk. Urine utDNA was more sensitive than plasma ctDNA at detecting residual disease within the bladder, and detectable urine utDNA in patients with a complete clinical response was associated with shorter bladder-intact survival (HR 6.47, 95% CI 1.34-31.31; log-rank P = 0.008). These findings establish the conceptual and experimental foundation for incorporating ctDNA and utDNA assays into the management of patients with MIBC, particularly with respect to the need for cystectomy.

Introduction Prostate cancer is one of the most commonly diagnosed cancers in the United States. Limited evidence exists for environmental pollutants that may increase risks of prostate cancer, which restricts primary prevention strategies. Private water wells can be a source of environmental contaminant exposure, as they are less regulated compared to public water systems. Contaminants such as heavy metals, pesticides, and microbial pathogens can leach into groundwater, posing potential health risks to individuals relying on private wells. Environmental exposure may be an important factor in understanding cancer risk and the need for future research to understand how certain contaminants might influence cancer severity. We aimed to study whether higher private well water density was associated with higher tumor grade in a national sample of elderly men, predicting that areas with higher private well water exposure will present with higher severity prostate cancer. Methods This study investigates the link between exposure to private well water and prostate cancer severity. We queried the Surveillance, Epidemiology, and End Results Database - Medicare (SEER-M) as our patient population, using a four-class SEER Tumor Grade classification schema as a proxy for prostate cancer severity (Table 1). Men diagnosed with prostate cancer between 2010 and 2017 with complete tumor grade information were included in our analysis. Private well water data was abstracted from U.S. Census and American Community Survey data and private well density (PWD) was used as a proxy for private well water exposure. PWD is defined as the number of private wells per population in each census tract in 2010. SEER-M and PWD data were examined using a multivariable ordinal proportional odds logistic regression model. Results Our cohort included 311,130 men diagnosed with prostate cancer. Median age was 68 years (IQR: 63-73) and median PWD was 4.0 wells per 1,000 people (IQR: 0.0 – 69.6). The distribution of SEER Tumor Grade in our cohort included 15% G1, 42% G2, 42% G3, and 1% G4. The multivariable model, including age, race/ethnicity, marital status, diagnosis year, and socioeconomic status, showed a significant positive association between increased PWD and increased severity of prostate cancer (OR: 1.12; 95% CI: 1.05–1.19). PWD was modeled as a continuous variable, with each unit representing an additional well per the population of the census tract. Older age at diagnosis and certain racial/ethnic groups (Black Non-Hispanic and Asian & Pacific Islander) were associated with higher tumor severity, while being married was associated with lower severity. Men diagnosed with prostate cancer in later years had lower odds of high tumor grade (Table 2). Conclusions Higher Census Tract-level PWD was associated with higher prostate cancer tumor severity. Understanding these factors and the etiologic contaminants can inform and improve targeted prevention and screening strategies for prostate cancer. Future analyses may explore spatiotemporal exposures to private well water or employ data sources with higher resolution, such as data at the census block group or block level and personal exposure measures, not just area-level measures. Additionally, future research should consider exposure to particular environmental contaminants and relevant confounders such as distance to biopsy centers to best understand their relationships with prostate cancer severity. This study demonstrated the need for continued investigation of the link between water-originated environmental exposures and prostate cancer. This is the first study, to our knowledge, using a large, national sample adjusted for demographic and socioeconomic factors to investigate potential associations between private well exposure and prostate cancer severity.

793 Background: Interim results of the randomized phase II trial of neoadjuvant tislelizumab +/- oral APL-1202 (nitroxoline) revealed promising pathological complete response (pCR) rates and met prespecified thresholds for study expansion (ASCO GU 2024). Here, we report the final primary endpoint analysis of this trial. Methods: Patients with cT2-T4aN0M0 urothelial cancer of the bladder based on local assessment, planned for radical cystectomy (RC), and ineligible for or refusing cisplatin-based chemotherapy were eligible. Patients were randomly assigned to APL-1202 plus tislelizumab (A+T) or tislelizumab (T), stratified by PD-L1 expression. Neoadjuvant tislelizumab was administered q3weeks for 3 cycles and APL1202 was administered orally tid. The primary endpoint was centrally assessed (pCR, pT0N0) rate and secondary endpoints included central pathologic response (PaR, < ypT2N0) rate and safety. Results: A total of 103 patients were enrolled; 28 patients declined RC after neoadjuvant treatment (A+T=16, T=12). Consequently, 75 patients remained in the efficacy analysis set (EAS); RC was completed after A+T in 42/43 patients and after T in 31/32 patients. The pCR and PaR results in the EAS are presented in the table. On retrospective central pathology review of baseline TURBT specimens, a large subset of patients were determined to be ineligible due to

ObjectiveTo assess 30‐ and 90‐day postoperative complication rates in patients who underwent robot‐assisted radical cystectomy (RARC) after receiving novel immunotherapy‐based neoadjuvant treatment.MethodsA bi‐centre analysis was conducted in patients who underwent RARC with intracorporeal urinary diversion and who received an immunotherapy‐based neoadjuvant regimen between 2017 and 2023. Complications were classified using the Clavien–Dindo system.ResultsThe cohort included 136 patients, with a median (interquartile range [IQR]) age of 66 (61–73) years, of whom 22 were female (16.2%). The overall 30‐day and 31–90‐day Clavien–Dindo grade ≥3a complication rates were 15.4%, and 14.7%, respectively. The most common cumulative 90‐day complications by category were infectious (59.6%), genitourinary (33.1%), and gastrointestinal (22.7%). The median (IQR) hospital stay was 11 (7–16) days, and 36 patients (26.5%) required readmission. Eighty‐four patients received monotherapy with an immune checkpoint inhibitor and 52 received combination immunochemotherapy. A higher rate of 30‐day infectious complications was seen in the immuno‐monotherapy group (46.4% vs 26.9%; P = 0.03), while pulmonary complications were more commonly reported in the combination immunochemotherapy group (9.6% vs 1.2%; P = 0.03). No statistically significant differences were found in the other complication categories between the groups. Eleven patients (8.1%) experienced 13 (9.6%) immune‐related adverse events (irAEs). The most common irAEs were hypothyroidism and dermatitis.ConclusionsThe cumulative 90‐day complication rate after novel immunotherapy‐based neoadjuvant treatment appears higher than those previously reported for RARC alone or for chemotherapy‐based neoadjuvant regimens. We observed irAEs in 8.1% of patients after RARC, highlighting the need for urologists to recognise such events.

Background and objective: Sequential intravesical gemcitabine/docetaxel (Gem/Doce) has emerged as a potential alternative to bacillus Calmette-Guerin (BCG) for the treatment of non-muscle-invasive bladder cancer (NMIBC). Our aim was to determine the comparative effectiveness of BCG and Gem/Doce for patients with intermediate-risk (IR) NMIBC, composed mainly of high-grade (HG) Ta disease. Methods: Patients with IR-NMIBC who received either BCG or Gem/Doce during 2013-2023 were included. Maintenance BCG (as per the Southwest Oncology Group protocol) and monthly Gem/Doce maintenance for 1 yr were offered to patients with no evidence of recurrence after induction. Routine surveillance with cystoscopy was performed according to the American Urological Association guidelines. The Kaplan-Meier method was used to assess high-grade and any-grade recurrence-free survival (RFS). Cox regression analysis was performed to find predictors of recurrence. Key findings and limitations: Of 483 patients, 127 had IR-NMIBC; 66 patients received BCG and 61 received Gem/Doce. Median age was 69 yr (interquartile range [IQR] 61-76) for the BCG group and 72 yr (IQR 62-76) for the Gem/Doce group. Median follow-up was 53.1 mo (IQR 25.3-71.2) for the BCG group and 20.2 mo (IQR 8.28-33.1) for the Gem/Doce group. The 2-yr high-grade RFS rates for primary high-grade tumors for BCG versus Gem/Doce groups were 81% versus 61%, with corresponding any-grade RFS rates of 60% versus 41%. Induction with Gem/Doce predicted any-grade recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.1-3.2) and high-grade recurrence for primary high-grade tumors (HR 3.4 95% CI 1.27-9.13), while receipt of maintenance therapy decreased the risk of any-grade recurrence (HR 0.4, 95% CI 0.22-0.72). This study is limited by its retrospective design. Conclusions and clinical implications: For patients with IR-NMIBC, BCG was associated with superior any-grade RFS and high-grade RFS for primary high-grade tumors. Maintenance therapy was associated with better RFS when receiving Gem/Doce. Standardization and longer maintenance therapy protocols should be considered for Gem/Doce treatment. Patient summary: We compared outcomes for patients who received two different in-bladder treatments for intermediate-risk bladder cancer. Bacillus Calmette-Guerin (BCG) led to better outcomes than gemcitabine + docetaxel (Gem/Doce). Monthly maintenance therapy improved recurrence-free survival for patients who received Gem/Doce. We conclude that maintenance therapy is essential for patients receiving Gem/Doce to avoid bladder cancer recurrence after treatment. (c) 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.