BACKGROUND AND OBJECTIVE:Trimodality therapy (TMT) is an accepted bladder-preserving option for selected patients with muscle-invasive bladder cancer (MIBC). Pembrolizumab has demonstrated activity in MIBC and may enhance the effects of chemotherapy and radiation. We evaluated the safety and efficacy of adding pembrolizumab to TMT. METHODS:In this multicenter phase 2 trial, patients with MIBC received one dose of pembrolizumab followed by maximal transurethral resection, then definitive bladder radiation with concurrent low-dose gemcitabine and pembrolizumab every 3 wk for three doses. The primary end point was 2-yr bladder-intact disease-free survival (BIDFS). Secondary end points included safety, metastasis-free survival (MFS), and overall survival (OS). KEY FINDINGS AND LIMITATIONS:Fifty-four patients were enrolled, including 48 in the efficacy cohort; 67% had clinical stage T2 disease. The 2-yr BIDFS was 60% (95% confidence interval [CI], 45-73). Two-yr MFS and OS were 81% (95% CI, 66-92) and 83% (95% CI, 69-91), respectively. Grade ≥3 treatment-related adverse events occurred in 25% of patients. Limitations include the single-arm design and modest sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS:Pembrolizumab combined with gemcitabine-based chemoradiation was feasible and showed efficacy comparable to standard TMT. Ongoing phase 3 trials will further define its role in bladder preservation.

PURPOSE:We report the duration of response to UGN-102 treatment in patients with recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG-IR-NMIBC) 24 months after achieving complete response (CR). MATERIALS AND METHODS:ENVISION is an ongoing, multinational, single-arm, phase 3 study in patients with biopsy-proven recurrent LG-IR-NMIBC. Patients received 6 once-weekly intravesical instillations of UGN-102. Patients underwent cystoscopy, urine cytology testing, and for-cause biopsy to determine bladder cancer presence at 3 months. Duration of response (from CR at 3 months to disease recurrence, progression, or death from any cause) at 24 months was estimated using the Kaplan-Meier method. RESULTS:A total of 240 patients were enrolled and received ≥ 1 dose of UGN-102. Most patients were White (98%), male (61%), and aged ≥ 65 years (68%). At 3 months, 191 patients (80%; 95% CI: 74-85) achieved CR. Among these responders, the probability of remaining event-free 24 months after CR was 72% (95% CI: 64-79; Kaplan-Meier estimate). Among patients with CR at 3 months (n = 191), 36 developed low-grade disease recurrence. A treatment-emergent adverse event that occurred in ≥ 10% of enrolled patients (N = 240) was dysuria. CONCLUSIONS:Patients who achieved CR after UGN-102 treatment had a high probability of remaining event-free 24 months later. These data indicate that UGN-102 is a novel, nonsurgical treatment that provides a durable CR for patients with recurrent LG-IR-NMIBC. Study limitations included the single-arm design and the limited racial diversity of the patients. TRIAL REGISTRATION:ClinicalTrials.gov: NCT05243550.

Increased heterogeneity in outcomes has been observed postnephrectomy in patients with renal cell carcinoma (RCC), with standard clinical parameters being primarily used for risk assessment. Currently, no blood-based biomarkers are available for molecular residual disease (MRD) detection in RCC. Herein, we performed a multicenter, real-world evaluation of the prognostic value of circulating tumor DNA (ctDNA) in resected RCC. This real-world evidence-based multi-institutional study included a cohort of 77 patients with stage I-IV RCC. Longitudinal ctDNA testing was performed on plasma samples (n = 295) using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc, Austin, TX). ctDNA results were analyzed, and association with recurrence-free survival was assessed. The patient cohort included 77 patients with stage I-IV RCC (clear cell: 64, non–clear cell: 13). Patients who tested ctDNA-positive during the MRD window experienced worse prognosis and a higher likelihood of recurrence (hazard ratios, 18; P < .0001) compared with their ctDNA-negative counterparts. Overall, we demonstrate the utility of ctDNA testing for MRD detection. Future prospective studies in RCC would be needed to validate the utility of ctDNA in informing clinical decision making.

Introduction: Estimated glomerular filtration rate (GFR, eGFR) from serum creatinine outlines global kidney function, subject to biases in clinical scenarios from muscle wasting and inflammation (prevalent in kidney cancer) and failure to estimate split renal function (SRF, crucial in operative planning). Measured GFR (mGFR) (or true mGFR [mGFRt] without body surface area normalization) from diethylene-triamine-pentaacetate (99mTc-DTPA) tracer clearance is the gold standard for bilateral kidney function, involving extended clearance times and radioactivity. Imaging-derived total kidney volumes are functional proxies but do not probe tissue quality. Methods: We employed advanced quantitative diffusion-weighted (DW) magnetic resonance (MR) imaging (MRI) at 3.0 T in addition to kidney volume measurements in a cohort of 27 patients with renal mass (26 and 18 underwent eGFR and mGFR tests, respectively). Cardiac-gated diffusion tensor imaging (DTI) and intravoxel incoherent motion (IVIM) parameters were derived. Individual MR metrics were evaluated for correlation with eGFR and mGFR with Pearson correlations and mixed-model analysis, respectively; LASSO-penalized multivariable regression was employed for mGFR prediction. The metrics were compared between proteinuria groups using 2-sample t tests. Results: Kidney volume correlated with renal function (split volume vs. split mGFR r = 0.54; split volume vs. split mGFRt r = 0.69). MR metrics correlated with individual kidney mGFR and mGFRt (r = 0.76 and 0.81, respectively). Mixed-effects LASSO multiple regression analysis predicted mGFR and mGFRt (R2 = 0.880 and 0.700, respectively). In addition, MR metrics differentiated proteinuria status. Discussion: Advanced DW MRI metrics may provide surrogates of mGFR and proteinuria. Parameters from bipolar encoding in diastole (emphasizing tubular flow) and flow compensation in systole (emphasizing vascular flow) were often informative.

Background Estimated glomerular filtration rate (eGFR) from serum creatinine outlines global kidney function, subject to biases in clinical scenarios from muscle wasting and inflammation (prevalent in kidney cancer) and failure to estimate split renal function (crucial in operative planning). Measured GFR (mGFR) (or true mGFRt without body surface area normalization) from 99mTc-DTPA tracer clearance is the gold standard for bilateral kidney function, involving extended clearance times and radioactivity. Imaging-derived total kidney volumes are functional proxies, but do not probe tissue quality. Methods We employed advanced quantitative diffusion-weighted MRI at 3.0 T in addition to kidney volume measurements in a cohort of 27 renal mass patients (26 and 18 underwent eGFR and mGFR tests, respectively). Cardiac-gated diffusion tensor imaging and intravoxel incoherent motion parameters, were derived. Individual MR metrics were evaluated for correlation with eGFR and mGFR with Pearson correlations and mixed-model analysis, respectively; LASSO-penalized multivariable regression was employed for mGFR prediction. Metrics were compared between proteinuria groups with two-sample t-tests. Results Kidney volume correlated with renal function (split volume vs. split mGFR r = 0.54; split volume vs. split mGFRt r = 0.69). MR metrics correlated with individual kidney mGFR and mGFRt (r=0.76 and 0.81, respectively). Mixed-effects LASSO multiple regression analysis predicted mGFR and mGFRt (R2 = 0.880 and 0.700, respectively). MR metrics also differentiated proteinuria status. Discussion Advanced diffusion-weighted MRI metrics may provide surrogates of mGFR and proteinuria. Parameters from bipolar encoding in diastole (emphasizing tubular flow) and flow compensation in systole (emphasizing vascular flow) were often informative.

Introduction Treatment patterns for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk non–muscle-invasive bladder cancer (NMIBC) who are ineligible for or decline radical cystectomy (RC) are inconsistently reported. We retrospectively described demographic, clinical, and treatment characteristics for these patients and assessed their clinical outcomes. Patients and Methods Medical charts of patients with BCG-unresponsive high-risk NMIBC (carcinoma in situ [cohort A] or T1/high-grade Ta [cohort B]) who were ineligible for or declined RC documented between January 1, 2011, and December 31, 2018, at 15 academic centers were reviewed. Primary objectives were to characterize demographic, clinical, and nonsurgical treatment characteristics. Secondary objectives included assessing real-world progression-free survival (rw-PFS) from muscle-invasive/metastatic disease, rw-PFS from worsening grade or stage, real-world complete response rate (rw-CRR) in cohort A, real-world event-free survival (rw-EFS) from high-risk NMIBC in cohort B, and overall survival. Results The study included 129 patients (cohort A, n = 57; cohort B, n = 72). Median age was 72.0 years (interquartile range, 64.0-80.0). Most patients were male (72.1%) and current/former smokers (69.8%). Median follow-up was 32.1 months (interquartile range, 20.7-47.6). BCG rechallenge with or without interferon-α (63.6%) was the most commonly utilized first nonsurgical therapy, followed by intravesical mitomycin C with or without electromotive drug administration or thermochemotherapy (15.5%), and intravesical valrubicin (10.9%); among those who received BCG rechallenge alone, 54.8% later received a non-BCG therapy in ≥2 subsequent treatments. 36-month rate for rw-PFS from muscle-invasive/metastatic disease was 73.5%, 66.8% for rw-PFS from worsening grade/stage, and 82.5% for overall survival. In cohort A, 6-month rw-CRR was 22.2%. In cohort B, 36-month rw-EFS rate from high-risk NMIBC was 50.2%. Conclusion After BCG-unresponsive disease, most patients with high-risk NMIBC received BCG rechallenge with or without other therapies, and >25% experienced disease progression within the first 3 years. Effective bladder-sparing options for BCG-unresponsive NMIBC are needed. Clinical trial registration N/A MicroAbstract We reviewed medical records from 15 international hospitals to understand treatment patterns and outcomes in patients with high-risk non–muscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin who were ineligible for or declined radical cystectomy. We found that bladder-sparing options were historically limited and more effective bladder-sparing options are needed for this patient population.

INTRODUCTION:The OPTIMA II phase 2b study (NCT03558503) treated patients with low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) with UGN-102, a reverse thermal hydrogel containing mitomycin. Efficacy and safety results have been reported for the 12-month parent study; here, we report 5-year follow-up data. PATIENTS AND METHODS:Patients who participated in the OPTIMA II study and achieved a complete response (CR) after 6 weekly doses of UGN-102 were followed for up to 9 months after initial CR. Those with CR at study completion were eligible to enroll in a further long-term follow-up (LTFU) study, during which there were no protocol-specified interventions/treatments, protocol-specified visits, or evaluations. Supervising physicians provided semiannual updates on patients' disease status. Duration of response (DoR) was calculated using the Kaplan-Meier method. RESULTS:Of the 41 patients achieving a CR at 3 months, 25 remained in CR at 12 months and 17 entered LTFU. For the 41 patients achieving a CR at 3 months the median Kaplan-Meier estimate of DoR was 24.2 months (95% confidence interval [CI], 9.72-42.09), with a median follow-up time of 35.8 months (95% CI, 10.78-60.98). For the 17 patients in the LTFU study the median DoR was 42.1 months (95% CI, 24.18-not estimable [NE]), with a median follow-up of 50.40 months (95% CI, 26.97-NE), CONCLUSION: These results demonstrate that treatment with UGN-102 results in clinically meaningful, and highly durable response in patients with LG-IR-NMIBC. UGN-102 may offer a promising non-surgical alternative to transurethral resection of bladder cancer (TURBT) for LG-IR-NMIBC patients.

PURPOSEPartial nephrectomy has been advocated as the preferred surgical approach for small kidney tumors over total nephrectomy. However, partial nephrectomy is associated with increased perioperative risk. Estimating renal function after nephrectomy can facilitate personalized patient counseling, guide surgical approach, and identify patients who could benefit from perioperative interventions. Existing prediction models have several limitations including the lack of external validation or a user-friendly tool or application, and most have used traditional statistical methods.METHODSWe used data from two academic medical institutions and machine learning (ML) methods to develop and externally validate renal function after nephrectomy-machine learning (RFAN-ML), a model to estimate long-term renal function after partial or total nephrectomy. Boruta feature selection was used to select four routinely available clinical features, specifically age, BMI, preoperative renal function, and nephrectomy type. In the training set of 1,932 patients, we compared six ML regression models representing a set of both ensemble and nonensemble ML algorithms and optimized for root mean squared error (RMSE). This model was evaluated in a test set of 1,995 patients, and the best performing model was selected as RFAN-ML.RESULTSWe compared RFAN-ML with existing renal function prediction benchmarks and found that RFAN-ML outperformed or had competitive performance with benchmarks on RMSE (16.6 [95% CI, 15.6 to 17.5]), R2, and mean absolute error.CONCLUSIONWe developed and externally validated RFAN-ML, a ML model to predict renal function after nephrectomy, and have deployed our model online. RFAN-ML has the potential to improve the care and outcomes in patients with kidney tumors by informing personalized patient counseling and guiding surgical planning.

4598 Background: Low-grade, intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) is a recurrent cancer inadequately controlled by the current standard of care: transurethral resection of bladder tumor (TURBT). ENVISION (NCT05243550), is an ongoing prospective, phase 3, multinational, single-arm trial, evaluating UGN-102 in patients with a history of LG-NMIBC requiring TURBT. Primary efficacy and safety results have been published previously, 1 here we report long term efficacy data with 18 months follow-up after complete response (CR) to UGN-102 at 3 months. Methods: Patients received6 weekly intravesical instillations of UGN-102, a reverse thermal hydrogel containing mitomycin (75 mg). 3 months after the first instillation of UGN-102, patients underwent cystoscopy, urine cytology testing, and for-cause biopsy, to determine the presence or absence of bladder cancer. Secondary endpoints included duration of response (DoR), defined as the time from CR at 3 months to the earliest date of disease recurrence, progression, or death from any cause, whichever occurred first. DoR data was calculated for all patients with a minimum follow-up of 18 months after 3-month CR was calculated using Kaplan–Meier (KM) method. Results: 240 patients with recurrent LG-IR-NMIBC were enrolled and received at least one dose of UGN-102; 95% (228) received all 6 doses. Patients were mainly white (98%), male (61%) and aged over 65 years old (68%). CR at 3 months was achieved by 191 patients (79.6%; 95% CI: 73.9–84.5). For these patients, the probability of remaining in response 18-months after CR was 80.6% (95% CI 74.0-85.7; KM estimate). Of those who experienced recurrence post CR, most experienced LG disease (17.3%). Conclusions: In the ENVISION study treatment with UGN-102 in patients with recurrent LG-IR-NMIBC resulted in a high and clinically meaningful CR rate. Patients who achieved an initial CR at 3 months had a high probability of remaining disease-free 18 months later. This data confirms that UGN-102 represents a valuable treatment option for patients with LG-IR-NMIBC. Clinical trial information: NCT05243550 . UGN-102 CR at 3 months (95% CI) 191/240, 79.6% (73.9–84.5) Follow-up time (months) for DoR, Median, months (95% CI)* 18.73 (18.23–20.27) DoR by Kaplan–Meier estimate at 18 months post CR 80.6% (95% CI 74.0–85.7) Patients with events at 18 months post CR 39/191 (20.4%) LG disease 33/191 (17.3%) Progression** 4/191 (2.1%) Death 2/191 (1.0%) *3-month CR patients only, estimated using reverse KM; ** Includes progression to high grade (HG) disease, T1 (Tumor Invades Lamina Propria), and Cis (Carcinoma in situ). Prasad SM et al. J Urol. 2025. 213:205–216.