Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

High serum sodium predicts immunotherapy response in metastatic renal cell and urothelial carcinoma.

OBJECTIVES: The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. METHODS: We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. RESULTS: We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. CONCLUSIONS: Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities.

RC48-Antibody-Drug Conjugate in Metastatic Urothelial Carcinoma: A Multicenter Real-World Study in China.

OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.

A single-arm, multicenter, phase 2 clinical study of recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate (MRG002) in HER2-positive unresectable locally advanced or metastatic urothelial carcinoma.

BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.

Association Between Serum Magnesium Levels and Outcomes of Atezolizumab in Patients With Metastatic Urothelial Carcinoma.

BACKGROUND/AIM: Evidence suggests that serum magnesium levels are associated with outcomes of immune checkpoint inhibitors (ICIs). However, this association remains under-explored in patients with metastatic urothelial carcinoma (UC) treated with ICIs. PATIENTS AND METHODS: This prognostic study used individual participant-level data from 1,281 patients with locally advanced or metastatic UC treated with atezolizumab (N=855) or chemotherapy (N=426) who participated in the IMvigor210 and the IMvigor211 trials. Multivariable Cox proportional hazards regression and Fine-Gray subdistribution hazards regression models were used to examine the association of baseline serum magnesium levels with overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). RESULTS: No evidence of an association was found between baseline serum magnesium levels and PFS or OS in patients treated with atezolizumab [PFS, hazard ratio (HR)=1.03, 95% confidence interval (CI)=0.78-1.35; OS, HR=1.13, 95%CI=0.84-1.51] or chemotherapy (PFS, HR=0.93, 95%CI=0.62-1.40; OS, HR=0.91, 95%CI=0.59-1.40). We also found no evidence of association with irAEs (subdistribution HR=1.29, 95%CI=0.81-2.07) in patients receiving atezolizumab. CONCLUSION: This study found no evidence of an association between baseline serum magnesium levels and treatment outcomes or irAEs in patients with metastatic UC receiving atezolizumab. Contrary to previous research suggesting a role for magnesium in cancer therapy, these results indicate that serum magnesium levels may not serve as a biomarker to predict outcomes in these patients.

Establishment and validation of a nomogram for predicting overall survival of upper-tract urothelial carcinoma with bone metastasis: a population-based study.

BACKGROUND: Bone metastasis (BM) carries a poor prognosis for patients with upper-tract urothelial carcinoma (UTUC). This study aims to identify survival predictors and develop a prognostic nomogram for overall survival (OS) in UTUC patients with BM. METHODS: The Surveillance, Epidemiology, and End Results database was used to select patients with UTUC between 2010 and 2019. The chi-square test was used to assess the baseline differences between the groups. Kaplan-Meier analysis was employed to assess OS. Univariate and multivariate analyses were conducted to identify prognostic factors for nomogram establishment. An independent cohort was used for external validation of the nomogram. The discrimination and calibration of the nomogram were evaluated using concordance index (C-index), area under receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). All statistical analyses were performed using SPSS 23.0 and R software 4.2.2. RESULTS: The mean OS for UTUC patients with BM was 10 months (95% CI: 8.17 to 11.84), with 6-month OS, 1-year OS, and 3-year OS rates of 41%, 21%, and 3%, respectively. Multi-organ metastases (HR = 2.21, 95% CI: 1.66 to 2.95, P < 0.001), surgery (HR = 0.72, 95% CI: 0.56 to 0.91, P = 0.007), and chemotherapy (HR = 0.37, 95% CI: 0.3 to 0.46, P < 0.001) were identified as independent prognostic factors. The C-index was 0.725 for the training cohort and 0.854 for the validation cohort, and all AUC values were > 0.679. The calibration curve and DCA curve showed the accuracy and practicality of the nomogram. CONCLUSIONS: The OS of UTUC patients with BM was poor. Multi-organ metastases was a risk factor for OS, while surgery and chemotherapy were protective factors. Our nomogram was developed and validated to assist clinicians in evaluating the OS of UTUC patients with BM.

Cardiac and Intramuscular Metastases Following Nephroureterectomy for Metachronous Urothelial Carcinoma.

BACKGROUND We present a case of metachronous cardiac and intramuscular metastases in a patient with a known history of radical nephroureterectomy for upper-tract urothelial carcinoma (UTUC). CASE REPORT A 58-year-old man had a history of metachronous renal pelvis urothelial carcinoma with prior left radical nephroureterectomy. He was also diagnosed with malignancy-associated deep vein thrombosis (DVT) and was on rivaroxaban. He presented at an oncology follow-up consult with shortness of breath and right scapular lump. CT scan revealed a soft-tissue mass at the surgical bed suspicious for local recurrence, as well as intracardiac hypodensities and intramuscular nodules in the right latissimus dorsi and right adductor muscles. The intracardiac hypodensities were located in the left atrial appendage and inter-atrial septum. Given that the patient had a history of DVT and in a pro-thrombotic state, differentials for the intracardiac densities included intracardiac thrombi or metastases. The intramuscular hypodensities were rim-enhancing. Given that the patient was on rivaroxaban, differentials included hematomas or metastases. As there was no overlying bruising and the lesions remained unchanged in size clinically, they were treated as metastases. The patient was treated with clexane but re-presented with worsening of shortness of breath and palpitations. CT scan showed increased size of intracardiac lesions, suggesting no response to anticoagulation, and therefore were likely metastatic in nature. He completed a 2-year course of IV pembrolizumab and was in complete remission. CONCLUSIONS Our case highlights the importance of this clinically challenging scenario when patients with known malignancy and on anticoagulation present with cardiac or musculoskeletal symptoms. Though these patients are at risk of thrombus and haematoma, cardiac and intramuscular metastasis should be considered, as the prognosis is guarded.

Management of Oligometastatic and Locally Recurrent Urothelial Carcinoma.

PURPOSE OF REVIEW: To summarize and evaluate the literature on treatment approaches for oligometastatic and locally recurrent urothelial cancer. RECENT FINDINGS: There is no clear definition for oligometastatic urothelial cancers due to limited data. Studies focusing on oligometastatic and locally recurrent urothelial cancer have been primarily retrospective. Treatment options include local therapy with surgery or radiation, and generalized systemic therapy such as chemotherapy or immunotherapy. Oligometastatic and locally recurrent urothelial cancers remain challenging to manage, and treatment requires an interdisciplinary approach. Systemic therapy is nearly always a component of current care in the form of chemotherapy, but the role of immunotherapy has not been explored. Consideration of surgical and radiation options may improve outcomes, and no studies have compared directly between the two localized treatment options. The development of new prognostic and predictive biomarkers may also enhance the treatment landscape in the future.

Derazantinib alone and with atezolizumab in metastatic urothelial carcinoma with activating FGFR aberrations.

BACKGROUND: This Phase 1b/2 study assessed the efficacy in terms of objective response rate (ORR) of the FGFR1/2/3 kinase inhibitor derazantinib as monotherapy or in combination with atezolizumab in patients with metastatic urothelial cancer (mUC) and FGFR1-3 genetic aberrations (FGFR1-3GA). METHODS: This multicenter, open-label study comprised 5 substudies. In Substudies 1 and 5, patients with mUC with FGFR1-3GA received derazantinib monotherapy (300 mg QD in Substudy 1, 200 mg BID in Substudy 5). In Substudy 2, patients with any solid tumor received atezolizumab 1200 mg every 3 weeks plus derazantinib 200 or 300 mg QD. In Substudy 3, patients with mUC harboring FGFR1-3GA received derazantinib 200 mg BID plus atezolizumab 1200 mg every 3 weeks. In Substudy 4, patients with FGFR inhibitor-resistant mUC harboring FGFR1-3GA received derazantinib 300 mg QD monotherapy or derazantinib 300 mg QD plus atezolizumab 1200 mg every 3 weeks. RESULTS: The ORR for Substudies 1 and 5 combined was 4/49 (8.2%, 95% confidence interval = 2.3% to 19.6%), which was based on 4 partial responses. The ORR in Substudy 4 was 1/7 (14.3%, 95% confidence interval = 0.4% to 57.9%; 1 partial response for derazantinib 300 mg monotherapy, zero for derazantinib 300 mg plus atezolizumab 1200 mg). In Substudy 2, derazantinib 300 mg plus atezolizumab 1200 mg was identified as a recommended dose for Phase 2. Only 2 patients entered Substudy 3. CONCLUSIONS: Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC. Clinicaltrials.gov NCT04045613, EudraCT 2019-000359-15.

Genomic Profiling and Molecular Characterisation of Metastatic Urothelial Carcinoma.

The clinical management of metastatic urothelial carcinoma (mUC) is undergoing a major paradigm shift; the integration of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) into the mUC therapeutic strategy has succeeded in improving platinum-based chemotherapy outcomes. Given the expanding therapeutic armamentarium, it is crucial to identify efficacy-predictive biomarkers that can guide an individual patient's therapeutic strategy. We reviewed the literature data on mUC genomic alterations of clinical interest, discussing their prognostic and predictive role. In particular, we explored the role of the fibroblast growth factor receptor (FGFR) family, epidermal growth factor receptor 2 (HER2), mechanistic target of rapamycin (mTOR) axis, DNA repair genes, and microsatellite instability. Currently, based on the available clinical data, FGFR inhibitors and HER2-directed ADCs are effective therapeutic options for later lines of biomarker-driven mUC. However, emerging genomic data highlight the opportunity for earlier use and/or combination with other drugs of both FGFR inhibitors and HER2-directed ADCs and also reveal additional potential drug targets that could change mUC management.

Association between comorbidities and survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

BACKGROUND: This study aims to investigate the relationship between comorbidities and survival in patients with mUC treated with pembrolizumab as a second-line treatment. METHODS: From February 2018 to October 2021, we analyzed the data of 185 consecutive patients with metastatic UC who received pembrolizumab as second-line therapy at The Jikei University Hospital and five affiliated hospitals. We used the Charlson Comorbidity Index (CCI) to assess the comorbidities. The outcomes of interest were progression-free survival (PFS) and overall survival (OS). To compare the survival differences, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and the IPTW-adjusted Cox regression hazards model were used. RESULTS: After IPTW adjustment, patient characteristics were well-balanced between patients with high CCI and those with low CCI. The IPTW-adjusted Kaplan-Meier curves of PFS and OS based on CCI revealed that the patients with high CCI (2 or more) had a shorter PFS (median, 1.6 vs. 2.8 months) and a shorter OS (median, 12.4 vs. 18.8 months) (0-1). Similarly, in the IPTW-adjusted Cox regression hazards model, patients with high CCI had significantly shorter PFS [HR, 1.84 (95% CI 1.26-2.68; p = 0.002)] and OS [HR, 1.98 (95% CI 1.20-3.27; p = 0.008)] than those with lower CCI. CONCLUSIONS: High CCI was associated with a higher risk of disease progression as well as overall mortality in mUC patients treated with second-line pembrolizumab.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).

Treatment Patterns and Survival Outcomes Before and After Access to Immune Checkpoint Inhibitors for Patients With Metastatic Urothelial Carcinoma: A Single-Center Retrospective Study From 2004 to 2021.

INTRODUCTION: Metastatic urothelial carcinoma (mUC) is a lethal disease with limited treatment options. We aimed to compare the treatment patterns and outcomes of patients with mUC who were treated before and after the introduction of immune checkpoint inhibitors (ICIs) at a tertiary hospital in Barcelona. METHODS: Single-center retrospective study from 2004 to 2021. Access to ICIs began in December 2014. We analyzed differences in clinical characteristics and survival outcomes, such as overall survival (OS), progression-free survival (PFS), and restricted mean survival time (RMST). RESULTS: A total of 206 patients were included. The median follow-up was 48.6 months. Ninety and 116 patients were treated during the pre-ICIs and the post-ICIs eras, respectively. We found high treatment attrition rates, with no differences in the number of patients who received second-line (48%) and third-line (26%) therapies between the two eras. In the second-line, ICIs became the predominant therapy (58%), leading to a 30% reduction in the utilisation of platinum-based ChT and non-platinum ChT. Innovative approaches including ICIs in the first-line treatment (18%) and targeted therapies in the third-line setting (34%) were observed. We found no differences in the median OS, 2-year OS, or 24-month RMST between the two periods. CONCLUSION: ICIs have emerged as a transformative treatment option, reshaping the treatment landscape. Nevertheless, substantial attrition rates from first-line to subsequent lines of systemic therapies might impede the potential impact of ICIs on long-term survival outcomes across the entire population.

Prognostic Value of Fibroblast Growth Factor Receptor Genetic Alterations in Metastatic Urothelial Carcinoma.

INTRODUCTION: Evidence is limited on whether fibroblast growth factor receptor gene alterations (FGFRalt) impact clinical outcomes in patients with locally advanced or metastatic urothelial cancer (mUC). This study evaluated progression-free survival (PFS) in patients with mUC based on FGFRalt status in the first-line setting (1L). PATIENTS AND METHODS: Data on mUC patients were retrieved via convenience sampling of oncologists/urologists surveyed between August and September 2020 who treated at least 1 FGFRalt patient between July 2017 and June 2019. The questionnaire included information on patient demographics, FGFR status, treatment, and clinical and radiographic measures of progression. Primary endpoint was time from metastatic diagnosis to disease progression from initial treatment for FGFRalt and FGFRwt (wild-type) mUC. Cox proportional hazards models quantified adjusted risk of FGFR status relating to PFS. RESULTS: A total of 414 patients were analyzed. Mean age was 64.5 years, 73.9% were male, and 52.7% had an FGFRalt. Among FGFRalt, 47.2% received chemotherapy, 27.5% immune checkpoint inhibition (ICI), 11.5% chemotherapy+ICI, and 13.8% other treatments in 1L. FGFR status did not influence PFS from time of mUC diagnosis or among 224 stratified patients receiving either chemotherapy or chemotherapy+ICI. However, among 97 patients with an FGFRalt receiving 1L ICI therapy only, adjusted risk of progression was twice that of FGFRwt (HR: 2.12; 95% CI: 1.13-4.00). CONCLUSION: Although FGFRalt did not predict outcomes in the overall cohort, for patients treated with 1L ICI, FGFRalt had significantly higher rates of progression than FGFRwt patients. Further validation is needed to determine whether FGFRalt has a decreased benefit from ICI therapy.

Metastatic upper tract urothelial carcinoma with nest-like features presenting as malignant pleural effusion.

Metastatic urothelial carcinoma is a rare cause of pleural effusions. We report a case of urothelial carcinoma of the upper urinary tract in an oldest-old male patient, a smoker, with situs inversus totalis, that presented uniquely with malignant pleural effusion at presentation without evidence of a primary tumor on imaging. Cytological smears of the massive left pleural effusion revealed epithelioid neoplastic cells arranged in short cords, small-to-large clusters, and raspberry-like morules, mimicking mesothelioma; cell block preparations highlighted the presence of tubules and nest-like structures. The tumor cells showed a high nuclear-to-cytoplasmic ratio, nuclear grooves, and mitotic figures. Cytomorphologic features coupled with the immunophenotype of neoplastic cells (p63, GATA3, and uroplakin II positive) allowed the diagnosis of metastatic urothelial carcinoma and a possible nested subtype. These findings were supported by a total body computed tomography (CT) showing no evidence of a mass in the bladder or elsewhere in the urinary tract but a concentric parietal thickening of the proximal left ureter, suggesting malignancy. To our knowledge, a malignant effusion as a primary manifestation of urothelial carcinoma with nest-like features originating in the upper urinary tract has never been described previously. Our case focuses on the value of cell block in the working-up of neoplastic effusions by revealing the architectural pattern of an uncommon malignancy and the correlation between cytopathology and imaging gross findings to reach an accurate diagnosis.

Enfortumab vedotin prolongs overall survival in metastatic urothelial carcinoma following pembrolizumab therapy in real-world data.

OBJECTIVE: In December 2021, enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4, was approved in Japan as a new treatment after platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. This study evaluated, using real-world data, the efficacy and safety of EV therapy in patients with metastatic urothelial carcinoma (mUC). MATERIALS AND METHODS: Fifty-five patients with mUC who discontinued pembrolizumab therapy due to disease progression between June 2018 and April 2023 at Yokohama City University Hospital were evaluated retrospectively. Of the 55 patients, 25 received EV therapy (EV group) and 30 did not (non-EV group). All patients who underwent EV therapy were diagnosed with disease progression after the approval of EV in Japan. RESULTS: The median (range) follow-up period after pembrolizumab discontinuation was 6.3 (0.7-31.1) months. There were eight (32.0%) deaths due to cancer in the EV group and 27 (90.0%) in the non-EV group. The overall survival (OS) after pembrolizumab discontinuation was not reached in the EV group versus 2.6 months in the non-EV group (p < 0.001). A multivariate analysis revealed that EV therapy (EV vs. non-EV group; hazard ratio 0.26; 95% confidence interval 0.16-0.41; p < 0.001) was an independent prognostic factor for OS. CONCLUSION: EV prolonged OS in mUC following pembrolizumab therapy in real-world data.

First-line Management of Metastatic Urothelial Cancer: Current and Future Perspectives After the EV-302 and CheckMate-901 Studies.

The standard of care for the first-line management of metastatic urothelial carcinoma has been recently challenged, with the combination of pembrolizumab and enfortumab vedotin (P-EV) strongly arising as a practice-changing option from classical platinum-based chemotherapies. With this paradigm shift on the horizon new questions, including the most suitable second line of treatment for these patients, and the role that the molecular characterization of these tumours will have when selecting these therapies will inevitably arise. Furthermore, after the negative results of the Keynote 361 and IMvigor 130 trials, the combination of nivolumab with platinum-based chemotherapy followed by nivolumab maintenance (Nivo GC-Nivo) has also shown positive results when compared with chemotherapy alone. Translational studies at a molecular, cellular, and functional level will be key to better explain these discordant results. In this Current Perspective, we discuss the potential impact of these results in clinical practice and propose specific guidance for prospective translational research.

Aggressive prostatic adenocarcinoma with urothelial-like morphology, with frequent CK7/CK20/HMWK expression and occasional diffuse neuroendocrine features: A clinicopathologic study of 12 cases.

INTRODUCTION: Prostatic adenocarcinoma can occasionally display urothelial carcinoma morphology, which prompts immunohistochemistry (IHC) studies to determine its lineage. Typically, prostate cancer is characterized by the lack of cytokeratin (CK) 7, CK20 and high molecular weight keratin (HMWK) expression, as opposed to bladder cancer. METHODS: We report a series of 12 prostatic adenocarcinoma cases with unusual urothelial-like morphology, diagnosed at two academic institutions in Toronto between 2018 and 2023, and analyzed by immunohistochemistry for prostatic, urothelial, and neuroendocrine marker expression. We collected patient age, androgen deprivation therapy (ADT) status, tumour site, histomorphology, Grade group (GG) and results of genetic testing. RESULTS: The median age of the 12 patients included in this case series was 75.5 years (range 41-85). A history of prostatic cancer was noted in 7/12 (58%) patients. Five of nine (56%) patients had elevated serum PSA level at diagnosis. Six of eleven (55%) patients had prior ADT. Tumour sites were prostate (n = 6), bladder (n = 3), liver metastases (n = 2), and lung metastasis (n = 1). GGs of the primary tumours were GG3 (n = 1) and GG5 (n = 8). The observed urothelial-like morphology was diffuse in ten cases, and focal in two cases. CK7 was strong/diffuse in 8/11 tested cases, and focal weak in one case. CK20, HMWK, p63 and GATA3 were patchy/focal/weak/moderate in 3/6, 4/7, 4/8 and 2/9 cases, respectively. Ten (83%) cases were positive for at least one prostatic marker; eight (67%) cases had loss/weak staining of at least one prostatic marker. AR loss was seen in 2/7 (29%) cases. Seven of ten (70%) cases had diffuse/strong expression of at least one neuroendocrine marker. No trend was evident between prior ADT/AR status and any IHC result. Molecular analyses for DNA damage repair (DDR) genes (n = 6) demonstrated one ATM deletion (bladder). In addition, one TMPRSS2:ERG fusion (lung metastasis) was identified. CONCLUSION: This series comprises high-grade and/or metastatic prostatic adenocarcinoma cases with distinctive urothelial-like morphology and frequent aberrant CK7/CK20/HMWK expression. Their histomorphology, highly suggestive of an urothelial origin, represents a diagnostic pitfall that can lead to considerable management repercussions. The fact that a high proportion of the reported cases had loss/weak expression of at least one of the tested prostatic-specific markers, and occasionally a diffuse positivity for neuroendocrine markers highlights the importance of (1) clinical history and (2) utilization of broad IHC panels to correctly diagnose such unusual prostate cancer cases.