OBJECTIVE:To examine characteristics associated with bacillus Calmette-Guerin (BCG) receipt and the impact of supply shortages on BCG utilization and potential healthcare disparities, given global supply shortages have strained access since 2012. METHODS:We analyzed 16,958 adults ≥66 years with newly diagnosed high-grade non-muscle invasive bladder cancer from 2002-2017 using SEER-Medicare. We examined the associations of baseline characteristics and 3 supply shortage events (in 2012, 2014, and 2017) with BCG receipt using multivariable regression, interrupted time series (ITS) analysis, and regression discontinuity analyses. RESULTS:BCG receipt increased from 37% in 2002 to 60% in 2017 in eligible patients. Overall, in multivariable analyses, later diagnosis year, higher income and education status, higher T stage, and higher annual surgeon TURBT volume were associated with increased likelihood of BCG receipt, while older age, single/widowed/divorced status, higher Charlson comorbidity index (CCI), and current/former smoking status were associated with lower likelihood. ITS and regression discontinuity analyses showed sustained growth in BCG utilization that was minimally impacted by supply shortages, aside from a significant growth acceleration after the 2014 shortage. Effect modification analyses demonstrated no consistent associations of patient or socioeconomic characteristics with supply shortage events to suggest a differential impact among specific subgroups. CONCLUSION:From 2002 to 2017, BCG utilization for high-risk NMIBC significantly increased from 37% to 60%, with minimal impact from supply shortages. While baseline characteristics influenced BCG receipt, there was no consistent evidence that BCG supply shortages exacerbated existing disparities.

The therapeutic landscape for renal cell carcinoma (RCC) and urinary tract cancer (UTC) has transformed dramatically, creating complexity in treatment selection and sequencing. The 2025 Advanced Urologic Cancer Consensus Conference was convened to establish evidence‐based expert consensus recommendations for optimal management. A multidisciplinary panel of 51 experts participated in a modified Delphi process addressing questions developed through iterative consensus‐building covering RCC and UTC management. Voting occurred before and after the conference, and analyses focused on postmeeting responses. Consensus was defined as ≥75% agreement, with strong consensus as >90%. Strong consensus was found on the use of adjuvant pembrolizumab for higher risk RCC (pathologic T2 [pT2], grade 4; pT3–pT4, any grade; pTXN1; or fully resected metastatic disease) and on neoadjuvant therapy before cystectomy for localized UTC. There was strong consensus on the use of enfortumab vedotin plus pembrolizumab as frontline therapy for metastatic UTC and the use of platinum‐based chemotherapy postprogression in biomarker‐negative UTC. For RCC, there was consensus on the role of single‐agent vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy after progression on frontline immune checkpoint inhibitor/vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy or dual immune checkpoint inhibitor therapy. However, there was a lack of consensus on other critical areas in the management of RCC and UTC. The 2025 Advanced Urologic Cancer Consensus Conference provides evidence‐informed guidance for complex clinical scenarios while identifying critical research priorities. The group recognizes that the lack of consensus across multiple areas highlights the need for improved patient selection and prospective studies enabling optimal combination and sequencing approaches. This iterative annual process will address evolving treatment paradigms to optimize outcomes.

INTRODUCTION:A delay beyond 12 weeks from diagnosis to radical cystectomy (RC) is considered to impart worse oncologic outcomes for patients with muscle-invasive bladder cancer (MIBC); however, no randomized clinical trials have examined this question. We therefore emulated a hypothetical target clinical trial using contemporary data to evaluate the association between time from diagnosis to RC and oncologic outcomes. METHODS:We conducted observational analyses using the National Cancer Database from 2006-2015 to emulate a hypothetical target trial in adults aged 40-79 years with incident cT2-4 N0 M0 urothelial carcinoma of the bladder, treated with RC from 4-18 weeks after diagnosis. We evaluated the association of late RC with pathologic upstaging at RC and overall survival (OS) and conducted exploratory analyses evaluating the association of time to RC with each outcome modeled flexibly. RESULTS:A total of 3747 patients were included, of which 2992 underwent early RC. Median followup was 32.2 months. In adjusted analyses, late RC was not associated with an increased risk of pathologic upstaging compared to early RC. In addition, there was no statistically significant difference in adjusted OS for late and early RC, respectively. Similar findings were observed across categories of cT stage, age, Charlson index, and gender. CONCLUSIONS:In observational analyses designed to emulate a hypothetical target trial of early vs. late RC, the timing of RC was not associated with a statistically significant increase in pathologic upstaging or a difference in OS when performed from 4-18 weeks after diagnosis. These results suggest the need to re-examine the traditional recommendations for timing of RC following diagnosis.

ETS2 expression in prostate cancer (PCa) shows variability, with overexpression and loss reported. ETS2 can be dysregulated through proteasomal degradation, but p53 missense mutants may stabilize ETS2 by preventing this process. TP53 mutations are more frequent in metastatic PCa, and their identification in primary tumors could serve as an early marker for patient stratification. In addition, TMPRSS2-ERG fusion often arises from an intrachromosomal deletion including ETS2 locus. ETS2, p53 and ERG protein expression were assessed by immunohistochemistry in a surgically treated PCa patients’ cohort (N = 199). ETS2 and TMPRRS2-ERG mRNA were evaluated by qPCR in an independent series (N = 80). Relationship between molecular markers, and with clinicopathological characteristics was analyzed. High ETS2 protein expression was observed in 34.7

Purpose: Trimodality therapy (TMT) is a bladder-sparing treatment approach for patients with muscle-invasive bladder cancer (MIBC). Although plasma circulating tumor DNA (ctDNA) is correlated with treatment response and outcomes following cystectomy for MIBC, the association of plasma ctDNA with clinical outcomes in patients treated with TMT is poorly characterized. Experimental Design: Patients with MIBC who received TMT at Dana-Farber/Brigham and Women's Cancer Center or Massachusetts General Hospital were consented to a research protocol and underwent ctDNA evaluation at baseline and at regular intervals following TMT using the commercially available Signatera assay. All patients also underwent routine post-TMT surveillance including cross-sectional imaging and cystoscopic evaluation. The association between ctDNA status and clinical disease status was assessed. Results: Eighty-four patients had at least one ctDNA result. Fifty-nine patients had a ctDNA test performed prior to chemoradiotherapy (CRT), and 19 (32%) had detectable ctDNA. Forty-six patients had paired pre- and post-CRT ctDNA results available: nearly all (29/31, 94%) patients with undetectable ctDNA prior to CRT also had undetectable ctDNA at the first post-CRT assessment, whereas 11 of 15 (73%) patients with detectable ctDNA prior to CRT converted to undetectable ctDNA following CRT. Sixteen (19%) patients developed metastatic disease, and detectable ctDNA following CRT was strongly correlated with metastatic recurrence (P < 0.0001). Conversely, no patients with an isolated muscle-invasive (n = 5) or non-muscle invasive (n = 7) bladder recurrence had a post-TMT test demonstrating detectable ctDNA prior to recurrence. Conclusions: ctDNA detectability is strongly correlated with metastatic but not local disease recurrence in patients with MIBC following TMT.

BACKGROUND:Enfortumab vedotin (EV) has transformed treatment for advanced urothelial carcinoma (aUC), but outcomes vary. Machine learning (ML) with explainable artificial intelligence (XAI) may improve survival prediction. METHODS:Data from 544 aUC patients receiving EV after platinum chemotherapy and immunotherapy (51 centers, 24 countries) were analyzed. Four machine learning (ML) algorithms (Random Survival Forest, XGBoost, Elastic Net-regularized Cox, Support Vector Machine) were trained (80%) and tested (20%) to predict overall survival (OS). SHapley Additive exPlanations (SHAP) analysis (on best performing ML model) provided interpretability. Performance was assessed by C-index and time-dependent area-under-the-curve (AUC). RESULTS:XGBoost (C-index 0.59) and Elastic Net (C-index 0.60) showed best discrimination. XGBoost achieved highest time-dependent AUCs (0.77, 0.87, 0.93 at 1, 2, 3 years). SHAP identified prior immunotherapy (pembrolizumab, atezolizumab/nivolumab), radiotherapy, and upper tract tumors with lower mortality risk; lung, liver, bone, soft tissue metastases increased risk. Eastern Cooperative Oncology Group performance status and metastatic distribution were key predictors. CONCLUSION:ML with XAI identifies clinically plausible survival predictors in EV-treated aUC. XGBoost and Elastic Net offer modest risk stratification, that are hypothesis generating but does not support routine clinical use. Functional status, metastatic pattern, and treatment context are key drivers, providing a foundation for externally validated prognostic tools.

4581 Background: The role of HER2 as a therapeutically actionable target has been validated with the DESTINY-PanTumor02 trial demonstrating meaningful clinical benefit to T-DXd across HER2-expressing bladder malignancies leading to the FDA approval in the immunohistochemical (IHC) 3+ population. We explore the clinical outcome of real-world patients with urothelial carcinoma (UCa) on T-DXd and its correlation with molecular and pathological findings across all the HER-2 IHC scores (e.g., 0 to 3+). Methods: We reviewed the clinical, pathologic, and molecular data of 29 patients with UCa, who received T-DXd between April 2024 and November 2025. Baseline clinical variables included age, sex, ECOG performance status, visceral metastases, line of therapy, and HER2 IHC score (adapted from gastric cancer scoring). Available genomic data included tumor mutational burden (TMB ≥10 mut/Mb), ERBB2 amplification and mutation, DNA damage response (DDR), FGFR alterations, and microsatellite instability (MSI) status. Outcomes of interest included Objective Response Rate (ORR), Disease Control Rate (DCR), and progression-free survival (PFS) and overall survival (OS) which were estimated using Kaplan–Meier methods and compared across groups using the log-rank test. Cox proportional hazards models were used to estimate hazard ratios. Results: Higher HER2 IHC scores were associated with greater clinical activity and higher ORR in IHC 2+ (n=7; 42.9; 95% CI = 9.9–81.6%) tumors and HER2 IHC 3+ (n=20; 55.0; 95% CI =31.5–76.9%). However, no response was seen in HER2 IHC 1+ (n=2). Median duration of response was 15.6 months in HER2 IHC 2+ and 11.6 months in HER2 IHC 3+ (15/30 patients received T-DXd in ≥3 lines). PFS and OS appeared comparable between HER2 2+ and HER2 3+ tumors, with no statistically significant difference by log-rank test (p = 0.67, p = 0.79 respectively). Elevated TMB was observed in 6/12 cases. ERBB2 amplification was detected in 3/10 of cases and ERBB2 mutation in 5/13 of cases. Alterations in DDR related genes and FGFR were identified in patients 2/11 and 1/12 respectively, while MSI-H was not observed in any case. Responses were numerically higher when T-DXd was given in 2 nd line (53.3%, 95% CI 26.6–78.7%) than in further lines (42.9%, 95% CI 17.7–71.1%) and so was DCR 93% (95% CI 68.1–99.8%) in 2 nd line than 71.4% (95% CI 41-91.6%) in further (≥3) lines. Conclusions: T-DXd demonstrated meaningful clinical activity not only in IHC 3+ but in IHC 2+ tumors as well, which is consistent with the results of the DESTINY-PanTumor02 trial. In this limited sample size, there was no statistically significant association between genomic features and patient outcomes. Larger studies are needed to further find predictors across different levels of IHC expression. HER2 IHC Score n Responders (CR/PR) ORR (%) 95% CI 1+ 2 0 0.0 0.0–84.2% 2+ 7 3 42.9 9.9–81.6% 3+ 20 11 55.0 31.5–76.9%

OBJECTIVE:The oncologic benefit of the extent of lymphadenectomy at the time of radical cystectomy (RC) for bladder cancer is uncertain. Although two randomized clinical trials have reported no difference in disease-free or overall survival for extended LND (eLND) compared to standard LND (sLND), real-world data are lacking. We therefore emulated a pragmatic clinical trial using a large, nationwide dataset. METHODS:We used SEER-Medicare to emulate the LEA AUO AB 25/02 clinical trial. We identified adults 66-79 years diagnosed with high-grade T1 or cT2-T4a, Nany, M0 urothelial carcinoma of the bladder from 2000 to 2017 and treated with RC with LND. sLND and eLND were defined as removal of 4-11 and >12 lymph nodes, respectively. A propensity score (PS) was estimated for receipt of eLND. Associations of LND type with cancer-specific (CSS) and overall survival (OS) were evaluated. RESULTS:A total of 1204 patients were included in the study cohort, of whom 794 underwent eLND and 410 underwent sLND. Pre-treatment characteristics were well-balanced after PS adjustment. Compared to sLND, eLND was not associated with a statistically significant difference in 5-year CSS (68% vs 64%; HR 0.83, 95% CI 0.64-1.06; P = .14) or OS (56% vs 55%; HR 0.82; 95% CI 0.68-1.01; P = .06). Results were similar when examining heterogeneity of treatment effects according to T stage, pN stage and age. CONCLUSION:In observational analyses designed to emulate the completed LEA AUO AB 25/02 trial, eLND was not associated with improved CSS or OS compared to sLND among patients undergoing RC.

693 Background: Overall survival (OS) remains the gold-standard endpoint in solid tumors, including metastatic bladder cancer (mBC), but requires extensive follow-up and resources. Real-world endpoints (RWE) such as real-world progression-free survival (rwPFS), time to next therapy (TTNT), time to end of first-line therapy (TTEFL), second-line rwPFS (rwPFS2), and treatment-free survival (TFS) may accelerate evidence generation if validated as OS surrogates. Methods: We analyzed 5,296 patients with mBC from who received first-line chemotherapy (n = 3,831) or single-agent immune checkpoint inhibitors (ICI, n = 1,465) using the Flatiron Health database. Patient-level surrogacy was assessed using Kendall’s tau. For group-level surrogacy, patients were stratified into 20 risk-based sub-cohorts via Cox regression–derived risk scores. The R² from linear regression quantified the association between 12-month OS rates and 3-month event-free rates for rwPFS, TTNT, and TTEFL across sub-cohorts. TFS was evaluated as the restricted mean survival time between TTEFL and TTNT over 12 months. Sensitivity analyses tested alternative timepoints and cohort sizes. Results: Median OS was 14.5 months (18-month OS, 43%) for chemotherapy and 8.9 months (18-month OS, 34%) for ICI. At patient level, rwPFS (τ = 0.67 chemotherapy; 0.71 ICI), TTNT (0.58; 0.78), and rwPFS2 (0.94; 0.96) showed robust correlations with OS, whereas TTEFL was weaker (0.30, 0.59). At group level, 3-month rwPFS (R² = 0.88) and TTNT (0.85) were strongly correlated with 12-month OS in chemotherapy, while in ICI, TTEFL (0.80) and TTNT (0.78) outperformed rwPFS (0.59) at 3 months. Extending rwPFS to 6 months against 18-month OS improved its correlation in ICI (0.70), reflecting delayed immunotherapy benefit. TFS paralleled OS in chemotherapy (R² = 0.85) but was less informative for ICI (0.03). Sensitivity analyses confirmed robustness across varied time horizons and cohort sizes. Conclusions: This study suggests RWEs as potential surrogates for OS in mBC, with optimal endpoints varying by treatment type. For chemotherapy, rwPFS and TTNT serve as reliable proxies. In ICI-treated patients, TTNT and TTEFL provide robust early signals, with rwPFS gaining predictive strength over longer follow-ups. These insights pave the way for faster, more effective evaluations of treatment outcomes in mBC, ultimately enhancing clinical and regulatory decision-making.

4588 Background: APEX (Associating Plasma Epigenomics with eXpression) is a machine-learning framework that infers genome-wide gene expression in cancer from plasma cell-free chromatin Immunoprecipitation sequencing (cfChIP) by integrating signal from multiple histone marks and fragmentomic features, enabling enhanced transcriptional readouts from liquid biopsy without tissue sampling. We investigated whether APEX can noninvasively quantify NECTIN4 expression to predict outcomes with EV, a NECTIN4-targeted antibody-drug conjugate, in metastatic bladder cancer. Methods: Baseline plasma (1 mL) was collected from patients with metastatic bladder cancer within 90 before to 8 days after start of EV monotherapy and profiled by cfChIP-seq, followed by APEX-based tumor gene-expression inference. APEX-inferred NECTIN4 expression was dichotomized into high and low groups by the cohort median and tested for association with objective response (CR/PR vs SD/PD). Progression-free survival (PFS) and overall survival (OS) were analyzed using log-rank test and multivariable Cox regression model, accounting for the presence of bone or liver metastases and cfDNA tumor fraction. APEX performance was then compared against NECTIN4 locus signal from individual histone marks, plasma tumor fraction, and NECTIN4 copy-number status/amplification. Results: In the EV-treated cohort ( n =24), baseline APEX-inferred NECTIN4 expression was significantly higher in responders versus non-responders (p = 0.002) and outperformed NECTIN4 estimates derived from single histone-mark features, tumor fraction, and NECTIN4 copy number. Patients with high plasma-inferred NECTIN4 had an objective response rate of 58%, whereas no responses were observed among those with low inferred NECTIN4 , supporting strong negative predictive value. High baseline APEX-inferred NECTIN4 was also significantly associated with improved progression-free and overall survival (HR = 0.22, 95%CI: 0.08 – 0.65, p = 0.005 and HR = 0.27, 95%CI: 0.10 – 0.75, p = 0.008, respectively), with stronger associations than plasma tumor fraction, NECTIN4 copy number/amplification, or individual histone-mark coverage. In multivariable Cox models, APEX-inferred NECTIN4 remained independently associated with survival. Moreover, responders were enriched for urothelial luminal genes known to associate with NECTIN4 expression and favorable outcomes, while non-responders showed increased activation of epithelial-mesenchymal transition-related genes, known to associated with worse outcomes. Conclusions: A machine learning framework for plasma-based inference of tumor gene expression identifies plasma-based NECTIN4 as a clinically actionable, expression-based biomarker that predicts EV response and survival in metastatic bladder cancer.

LBA639 Background: PPARG is a master regulator of luminal lineage in UC with two-thirds of adv tumors classified as luminal. FX-909 is a first-in-class oral small molecule that potently and selectively inhibits both ligand-mediated and basal PPARG activity, offering a novel approach to targeting key cancer cell-intrinsic biology. Preliminary phase 1A data have demonstrated objective responses with FX-909 monotherapy (Gao, AACR Targets 2025). Here we report updated safety, tolerability, antitumor activity and predictive biomarker discovery to identify pts most likely to benefit from FX-909. Methods: 56 pts enrolled in a phase 1A open-label dose escalation study (30-100 mg PO QD, 28-day cycles), including additional 10 adv UC patients in 30 mg PO and 50 mg PO QD backfill cohorts. Baseline archival tissue (<30 months old) or a fresh biopsy collected for PPARG IHC (SP500 clone) and NGS correlative biomarker analysis. A provisional PPARG TPS cutoff was determined using linear regression modeling leveraging molecular real-world data (RWD) (N=2609 adv UC pts, Tempus xT). Serial blood samples collected for ctDNA analysis. Results: As of Nov 10, 2025, 46 pts with adv UC have been treated across four dose levels; 30 mg (17); 50 mg (16); 70 mg (11); and 100 mg (2). Median age was 71 (range 44-86), 71.7% ECOG PS 1, and 100% had mUC. Median lines of prior therapy was 3 (range, 1-8), including prior EV and anti-PD(L)1 treatment in 69.6%. Concordance between PPARG mRNA and TPS (r = 0.88, p<0.001) supported linear regression modeling, which inferred a provisional TPS cutoff of ≥60% (PPARG high ). Among 40 efficacy-evaluable adv UC pts, 35 had PPARG IHC results. 18/26 PPARG high pts showed tumor regressions, including 5 confirmed and 1 unconfirmed partial response. Decreases in ctDNA VAF occurred in 7/8 PPARG high pts with available results at cycle 2 (3 PR, 3 SD). Additional data demonstrating the relationship between PPARG high status, luminal subtype, and specific genomic alterations (PPARG(CN≥3), RXRA S427F and FGFR3) will be presented. At 30mg and 50mg doses, the most common ≥Gr3 TRAEs were anemia (18.9%), thrombocytopenia (16.2%) and fatigue (10.8%). Other common TEAEs were diarrhea (32.4%), hypertriglyceridemia (27%) and hyperglycemia (24.3%). The 30 mg dose was associated with fewer Gr3 TRAEs (35.3%), longer time to TRAE onset (52 days, range 44, 85), and fewer dose interruptions (29.4%) and dose reductions (11.8%). Conclusions: FX-909, a first-in-mechanism orally bioavailable PPARG inhibitor, demonstrates clinical proof-of-concept for targeting the master regulator of luminal lineage in heavily pretreated adv UC pts and may offer a novel therapeutic strategy for PPARG high adv UC. A randomized phase 1B expansion study is ongoing (NCT05929235). A combination study of FX-909/anti-PD1 is planned for early 2026. Clinical trial information: NCT05929235 .

Overall survival (OS) remains the gold standard end point in neoadjuvant trials for muscle-invasive bladder cancer (MIBC), yet its assessment requires prolonged follow-up. Whether pathological complete response (pCR) at radical cystectomy (RC) can serve as a valid trial-level surrogate remains unclear. To test this hypothesis, we conducted a systematic review and meta-analytic surrogacy analysis (PROSPERO CRD420251050357) of prospective nonrandomized trials and randomized controlled trials (RCTs) evaluating neoadjuvant therapies followed by RC in nonmetastatic MIBC (2003-2026). Eligible trials reported pCR and provided 3- and/or 4-yr OS via Kaplan-Meier curves, enabling survival reconstruction. Analyses followed an intention-to-treat approach. Surrogacy was evaluated using a two-step trial-level framework: (1) association between trial-arm pCR rates and landmark 3- or 4-yr OS using inverse-variance-weighted linear regression and (2) association between treatment effects log(1/Odds ratio (OR)) on pCR and log(hazard ratio [HR]) for OS, with the coefficient of determination (R2) quantifying surrogacy strength. Twelve trials (n = 3119 patients) met the eligibility criteria. In first-step analyses, the association between pCR and 3-yr OS across all trials was weak (R2 = 0.30, 95% confidence interval [CI] = 0-0.70) and improved to moderate after excluding trials at high risk of bias (R2 = 0.50, 95% CI = 0.20-0.80). In second-step analyses across eight RCTs (n = 2622), the association between treatment effects on pCR and OS was poor (R2 = 0.06, 95% CI = 0-0.84) and improved to weak after excluding high-risk trials (R2 = 0.42). Sensitivity analyses restricted to chemotherapy-only or immunotherapy-containing RCTs yielded similarly limited surrogacy performance. To conclude, although pCR remains prognostically informative, it did not meet formal trial-level surrogacy criteria for OS. These findings do not support the use of pCR as a stand-alone surrogate end point for designing or powering registrational neoadjuvant-based MIBC trials.

INTRODUCTION:Trimodality therapy is a bladder-preserving treatment approach for select patients with muscle-invasive bladder cancer (MIBC), and the addition of a concurrent radiosensitizing chemotherapy to bladder radiation improves outcomes. However, a subset of patients is unwilling or unable to receive concurrent chemotherapy with radiation, and the optimal treatment strategy for these patients is unknown. PATIENTS AND METHODS:We performed a single-arm Phase II investigator-initiated trial of radical dose bladder radiation plus concurrent and adjuvant avelumab in patients with MIBC unable to receive concurrent cisplatin-based chemotherapy. The primary endpoint was clinical complete response (cCR) at 3 months following completion of radiation RESULTS: A total of 14 patients were enrolled, and the median age was 83 years (range 79-95 years). All patients completed radiation, and 11 of 14 (79%) completed all 6 planned avelumab infusions. Median follow-up is 21.7 months. The cCR rate was 64%, and the median overall survival was 30.9 months. Three patients experienced a Grade 3 toxicity; no Grade 4 or 5 toxicities were observed. CONCLUSION:In this population of cisplatin-ineligible patients with MIBC, many of whom had advanced age and/or medical comorbidities, the combination of radical dose bladder radiation plus concurrent and adjuvant avelumab appeared to be safe and active.

666 Background: Enfortumab vedotin + pembrolizumab (EV+P) is now the preferred 1L tx for la/mUC, showing superior OS vs platinum-based chemotherapy (PBC) in the pivotal EV-302 trial. EV is associated with distinct adverse events, and clinical factors have been proposed to identify pts who are potentially EV unsuitable (EVU) to minimize serious toxicity. This study analyzed rw txs of pts with frailty or certain comorbidities ineligible for EV-302. Methods: This retrospective cohort study analyzed data from pts diagnosed with la/mUC between Jul 1, 2020, and Aug 31, 2024 using the Flatiron Health Research Database. Based on proposed criteria, pts were divided into 2 hypothetical/mutually exclusive cohorts: EVU and EV suitable (EVS), and within each group, by 1L tx status (treated, untreated) and tx choice. EVU was defined as having ≥1 of these factors: hemoglobin A1c ≥11% or blood glucose > 200 mg/dL in 2 consecutive samples within 1 week; creatinine clearance or glomerular filtration rate ≤20 mL/min; liver impairment grade ≥2; ECOG PS ≥3; neuropathy; corneal or retinal abnormality. EVU prevalence, pt characteristics at index, and tx patterns were summarized with descriptive statistics. Kaplan-Meier method was used to estimate rwOS from index date (treated: 1L tx date; untreated: la/mUC diagnosis date) to death. Cox proportional hazards regression was used to compare rwOS between treated EVU and EVS pts. Results: This study included 3500 pts with la/mUC (median age, 74 years; male, 72%; ECOG PS 0-1, 55%; bladder as primary site, 77%; median follow-up, 7 mos). A total of 748 (28%) of pts were identified as EVU, of whom 24% were untreated. The most common EVU factor was neuropathy (14%). Median rwOS was shorter in EVU vs EVS untreated (2.4 vs 7.0 mos) and treated pts (9.3 vs 17.0 mos) regardless of 1L tx. Immunotherapy monotherapy (IO mono) was the most common agent in EVU (38%). In the treated EVU group, rwOS was not significantly different between EV+P, PBC, or IO mono groups (Table). EVU vs EVS pts had 67% higher risk of death. Conclusions: In this study, 28% of pts with la/mUC in rw practice were EVU, representing a population typically excluded from clinical trials, and 24% were untreated. In pts treated with standard therapies, rwOS was shorter in EVU vs EVS. As tx outcomes did not significantly differ in the EVU group, shared tx decisions that incorporate various factors, including patient goals and preferences, tx tolerance, financial issues and quality of life in the context of advanced disease, has become increasingly important for this vulnerable group. Treated EVU n (%) EVU rwOS, median, mos Adjusted HR (95% CI); P value) Overall 748 (28) 9.3 Ref EVS: 171.67 (1.50-1.87); p<.001 EV+P 90 (12) Not reached Ref PBC 257 (34) 10.9 1.14 (0.70-1.86); p=0.60 IO mono 284 (38) 6.4 1.60 (0.99-2.58); p=0.06 Other tx 117 (16) 8.8 1.57 (0.95-2.59); p=0.08

Peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator of luminal lineage in urothelial carcinoma. FX-909 is a first-in-class oral small-molecule PPARγ inverse agonist. Here we report the first part of FX-909-CLINPRO-1, a phase 1A 3 + 3 dose-escalation study of FX-909, that enrolled 56 patients with advanced solid tumors, including 46 with urothelial carcinoma. The primary end point was safety and tolerability; secondary end points included recommended phase 2 dose determination, pharmacokinetics and preliminary antitumor activity. FX-909 exhibited an acceptable safety and tolerability profile. Grade ≥3 adverse events included anemia (26.8%), thrombocytopenia (21.4%), fatigue (10.7%) and hyperglycemia (7.1%). Doses of 30 mg and 50 mg daily were selected for recommended phase 2 dose optimization. Objective responses were observed in 17.5% of patients with urothelial carcinoma across all dose levels. Exploratory analyses revealed that tumor responses were enriched in patients with high PPARγ expression. FX-909 demonstrated acceptable safety and tolerability with preliminary antitumor activity, supporting further clinical development in urothelial cancer. ClinicalTrials.gov identifier: NCT05929235 .

INTRODUCTION:Although a single randomized trial demonstrated improved survival with adjuvant chemotherapy (AC) for locally advanced (pT2-4 or N+) upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU), this survival benefit was not observed in pT2 or N+ patients, and real-world data are lacking. We therefore emulated the completed POUT trial using a large, nationwide cancer registry. METHODS:We identified patients aged 50-79 years with pT2-4 or pN+, non-metastatic UTUC treated with RNU from 2006-2020 in the National Cancer Database (NCDB). A propensity score for receipt of multiagent AC within three months of RNU was estimated using logistic regression, and the associations of AC with overall survival (OS) were evaluated after reweighting by stabilized inverse probability of treatment weights (sIPW). RESULTS:The study cohort comprised 3206 patients, of whom 802 (25%) received AC. pT stage was £pT2 in 954 (30%) patients, and 167 (5%) patients had pN+ disease. Median followup was 47.0 (interquartile range 24.0-86.0) months. After IPW-reweighting, AC was not associated with improved OS compared to observation, with five-year OS of 60% vs. 58%, respectively (hazard ratio 0.92, 95% confidence interval 0.79-1.08, p=0.30). When examining treatment effects across baseline characteristics, AC was not associated with improved survival for any pT or pN category. CONCLUSIONS:In analyses designed to emulate the POUT trial, we did not observe improved OS with AC in the overall cohort, nor in specific pT or pN categories. These findings suggest the need to examine the real-world comparative effectiveness of AC in locally advanced UTUC in further studies.