Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma.

BACKGROUND: Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment. METHODS: We conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival. RESULTS: A total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively). CONCLUSIONS: Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).

Impact of baseline body composition on prognostic outcomes in urological malignancies treated with immunotherapy: a pooled analysis of 10 retrospective studies.

OBJECTIVE: Numerous epidemiological investigations have explored the impact of body composition on the effectiveness of immune checkpoint inhibitors (ICIs) in urological malignancies (UM) patients, yielding conflicting findings. As a result, our study aims to elucidate the influence of baseline body composition on the long-term prognosis of UM patients treated with ICIs. METHODS: We employed a rigorous systematic search across various databases, including PubMed, Embase, the Cochrane Library, and Google Scholar, to identify studies meeting our inclusion criteria. Our primary endpoints of interest encompassed overall survival (OS) and progression-free survival (PFS). RESULTS: This analysis included a total of 10 articles with a combined patient cohort of 707 individuals. Our findings revealed a noteworthy association between several body composition parameters and unfavorable OS outcomes, including low psoas muscle index (PMI; HR: 3.88, p < 0.001), low skeletal muscle index (SMI; HR: 1.63, p < 0.001), sarcopenia (HR: 1.88, p < 0.001), low visceral adipose index (VAI; HR: 1.38, p = 0.018) and low subcutaneous adipose index (SAI; HR: 1.37, p = 0.018). Furthermore, our analysis demonstrated that low PMI (HR: 2.05, p = 0.006), low SMI (HR: 1.89, p = 0.002), sarcopenia (HR: 1.80, p < 0.001), and low VAI (HR:1.59, p = 0.005) were significantly correlated with inferior PFS. Conversely, SAI did not manifest a pronounced association with PFS in UM patients treated with ICIs. CONCLUSION: Collectively, our study findings underscore a substantial relationship between baseline body composition and reduced clinical efficacy in UM patients undergoing ICI therapy.

Immunotherapy for advanced or metastatic urothelial carcinoma: an abridged Cochrane review.

OBJECTIVES: To assess the effects of immunotherapy compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. METHODS: Based on a published protocol, we performed a systematic search of multiple databases. Two review authors independently performed the literature selection, identified relevant studies, assessed the eligibility of studies for inclusion, and extracted data. We performed statistical analyses using a random-effects model and assessed the quality of the evidence on a per-outcome basis according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included five randomised controlled trials and also identified seven single-arm studies. When used as first-line therapy, immunotherapy probably has little to no effect on the risk of death from any cause compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87-1.07; moderate-certainty evidence). immunotherapy probably has little to no effect on health-related quality of life (mean difference [MD] 4.10, 95% CI 3.83-4.37; moderate). Immunotherapy probably reduces grade 3-5 adverse events (risk ratio [RR] 0.47, 95% CI 0.29-0.75; moderate). In the second-line setting immunotherapy may reduce the risk of death from any cause (HR 0.72, 95% CI 0.63-0.81; low). Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; low). Immunotherapy may reduce grade 3-5 adverse events (RR 0.89, 95% CI 0.81-0.97; low). CONCLUSIONS: Compared to chemotherapy, immunotherapy has little to no effect on the risk of death from any cause in a first-line setting. Nevertheless, it may reduce the risk of death from any cause when used as second-line therapy. The health-related quality of life of participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce grade 3-5 adverse events when used as first- and second-line therapy, respectively.

Pre-first-line chemotherapy risk stratification for overall survival in advanced urothelial carcinoma in sequential therapy era.

PURPOSE: To explore pre-treatment risk factors for overall survival (OS) in advanced urothelial carcinoma (UC) patients treated with first-line (1L) chemotherapy in sequential therapy (ST) era. Additionally, to evaluate the proportion of patients who were not able to undergo subsequent immune checkpoint inhibitor (ICI) therapy according to the subgroups stratified by the risk factors. METHODS: A multicenter retrospective study was conducted. Metastatic or locally advanced UC patients treated between 2017 and 2022 were included. The Kaplan-Meier method with the log-rank test and multivariate Cox regression models were used to address OS. RESULTS: Three hundred and fourteen patients treated with 1L chemotherapy were included in the study and 57 (18.2%) patients were not able to proceed to subsequent ICI therapy. Pre-chemotherapy risk factors for OS in 314 patients were ECOG-PS 1 or more, having no primary site resection, C-reactive protein (CRP) level of 3 mg/dL or more, and non-cisplatin-based regimen. Patients having 3 or 4 risk factors had higher risk for not being able to receive ST (Mann-Whitney U test, P < 0.001). As risk factors for OS in 230 patients who were able to receive ST, having no primary site resection, a neutrophil to lymphocyte ratio of 3 or more, and the presence of liver metastasis were identified. CONCLUSION: We reported the risk factors for OS in advanced UC patients treated with 1L chemotherapy in ST era. Patients with high risk for OS may not be able to proceed to subsequent ICI therapy even in the ST era.

Treatment patterns and clinical outcomes in metastatic urothelial carcinoma: a German retrospective real-world analysis.

Aim: This study assessed real-world treatment in patients with metastatic urothelial carcinoma (mUC) in Germany. Materials & methods: Patients diagnosed with mUC from 2015 to 2019 were identified in two claims databases: AOK PLUS and GWQ. Results: 3226 patients with mUC were analyzed; 1286 (39.9%) received systemic treatment within 12 months of diagnosis (platinum-based chemotherapy: 64.2%). Factors associated with receiving treatment were: younger age, male sex, less comorbidity and recent diagnosis. In AOK PLUS and GWQ populations, unadjusted median overall survival (interquartile range) from diagnosis in treated patients was 13.7 (6.8-32.9) and 13.8 (7.1-41.7) months, and in untreated patients was 3.0 (1.2-10.8) and 3.6 (1.2-18.8) months, respectively. Conclusion: A significant proportion of patients with mUC in Germany receive no systemic treatment.

What is this article about? This article reports the results from a study in Germany between 2015 and 2019 that investigated how advanced bladder cancer that has spread to other organs was treated and how long people lived after diagnosis. The study looked at systemic therapies, which means treatments that affect the entire body.What were the results? Only 40% of people diagnosed with advanced bladder cancer received systemic treatment within the first 12 months. Of those who did receive systemic treatment, the majority received combination therapy that included a chemotherapy drug containing platinum (64%). Systemic treatment was more likely to be given to people who were younger, less sick, male, or more recently diagnosed. After 12 months, 56% of treated people were still alive, compared with 26% of people without treatment. On average, people who received systemic treatment lived for about 14 months, while people without systemic treatment lived for only 3 to 4 months.What do the results of the study mean? Many people with advanced bladder cancer in Germany do not receive systemic treatment. People who receive treatment are likely to live longer than those who do not receive treatment.

Comparing survival in trial- versus routine-care advanced urothelial cancer patients on immune checkpoint blockade.

PURPOSE: Although recent trials involving first-line immune checkpoint inhibitors have expanded treatment options for patients with advanced urothelial carcinoma (aUC) who are ineligible for standard cisplatin-based chemotherapy, there exists limited evidence for whether trial efficacy translates into real-world effectiveness for patients seen in routine care. This retrospective cohort study compares differences in overall survival (OS) between KEYNOTE-052 trial participants and routine-care patients receiving first-line pembrolizumab monotherapy. METHODS: A routine-care patient cohort was constructed from the Flatiron Health database using trial eligibility criteria and was weighted to balance EHR and trial patient characteristics using matching-adjusted indirect comparisons. RESULTS: The routine-care cohort was older, more likely to be female, and more often cisplatin-ineligible due to renal dysfunction. ECOG performance status was comparable between the cohorts. Median OS was 9 months (95% CI 7-16) in the weighted routine-care cohort and 11.3 months (9.7-13.1) in the trial cohort. No significant differences between the Kaplan-Meier OS curves were detected (p = 0.76). Survival probabilities were similar between the weighted routine-care and trial cohorts at 12-, 24-, and 36- months (0.45 vs. 0.47, 0.31 vs. 0.31, 0.26 vs. 0.23, respectively). Notably, routine care patients had modestly lower survival at 3 months compared to trial participants (0.69 vs. 0.83, respectively). CONCLUSION: Our results provide reassurance that cisplatin-ineligible aUC patients receiving first-line immunotherapy in routine care experience similar benefits to those observed in trial patients.

Urological cancer statistics on incidence from 1975 to 2019 and mortality from 1958 to 2022 in Japan.

BACKGROUND: In Japan, comprehensive cancer statistics are collected through cancer registries. However, data on urological cancers are rarely summarized or published in research papers. METHODS: This retrospective study was performed using publicly available statistical data on urological cancers (prostate cancer [PCa], bladder cancer [BCa], and cancers of kidney and urinary tract [except urinary bladder]) in Japan, including a summary of the Ministry's mortality statistics, cancer incidence statistics from the Regional Cancer Registries through 2015, and the National Cancer Registry statistics from 2016. We examined the incidence and mortality rates of urological cancers stratified by age groups. RESULTS: The number of new cases of PCa, BCa, and cancers of kidney and urinary tract (except urinary bladder) in 2019 was 94,748, 23,383, and 30,458, respectively, and the number of deaths in 2022 was 13,439, 9,598, and 9,795, respectively. The incidence and mortality rates of urological cancers have consistently increased. Since 2000, there has been a noteworthy increase in the mortality rate of urological cancers among individuals aged > 85 years. The incidence and mortality rates of BCa and cancers of kidney and urinary tract (except urinary bladder) were significantly higher in males than in females. CONCLUSIONS: Urological cancers in very elderly patients (> 85 years) will become increasingly important in the future.

Gustave Roussy Immune score as a prognostic biomarker in patients with platinum-refractory metastatic urothelial carcinoma treated with pembrolizumab: YUSHIMA study.

BACKGROUND: This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. METHODS: This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. RESULTS: During the median follow-up period of 7.3 months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2 g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42 mg/L was a significant prognostic factor for OS (p = 0.001). CONCLUSION: The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

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.

Real-World Evidence of Tumor and Patient Characteristics and Survival with Avelumab Maintenance after Chemotherapy for Advanced and Metastatic Urothelial Carcinoma.

INTRODUCTION: Despite the prospective randomized controlled JAVELIN Bladder 100 trial, no real-world evidence exists regarding tumor characteristics, adverse events (AEs), and survival of avelumab maintenance (AVM)-treated patients with partial/complete response or stable disease after previous platinum-based chemotherapy for advanced/metastatic urothelial carcinoma (mUC). METHODS: We relied on our institutional database to identify mUC patients who received AVM between January, 2021 and December, 2023. The main outcomes consisted of overall survival (OS) and progression-free survival (PFS) and were computed by Kaplan-Meier estimates. Stratification was performed according to programmed death ligand 1 (PD-L1) status. RESULTS: Overall, 24 AVM patients were identified at a median age of 71 (interquartile range [IQR]: 67-76) years, of which 67% were males. Of these, 63%, 21%, and 17% received AVM therapy for bladder cancer and upper tract urothelial carcinoma or both, respectively. PD-L1 status was positive in 45% of patients. During AVM treatment, AEs were observed in 33% of patients; however, they were limited to ≤2 grade AEs. At a median follow-up of eight (IQR 4-20) months, 71% of patients had progressed under AVM with median PFS of 6.2 months (confidence interval [CI]: 3.2-18.2). Median OS was 13.4 (CI: 6.9 - not reached [NR]) months. One-year OS after AVM was 52%. In PD-L1-positive patients, median PFS and OS were 6.4 (CI: 2.7 - NR) months and 13.4 (CI: 7.7 months - NR), respectively. CONCLUSION: AVM is associated with moderate AE rates. Despite similarities in baseline characteristics compared to trial-selected JAVELIN Bladder 100 mUC patients, AVM resulted in longer/similar PFS but significantly shorter OS in real-world setting.

J-AVENUE: A retrospective, real-world study evaluating patient characteristics and outcomes in patients with advanced urothelial carcinoma treated with avelumab first-line maintenance therapy in Japan.

OBJECTIVES: The JAVELIN Bladder 100 phase 3 trial showed that avelumab first-line maintenance + best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with advanced urothelial carcinoma who were progression-free following first-line platinum-based chemotherapy. We report findings from J-AVENUE (NCT05431777), a real-world study of avelumab first-line maintenance therapy in Japan. METHODS: Medical charts of patients with advanced urothelial carcinoma without disease progression following first-line platinum-based chemotherapy, who received avelumab maintenance between February and November 2021, were reviewed. Patients were followed until June 2022. The primary endpoint was patient characteristics; secondary endpoints included time to treatment failure and progression-free survival. RESULTS: In 79 patients analyzed, median age was 72 years (range, 44-86). Primary tumor site was upper tract in 45.6% and bladder in 54.4%. The most common first-line chemotherapy regimen was cisplatin + gemcitabine (63.3%). Median number of chemotherapy cycles received was four. Best response to chemotherapy was complete response in 10.1%, partial response in 58.2%, and stable disease in 31.6%. Median treatment-free interval before avelumab was 4.9 weeks. With avelumab first-line maintenance therapy, the disease control rate was 58.2%, median time to treatment failure was 4.6 months (95% CI, 3.3-6.4), and median progression-free survival was 6.1 months (95% CI, 3.6-9.7). CONCLUSIONS: Findings from J-AVENUE show the effectiveness of avelumab first-line maintenance in patients with advanced urothelial carcinoma in Japan in clinical practice, with similar progression-free survival to JAVELIN Bladder 100 and previous real-world studies, supporting its use as a standard of care.

Real-world sequential treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in Japan.

OBJECTIVES: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre-enfortumab vedotin era, many patients could not receive third-line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real-world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third-line treatment. METHODS: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort. RESULTS: At the median follow-up of 28.5 months, the median overall survival from first-line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second- and third-line treatment. Notably, 52% had their treatment terminated before the opportunity for third-line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil-to-lymphocyte ratio (≥3), and low body mass index (<21 kg/m2) at the start of first-line treatment were independent risk factors for not proceeding to third-line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three. CONCLUSIONS: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects.

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.

Laparoscopic Versus Open Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis of Propensity-Score Matched Studies.

BACKGROUND: The effectiveness of laparoscopic nephroureterectomy (LNU) vs open nephroureterectomy (ONU) for upper tract urothelial carcinoma (UTUC) is unclear. METHODS: We conducted a meta-analysis of studies based on propensity score-matched cohorts to compare the surgical and oncological outcomes of LNU and ONU in UTUC patients. A literature search was conducted on PubMed, Embase, and Cochrane Library until July 12, 2023. The Newcastle-Ottawa Scale was utilized to assess the quality of eligible studies. Measurements of surgical and oncological outcomes were extracted and pooled including mean difference (MD), risk ratio (RR), hazard ratios (HR), and 95% confidence intervals (CI). RESULTS: Five high-quality retrospective studies were included, totaling 6422 patients; 2080 (32.4%) underwent LNU, and 4342 (67.6%) underwent ONU. With respect to surgical outcomes, patients in the LNU group experienced less estimated blood loss and had shorter hospital stay than those in the ONU group, but there was no significant difference in complication rates and operation time. In regard to oncological outcomes, there were no significant differences between the LNU and ONU groups in 3-year overall survival (OS) and cancer-specific survival (CSS). However, 3-year intravesical recurrence free survival (IVRFS) was worse in the LNU group compared to the ONU group. CONCLUSION: LNU was associated with less estimated blood loss and shorter hospital stays than ONU, but there were no differences in OS and CSS between the surgical modalities. Nonetheless, LNU might result in poorer IVRFS than ONU.

Dose-response relationship between arsenic in drinking water and mortality of urinary cancers in Taiwan.

Ingested arsenic is carcinogenic to the human urinary tract, but uncertainties remain regarding the dose-response relationship. To assess dose-response relationships between arsenic ingestion and urinary cancers, we evaluated the associations between the arsenic level in drinking water and mortality of cancers of the bladder, kidney, and prostate in Taiwan. We utilized the 1971-2000 Taiwan death registry data and calculated the age-standardized mortality rates (ASMRs) using the 1976 world standard population as the reference group. We used the data from a 1974-1976 census survey of wells on the arsenic levels in drinking water conducted by the government to assess exposure levels, which had been divided into three categories: below 0.05 ppm, 0.05-0.35 ppm, and above 0.35 ppm. The data were analyzed using multiple linear regression models and geographical information system. We found no increase in ASMR for all, or any, of the urinary cancers at exposure levels of 0.05-0.35 ppm arsenic, but at exposure levels > 0.35 ppm arsenic was associated with increased ASMR in both males and females for bladder cancer, kidney cancer, and all urinary cancers combined. There was no increased ASMR associated with prostate cancer observed for either exposure category.

Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety. RESULTS: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

Tislelizumab in Asian patients with previously treated locally advanced or metastatic urothelial carcinoma.

Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This single-arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD-L1-positive urothelial carcinoma who progressed during/following platinum-containing therapy and had no prior PD-(L)1 inhibitor treatment. Patients were considered PD-L1 positive if ≥ 25% of tumor/immune cells expressed PD-L1 when using the VENTANA™ PD-L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow-up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy-evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression-free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment-related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3-4 treatment-related adverse events and occurred in ≥ 5% of patients. Three investigator-assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD-L1-positive urothelial carcinoma and had a manageable safety profile.

Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab.

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil-to-lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low-, intermediate-, and high-risk groups (discovery cohort) were not yet reached (NYR) (NYR-19.1), 6.8 mo (5.8-8.9), and 2.3 mo (1.2-2.6), respectively. The HRs (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.07 (0.04-0.11) and 0.23 (0.15-0.37), respectively. The objective response rates for in the low-, intermediate-, and high-risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first-line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab-treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design.

The effect of primary urological cancers on survival in men with secondary prostate cancer.

BACKGROUND: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). METHODS: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. RESULTS: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. CONCLUSIONS: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.