Hypermethylated TAGMe as a universal-cancer-only methylation marker and its application in diagnosis and recurrence monitoring of urothelial carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is the second most common urological malignancy. Despite numerous molecular markers have been evaluated during the past decades, no urothelial markers for diagnosis and recurrence monitoring have shown consistent clinical utility. METHODS: The methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation. RESULTS: We identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4-94.1%) and specificity of 90.0% (95% CI: 81.9-95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging. CONCLUSION: TAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021.

[Urinary cytology for the detection of urothelial lesions]. / Rôle de la cytologie urinaire dans le dépistage des lésions urothéliales.

Urine cytology is a long-used technique for the detection of high grade neoplastic urothelial lesions. Since 2016, «The Paris System¼ classification has revolutionized this field by introducing a standardized terminology widely adopted by cytopathologists and urologists. In this article, we explain this classification and discuss its impact on the clinical management of patients with urothelial lesions, as well as its role in the secondary prevention of these lesions.

La cytologie urinaire est une technique utilisée depuis longtemps dans la détection des lésions urothéliales tumorales de haut grade. Depuis 2016, la classification «The Paris System¼ a révolutionné ce domaine en introduisant une terminologie standardisée largement adoptée par les cytopathologistes et les urologues. Dans cet article, nous expliquons cette classification et discutons de son impact sur la prise en charge clinique des lésions urothéliales, ainsi que son rôle dans la prévention secondaire de ces lésions.

Enfortumab vedotin and pembrolizumab combination as a relevant game changer in urothelial carcinoma: What is left behind?

The EV-302 study1 marks a pivotal leap in the management of advanced urothelial carcinoma, setting a new benchmark for frontline therapy. Enfortumab vedotin plus pembrolizumab is the first combination therapy that has ever outperformed standard chemotherapy. The degree of benefit and the reported safety profile should make this combination a first-choice option for most patients with advanced-stage urothelial carcinoma.

Quality and Readability of Online Health Information on Common Urologic Cancers: Assessing Barriers to Health Literacy in Urologic Oncology.

INTRODUCTION: A growing number of Americans search online for health information related to urologic oncologic care each year. The American Medical Association recommends that medical information be written at a maximum sixth-grade level in order to be comprehensible by the majority of patients. As such, it is important to assess the quality and readability of online patient education material that patients are being exposed to. METHODS: A Google search was performed using the terms "testicular cancer," "prostate cancer," "kidney cancer," and "bladder cancer," and the top 30 results for each were reviewed. Websites were categorized based on their source. Readability was assessed using the Flesch-Kincaid Grade Level, the Gunning Frequency of Gobbledygook, and the Simple Measure of Gobbledygook indices. Quality was assessed using the DISCERN Quality Index (1-5 scale). RESULTS: A total of 91 websites were included in our analysis. On average, online health information pertaining to urologic cancers is written at a 10th- to 11th-grade reading level, which is significantly higher than that of an average American adult and that recommended by the American Medical Association (P < .01). The overall quality of websites was 3.4 ± 0.7, representing moderate to high quality. There was no significant difference in readability based on cancer type or information source. CONCLUSIONS: Despite being of moderate to high quality, online patient education materials related to common urologic cancers are often written at a grade level that exceeds the reading level of an average American adult. This presents as a barrier to online health literacy and calls into question the utility of these resources.

Ambient air pollution and urological cancer risk: A systematic review and meta-analysis of epidemiological evidence.

Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 µg/m3 increase in PM2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 µg/m3 increase in NO2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM2.5 levels to 5.8 µg/m3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden.

Frontline immune checkpoint inhibitors in patients ≥ 90 years with advanced urothelial cancer: a single center experience.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are approved for advanced urothelial cancer alone and as first-line in combination with enfortumab vedotin. Platinum based chemotherapy which is another frontline choice is often not a treatment option for older patients due to comorbidities that increase with age. Despite ICIs being better tolerated compared to traditional chemotherapy little is known about their efficacy and toxicity in patients ≥ 90 years due to the rarity of this population in clinical trials. Our objective was to analyze the efficacy and toxicity of immune checkpoint inhibitors in patients ≥ 90 years. MATERIALS AND METHODS: We conducted a single center retrospective review of patients ≥ 90 years treated between July 2019 and September 2023 with standard of care ICIs for advanced urothelial cancer. RESULTS: Six patients treated with pembrolizumab were identified. Four (66.7%) were male and mean age was 93.5 years at the time of treatment initiation. Response rate was 66.7% (4 patients) with 3 complete responses, which were durable off therapy. Median follow up was 18.2 months. Median progression free survival (PFS) was 10.2 months [95%confidence interval (95%CI): 1.77, not reached (NR)] and median overall survival (OS) was 18.2 months (95%CI: 12.1, NR). Side effects presented in 4 (66.7%) patients and included hypothyroidism, diarrhea, anemia, thrombocytopenia, rash, and bullous dermatitis. One patient developed grade 3 anemia and no patients experienced grade 4 events or required hospitalization due to treatment side effects. CONCLUSIONS: Our experience in a small cohort of patients ≥ 90 years indicate that ICIs are well tolerated and effective for the treatment of advanced urothelial carcinoma in this patient population.

Adoption of robot-assisted radical nephroureterectomy permits a minimally invasive option for management of upper tract urothelial carcinoma in geriatric patients: comparison with non-geriatric patients with intermediate-term oncologic follow-up.

To assess the oncologic efficacy and safety of robot-assisted approach to radical nephroureterectomy (RARNU) in geriatric versus younger patients with upper tract urothelial carcinoma (UTUC). A single-center, retrospective cohort study was conducted from 2009 to 2022 of 145 patients (two cohorts: < 75 and ≥ 75 years old) with non-metastatic UTUC who underwent RARNU. Primary endpoint was UTUC-related recurrence of disease during surveillance (bladder-specific and metastatic). Safety was assessed according to 30-day, modified Clavien-Dindo (CD) classifications (Major: C.D. III-V). Survival estimates were performed using Kaplan-Meier method. There were 89 patients < 75 years (median 65 years) and 56 patients ≥ 75 years (median 81 years). Comparing the young versus geriatric cohorts: median follow-up 38 vs 24 months (p = 0.03, respectively) with similar 3-year bladder-specific recurrence survival (60% vs 67%, HR 0.70, 95% CI [0.35, 1.40], p = 0.31) and metastasis-free survival (79% vs 70%, HR 0.71, 95% CI [0.30, 1.70], p = 0.44). Expectedly, the younger cohort had a significant deviation in overall survival compared to the geriatric cohort at 1-year (89% vs 76%) and 3-years (72% vs 41%; HR 3.29, 95% CI [1.88, 5.78], p < 0.01). The 30-day major (1% vs 0) and minor complications (8% vs 14%, p = 0.87). Limitations include retrospective study design of a high-volume, single-surgeon experience. Compared to younger patients with UTUC, geriatric patients undergoing RARNU have similar oncologic outcomes at intermediate-term follow-up with no increased risk of 30-day perioperative complications. Thus, age alone should not be used to disqualify patients from definitive surgical management of UTUC with RARNU.

Optimal Number of Cycles of First-line Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma.

BACKGROUND/AIM: In recent years, switch maintenance after platinum-based chemotherapy has been a standard of care. However, the appropriate number of systemic chemotherapy cycles against advanced-stage urothelial carcinoma (UC) remains unclear. This study assessed the survival outcomes of first-line platinum-based chemotherapy according to treatment cycles in patients with metastatic disease. PATIENTS AND METHODS: We retrospectively evaluated patients with metastatic bladder and upper urinary tract cancer who received platinum-based combination therapy. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test. RESULTS: Of 179 patients, 47 (26.3%) were women, and 73 (40.8%) had upper urinary tract cancer. Furthermore, 47 (26.3%) who were not eligible for cisplatin received carboplatin. The median number of treatment cycles was 3 (range=1-14 cycles). The rates of progressive disease within two cycles, from two to four cycles, and from four to six cycles were 18.4%, 19.2%, and 30.6%, respectively. The median OS of patients with 2, 3, 4, 5-6, and ≥7 treatment cycles were 8.6, 14.3, 21.3, 24.4, and 26.1 months, respectively. The OS did not significantly differ between patients receiving four treatment cycles and those receiving ≥5 treatment cycles. In patients with disease control (complete or partial response or stable disease) receiving ≥4 treatment cycles, there was no significant difference in terms of OS between patients receiving four cycles and those receiving six cycles. CONCLUSION: Four cycles of first-line platinum-based chemotherapy can be effective in patients with metastatic UC.

C-reactive Protein Is a Prognostic Factor for Survival in Metastatic Upper Tract Urothelial Carcinoma Patients Receiving Pembrolizumab.

BACKGROUND/AIM: The number of available treatment options for urothelial carcinoma has increased recently. Upper tract urothelial carcinoma (UTUC) is relatively rare compared with bladder cancer. There are few reports on the efficacy of immune checkpoint inhibitors (ICIs) for metastatic UTUC, and ICIs may occasionally show less efficacy and cause severe side effects. Therefore, it is important to predict the treatment response and change the treatment strategy as appropriate. We investigated the prognostic factors for treatment response in patients with metastatic UTUC treated with pembrolizumab at our hospital. PATIENTS AND METHODS: Patients who received pembrolizumab for UTUC between January 2018 and June 2023 were analyzed. Patients who presented with bladder cancer complications at initial diagnosis were excluded. The primary endpoints assessed were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted using laboratory values obtained before and after pembrolizumab administration. The relationship between cancer and inflammation is important. Therefore, we analyzed this relationship using prognostic factors for urothelial carcinoma as previously reported. Specifically, pretreatment C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and NLR/albumin values were examined. RESULTS: Forty-seven patients were analyzed. The median PFS was 66 days (24-107 days), and the median OS was 164 days (13-314 days). A CRP level <1 before the first cycle was a useful factor in the multivariate analysis for both OS and PFS [OS: p=0.004, hazard ratio (HR)=3.244, 95% confidence interval (CI)=1.464-7.104; PFS: p=0.003, HR=2.998, 95%CI=1.444-6.225]. CONCLUSION: CRP level is a prognostic factor for pembrolizumab treatment response in patients with UTUC.

Implications of c-Myc in the pathogenesis and treatment efficacy of urological cancers.

Urological cancers, including prostate, bladder, and renal cancers, are significant causes of death and negatively impact the quality of life for patients. The development and progression of these cancers are linked to the dysregulation of molecular pathways. c-Myc, recognized as an oncogene, exhibits abnormal levels in various types of tumors, and current evidence supports the therapeutic targeting of c-Myc in cancer treatment. This review aims to elucidate the role of c-Myc in driving the progression of urological cancers. c-Myc functions to enhance tumorigenesis and has been documented to increase growth and metastasis in prostate, bladder, and renal cancers. Furthermore, the dysregulation of c-Myc can result in a diminished response to therapy in these cancers. Non-coding RNAs, ß-catenin, and XIAP are among the regulators of c-Myc in urological cancers. Targeting and suppressing c-Myc therapeutically for the treatment of these cancers has been explored. Additionally, the expression level of c-Myc may serve as a prognostic factor in clinical settings.

Stereotactic body radiation therapy is beneficial for a subgroup of patients with urothelial cancer and solitary metastatic disease: a single institution real-world experience.

BACKGROUND: Standard treatment options for patients with metastatic urothelial cancer (mUC) include systemic platinum-based chemotherapy, immunotherapy, antibody-drug-conjugates, and targeted therapy. Oligometastatic disease (OMD) may be an intermediate state between localized and generalized cancer. The best treatment strategy for OMD and oligoprogressive (OPD) disease is poorly studied in mUC but local stereotactic body radiation therapy (SBRT) could be an option to avoid or delay systemic treatment. The aim of this study was to assess the efficacy and feasibility of SBRT given in a real-world patient population. METHODS: All patients with mUC treated with SBRT at Karolinska University Hospital, Stockholm, Sweden between 2009 and 2022 were included in this study. Baseline clinical characteristics, treatment data, SBRT dosimetry data and treatment outcome were collected retrospectively. The study endpoints were local control rate (LCR), progression-free-survival (PFS), overall survival (OS) and feasibility of SBRT. RESULTS: In total 39 patients were treated with SBRT. The median follow-up was 25.6 months. The LCR was 82%. PFS and OS were 4.1 and 26.2 months, respectively. Treatment was well tolerated; all patients but one (treatment related pain) completed the planned SBRT. Number of metastases irradiated with SBRT was significantly associated with outcome; patients with only one irradiated lesion had more favourable PFS compared to individuals with 2 or more metastases (HR 4.12, 95% CI: 1.81-9.38, p = 0.001). A subgroup of patients (15%) achieved a sustained long-term survival benefit and never required systemic treatments after SBRT. CONCLUSIONS: SBRT was well tolerated and associated with high LCR. A subpopulation of patients with single metastatic lesion achieved long-term OS and never required subsequent systemic treatment after SBRT. Prospective randomized studies are warranted to discover treatment predictive biomarkers and to investigate the role of SBRT in oligometastatic UC.

Cutaneous and Renal Toxicities of Enfortumab Vedotin for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023. RESULTS: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938). CONCLUSION: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function.

Development and deployment of a histopathology-based deep learning algorithm for patient prescreening in a clinical trial.

Accurate identification of genetic alterations in tumors, such as Fibroblast Growth Factor Receptor, is crucial for treating with targeted therapies; however, molecular testing can delay patient care due to the time and tissue required. Successful development, validation, and deployment of an AI-based, biomarker-detection algorithm could reduce screening cost and accelerate patient recruitment. Here, we develop a deep-learning algorithm using >3000 H&E-stained whole slide images from patients with advanced urothelial cancers, optimized for high sensitivity to avoid ruling out trial-eligible patients. The algorithm is validated on a dataset of 350 patients, achieving an area under the curve of 0.75, specificity of 31.8% at 88.7% sensitivity, and projected 28.7% reduction in molecular testing. We successfully deploy the system in a non-interventional study comprising 89 global study clinical sites and demonstrate its potential to prioritize/deprioritize molecular testing resources and provide substantial cost savings in the drug development and clinical settings.

Unmarried Status Effect on Stage at Presentation and Treatment Patterns in Non-Metastatic Upper Tract Urothelial Carcinoma Patients.

BACKGROUND: Unmarried status has been associated with higher proportions of locally advanced stage and lower treatment dose intensification rates in several urological and non-urological malignancies. However, no previous investigators focused on the association between unmarried status and advanced stage (T3-4N0-2) at presentation and lower nephroureterectomy (RNU) and systemic therapy (ST) rates in non-metastatic upper tract urothelial carcinoma (UTUC) patients. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database 2000-2020, all non-metastatic UTUC patients were identified. Multivariable logistic regression models (LRMs) tested for differences in stage at presentation and treatment (RNU and ST) according to marital status (married vs unmarried), in a sex-specific fashion. RESULTS: Of all 8544 non-metastatic UTUC patients, 4748 (56%) were male vs 3190 (44%) were female. Of all 4748 male UTUC patients, 1191 (25%) were unmarried. Of all 3190 female UTUC patients, 1608 (50%) were unmarried. In multivariable LRMs predicting RNU, unmarried status was an independent predictor of lower RNU rates in male (Odds Ratio [OR]: 0.56; P < .001), but not in female (OR: 0.81; P = .1) non-metastatic UTUC patients. In multivariable LRMs predicting ST exposure, unmarried status was an independent predictor of lower ST rates in both male (OR:0.73; P = .03) and female (OR:0.64; P < .001) UTUC patients. In multivariable LRMs predicting locally advanced stage (T3-4N0-2), unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male (OR: 0.95; P = .5) or female (OR: 0.99; P = .9) UTUC patients. CONCLUSIONS: Unmarried male UTUC patients appear at risk of less being able to access RNU, relative to their married counterparts. Moreover, unmarried UTUC patients appear to less benefit from ST, regardless of sex. Conversely, unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male or female UTUC patients.

Effect of Antacids on the Survival of Patients With Metastatic Urothelial Carcinoma Treated With Pembrolizumab.

INTRODUCTION: Concomitant medications can affect the efficacy of immune checkpoint inhibitors. The association between histamine-2 receptor antagonists (H2RAs), major antacids similar to proton pump inhibitors (PPIs), and the efficacy of pembrolizumab for metastatic urothelial carcinoma (mUC) treatment has been poorly evaluated. We evaluated the impact of PPIs and H2RAs on oncological outcomes in mUC patients treated with pembrolizumab. PATIENTS AND METHODS: This retrospective multicenter study included patients with mUC treated with pembrolizumab. Patients prescribed PPIs or H2RAs within 30 days before and after the initial administration were extracted. The overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rates (ORR) were assessed. Kaplan-Meier survival curve analysis and multivariable Cox proportional hazard models were employed to assess the association between PPIs or H2RAs and survival outcomes. RESULTS: Overall, 404 patients were eligible for this study; 121 patients (29.9%) used PPIs, and 34 (8.4%) used H2RAs. Kaplan-Meier analysis showed significantly worse OS, CSS, and PFS in patients using PPIs compared to no PPIs (P = .010, .018, and .012, respectively). In multivariable analyses, the use of PPIs was a significant prognostic factor for worse OS (HR = 1.42, 95% CI 1.08-1.87, P = .011), CSS (HR = 1.45, 95% CI 1.09-1.93, P = .011), and PFS (HR = 1.35, 95% CI 1.05-1.73, P = .020). PPIs were not associated with ORRs. The use of H2RAs was not associated with survival or ORRs. CONCLUSION: PPIs were significantly associated with worse survival of patients with mUC treated with pembrolizumab, and H2RAs could be an alternative during administration. Both the oncological and gastrointestinal implications should be carefully considered when switching these antacids.

Neutrophil-to-Eosinophil Ratio Predicts the Efficacy of Avelumab in Patients With Advanced Urothelial Carcinoma Enrolled in the MALVA Study (Meet-URO 25).

BACKGROUND: Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb ([MALVA] in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25). PATIENTS AND METHODS: Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported. RESULTS: At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (

The role of planetary health in urologic oncology.

INTRODUCTION: Climate change and global warming are an omnipresent topic in our daily lives. Planetary health and oncology represent two critical domains within the broader spectrum of healthcare, each addressing distinct yet interconnected aspects of human well-being. We are encouraged to do our part in saving our planet. This should include the decisions we make in our professional life, especially in uro-oncology, as the healthcare sector significantly contributes to environmental pollution. AREAS COVERED: There are many aspects that can be addressed in the healthcare sector in general, as there are structural problems in terms of energy consumption, water waste, therapeutic techniques, transportation and drug manufacturing, as well as in uro-oncology specific areas. For example, the use of different surgical techniques, forms of anesthesia and the use of disposable or reusable instruments, each has a different impact on our environment. The literature search was carried out using PubMed, a medical database. EXPERT OPINION: We are used to making decisions based on the best outcome for patients without considering the impact that each decision can have on the environment. In the present article, we outline options and choices for a more climate-friendly approach in urologic oncology.

Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma: A Nonrandomized Clinical Trial.

Importance: Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective: To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants: In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions: All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures: The primary end point was objective response rate. Results: The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance: In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration: ClinicalTrials.gov Identifier: NCT03219775.