Antibody-drug conjugates (ADCs), particularly enfortumab vedotin (EV) in combination with pembrolizumab, have emerged as transformative treatments for advanced bladder cancer (BC). However, platinum-based chemotherapy, especially gemcitabine-cisplatin (GC), remains a widely used, first-line standard globally. This study investigated the impact of GC-therapy on subsequent ADC responsiveness. Using novel, patient-derived BC models, in vitro selection for acquired GC-resistance consistently resulted in downregulation of the EV target, Nectin-4, and corresponding EV cross-resistance in GC-resistant (GC/R) cells. This decrease in membranous Nectin-4 expression was validated in two independent human BC cohorts: (1) matched transurethral resections and radical cystectomy/lymph node specimens during neoadjuvant therapy and (2) primary tumors and distant metastases during adjuvant GC chemotherapy. Transcriptomic profiling indicated that GC-resistance and Nectin-4 downregulation were linked to a transcriptional shift toward an epithelial-to-mesenchymal transition (EMT)-like phenotype. Large-scale drug screening and transcriptomic data highlighted potential vulnerabilities in GC/R cells, notably associated with the transforming growth factor beta (TGF-beta) signaling pathway. These findings suggest that platinum-based chemotherapy may promote EMT-like transcriptional reprogramming in BC, associated with Nectin-4 loss and EV resistance. As such, assessing membranous Nectin-4 expression prior to EV therapy might be particularly relevant in postplatinum settings. Additionally, identifying alternative, chemotherapy-induced druggable vulnerabilities can inform more effective treatment strategies.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy. Yet, no rapid, non-invasive biomarkers are available for diagnosis or screening. Urine represents an ideal analyte matrix due to its accessibility, low invasiveness, longitudinal sampling, and the kidney’s central role in filtration. Here, we integrated proteomic, lipidomic, and metabolomic analyses of urine from ccRCC patients and controls to identify diagnostic biomarkers. Multi-omics profiling revealed urogenital metabolic dysregulation in ccRCC, including increased lipid metabolism, altered mitochondrial respiration signatures, and elevated urinary lipid content. We identified three urinary protein biomarkers: serum amyloid A1 (SAA1), haptoglobin (HP), and lipocalin 15 (LCN15). Using a parallel reaction monitoring mass spectrometry workflow, we developed a rapid and sensitive assay and combined these markers into a diagnostic UrineScore. The UrineScore achieved 0.96 in an area under the receiver operating characteristic curve analysis in the discovery cohort, and 0.95 in an independent validation cohort. Together, these results support the feasibility of multi-omics-guided urinary biomarker discovery and represent a step toward accessible diagnostic platforms for ccRCC. Urine multi-omics profiling of ccRCC patients identifies a three-protein diagnostic signature (HP, SAA1, and LCN15) that forms a composite UrineScore with an AUROC of 96

Background and objective:The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy. Methods:Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data. Key findings and limitations:Twenty-five patients (54%) had a response (<pT2 pN0 cM0) to NAC. Responders had more somatic DDR gene variants in preNAC (53 vs 11; p < 0.001) and postNAC (51 vs 9; p = 0.038) tumor tissue in comparison to nonresponders, as well as significantly greater phosphorylation of H2AX after NAC. ERCC2 was significantly co-mutated with REV3L among responders. Owing to the small cohort, no specific mutation was significantly positively associated with therapy response. However, accumulation of CDK12, NBN, MSH3, MLH1, ATR, BRCA1, BRCA2, REVL3L, and SLX4 variants was observed for responders. Conclusions and clinical implications:Patients with MIBC who responded to cisplatin-based NAC had more somatic DDR gene variants than nonresponders. Moreover, responders exhibited significantly greater DNA damage after NAC. Patient summary:Patients with muscle-invasive bladder cancer who have mutations in genes that are involved in repair of DNA damage are more likely to respond to cisplatin-based chemotherapy. Testing to identify these gene mutations could help in selecting the patients who are most likely to benefit from this treatment.

Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC. Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC.Patient summaryWe compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.

PURPOSE:The quantitative objective of the current systematic review was to identify the potential role of urinary microbiota in bladder cancer (BC) carcinogenesis, invasiveness, progression, and metastasis.MATERIALS AND METHODS:The proposed systematic review was conducted in accordance with critical review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, and the Joanna Briggs Institute (JBI) methodology for systematic reviews. The search strategy aimed to find both published and unpublished studies up to the January 2024. A JBI appraisal checklist was used to assess possible biases.RESULTS:This systematic review was centered on 27 studies comprising 926 BC patients. Overall, 412 control individuals were compared with BC patients. The most common sampling method was midstream urine collection. Regarding microbial alpha diversity, there was no statistically significant difference between cancerous and healthy samples (n = 8), recurrent and not recurrent (n = 1), responders versus non-responders(n = 1), tumor grades (n = 1), and collection methods (n = 1). However, five studies reported higher diversity in controls, and five other studies reported, conversely, high levels of alpha diversity in BC patients or recurrent cases. Furthermore, a responder (RE) to treatment and a non-muscle invasive bladder cancer (NMIBC) groups demonstrated significant difference with non-responder (NR) and muscle invasive bladder cancer (MIBC), respectively. In terms of beta-diversity, nine studies reported significant diversity between BC patients and controls, one article demonstrated difference between recurrent and not recurrent patients, a study reported significant difference in RE and NR groups whereas another showed opposite, and others (n = 4) did not find any difference between BC, controls, MIBC and NMIBC patients, or between tumor grades. One study reported a difference between the collection method and beta-diversity in males and another reported the difference in females.CONCLUSION:The included studies demonstrate that the composition of urinary microbiota is altered in patients with BC. However, the differentially enriched genera in the urine of these patients vary between studies, and there is too much heterogeneity across studies to make any reliable and valid conclusions. Furthermore, well-designed research is necessary to assess the role of microbiota in the carcinogenesis and progression of BC.

BACKGROUNDS:SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity. METHODS:Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival. RESULTS:SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis. CONCLUSIONS:In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa.

Clear cell renal cell carcinoma (ccRCC) is the kidney malignancy with the highest incidence and mortality rates. Despite the high patient burden, there are no biomarkers for rapid diagnosis and public health surveillance. Urine would be an ideal source of ccRCC biomarkers due to the low invasiveness, easy accessibility, and the kidney's intrinsic role in filtering urine. In the present work, by combining proteomics, lipidomics and metabolomics, we detected urogenital metabolic dysregulation in ccRCC patients with increased lipid metabolism, altered mitochondrial respiration signatures and increased urinary lipid content. Importantly, we identify three early-stage diagnostic biomarkers for ccRCC in urine samples: Serum amyloid A1 (SAA1), Haptoglobin (HP) and Lipocalin 15 (LCN15). We further implemented a parallel reaction monitoring mass spectrometry protocol for rapid and sensitive detection of SAA1, HP and LCN15 and combined all three proteins into a prognostic UrineScore. In our discovery cohort, this score had a performance accuracy of 96% in receiver operating characteristic curve (ROC) analysis for classification of ccRCC versus control cases. Our data identifies tractable and highly efficacious urinary biomarkers for ccRCC diagnosis and serve as a first step towards the development of more rapid and accessible urinary diagnostic platforms. ### Competing Interest Statement IMBA has filed a European patent application based on the results presented herein. G.J., T.O. and J.M.P. are inventors on this patent.

The incidence of nephrolithiasis is rising worldwide. Although it is a multifactorial disease, lifestyle plays a major role in its etiology. Another considerable factor could be an aberrant microbiome. In our observational single-center study, we aimed to investigate the composition of bacteria in kidney stones and urine focusing on patients with features of metabolic syndrome. Catheterized urine and kidney stones were collected prospectively from 100 consecutive patients undergoing endoscopic nephrolithotomy between 2020 and 2021 at our clinic. Microbiome composition was analyzed via 16S rRNA gene amplicon sequencing. Detection of bacteria was successful in 24% of the analyzed kidney stones. These patients had a prolonged length of stay compared to patients without verifiable bacteria in their stones (2.9 vs 1.5 days). Patients with features of metabolic syndrome were characterized by kidney stones colonized with classical gastrointestinal bacteria and displayed a significant enrichment of Enterococcaceae and Enterobacteriaceae. Stones of patients without features of metabolic syndrome characterized by Ureaplasma and Staphylococcaceae. Patients with bacteria in their kidney stones exhibit a longer length of stay, possibly due to more complex care. Patients presenting with features of metabolic syndrome displayed a distinct stone microbiome compared to metabolically fit patients. Understanding the role of bacteria in stone formation could enable targeted therapy, prevention of post-operative complications and new therapeutic strategies.

Squamous cell carcinoma of the penis (PSC) is a rare disease with limited information on the molecular events leading to malignant transformation. In a third of PSC cases, presence of human papilloma virus (HPV) is found. The APOBEC3 family of proteins is known to play a significant role in defense against HPV infection, but their role in PSC is largely unknown. In this study, we aim to assess mRNA expression levels of APOBEC3 family members in HPV+ and HPV− PSC to get insight into their association with clinicopathological features and to evaluate their prognostic impact. Expression levels of six APOBEC3 family members in tissue from 50 patients with PSC were determined by RT-PCR and correlated with clinical and histopathological features. Lower expression of APOBEC3A, APOBEC3B, and APOBEC3C was observed in advanced PSC stages. Except for APOBEC3D, HPV+ samples showed higher expression of APOBEC3s compared to HPV− samples. In univariate analyses, APOBEC3A and APOBEC3C expression tended to be associated with disease-free survival and APOBEC3A expression with overall survival; however, multivariable analyses failed to confirm these associations with outcome. More extensive external validation and functional laboratory studies are needed to evaluate further their role in PSC development and progression.

Background: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. Objective: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. Design, setting, and participants: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. Outcome measurements and statistical analysis: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. Results and limitations: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patientderived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patientderived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). Conclusions: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. Patient summary: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

The gene coding for histone methyltransferase KMT2D is found among the top mutated genes in upper tract urothelial carcinoma (UTUC); however, there is a lack of data regarding its association with clinicopathologic features as well as survival outcomes. Therefore, we aimed to investigate KMT2D expression, mutation patterns, and their utility as prognostic biomarkers in patients with UTUC. A single-center study was conducted on tumor specimens from 51 patients treated with radical nephroureterectomy (RNU). Analysis of KMT2D protein expression was performed using immunohistochemistry (IHC). Customized next-generation sequencing (NGS) was used to assess alterations in KMT2D exons. Cox regression was used to assess the relationship of KMT2D protein expression and mutational status with survival outcomes. KMT2D expression was increased in patients with a previous history of bladder cancer (25% vs. 0%, p = 0.02). The NGS analysis of KMT2D exons in 27 UTUC tumors revealed a significant association between pathogenic KMT2D variants and tumor location (p = 0.02). Pathogenic KMT2D variants were predominantly found in patients with non-pelvic or multifocal tumors (60% vs. 14%), while the majority of patients with a pelvic tumor location (81% vs. 20%) did not harbor pathogenic KMT2D alterations. Both IHC and NGS analyses of KMT2D failed to detect a statistically significant association between KMT2D protein or KMT2D gene alteration status and clinical variables such as stage/grade of the disease or survival outcomes (all p > 0.05). KMT2D alterations and protein expression were associated with UTUC features such as multifocality, ureteral location, and previous bladder cancer. While KMT2D protein expression and KMT2D mutational status do not seem to have prognostic value in UTUC, they appear to add information to improve clinical decision-making regarding the type of therapy.

You have accessJournal of UrologyCME1 May 2022MP40-16 EXPRESSION ANALYSIS AND MUTATIONAL STATUS OF HISTONE METHYLTRANSFERASE KMT2D IN UPPER TRACT UROTHELIAL CARCINOMA Ekaterina Laukhtina, Ursula Lemberger, Andreas Bruchbacher, Dafina Ilijazi, David D’Andrea, Martin Susani, Dmitry Enikeev, Eva Compérat, Shahrokh F. Shariat, and Melanie R. Hassler Ekaterina LaukhtinaEkaterina Laukhtina More articles by this author , Ursula LembergerUrsula Lemberger More articles by this author , Andreas BruchbacherAndreas Bruchbacher More articles by this author , Dafina IlijaziDafina Ilijazi More articles by this author , David D’AndreaDavid D’Andrea More articles by this author , Martin SusaniMartin Susani More articles by this author , Dmitry EnikeevDmitry Enikeev More articles by this author , Eva CompératEva Compérat More articles by this author , Shahrokh F. ShariatShahrokh F. Shariat More articles by this author , and Melanie R. HasslerMelanie R. Hassler More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002600.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The gene coding for histone methyltransferase KMT2D is found among the top mutated genes in upper tract urothelial carcinoma (UTUC); however, there is a lack of data regarding its association with clinicopathologic features as well as survival outcomes. Therefore, we aimed to investigate KMT2D expression and mutation patterns and their utility as prognostic biomarkers in patients with UTUC. METHODS: A retrospective single-center study was conducted on tumor specimens from 51 patients treated with radical nephroureterectomy (RNU). Analysis of KMT2D expression on the protein level was performed by immunohistochemistry (IHC). Customized Next Generation Sequencing (NGS) was used to assess alterations in KMT2D exons. Cox-regression analyses were used to correlate KMT2D protein expression and mutational status with survival outcomes such as disease-free and overall survival. RESULTS: KMT2D expression was increased in patients with a previous history of bladder cancer (25% vs. 0%, p=0.02). NGS analysis of KMT2D exons in 27 UTUC tumors revealed a significant association between pathogenic KMT2D variants and tumor location (p=0.02). Pathogenic KMT2D variants were predominantly found in patients with non-pelvic or multifocal tumors (60% vs. 14%), while the majority of patients with pelvic tumor location (81% vs. 20%) did not harbor pathogenic KMT2D alterations. Both IHC and NGS analyses of KMT2D failed to detect a statistically significant association between KMT2D protein or KMT2D gene alteration status and clinical variables such as stage/grade of the disease as well as survival outcomes (all p >0.05). CONCLUSIONS: In this study, KMT2D protein expression and KMT2D mutational status did not emerge as prognostic markers for UTUC. However, KMT2D alterations and protein expression were associated with features of biologically aggressive UTUC such as multifocality, ureteral location, and previous bladder cancer. Therefore, KMT2D seems to hold the potential of improving our clinical decision in UTUC regarding perioperative systemic therapy and/or additional intravesical therapy. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e681 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ekaterina Laukhtina More articles by this author Ursula Lemberger More articles by this author Andreas Bruchbacher More articles by this author Dafina Ilijazi More articles by this author David D’Andrea More articles by this author Martin Susani More articles by this author Dmitry Enikeev More articles by this author Eva Compérat More articles by this author Shahrokh F. Shariat More articles by this author Melanie R. Hassler More articles by this author Expand All Advertisement PDF downloadLoading ...

Purpose of review In this review, we aimed to summarize the available evidence on pretreatment molecular biomarkers that may help to predict oncologic and pathologic outcomes in patients treated with neoadjuvant systemic therapy (NAST) for urothelial carcinoma of the bladder (UCB). Recent findings Several readily available and easily measurable blood-based biomarkers (e.g., neutrophil to lymphocyte or platelet–lymphocyte ratios) seems to help improve the selection of UCB patients who are most likely to benefit from NAST. Recent evidence suggests liquid biopsy including circulating tumor DNA (ctDNA) to be a promising tool to guide the administration of NAST in UCB patients. Pretreatment molecular and genetic characterization of transurethral resection of the bladder tumor samples may also help understand the tumor biology as luminal and basal tumor subtypes seems to be more responsive to NAST, while claudin-low and luminal-infiltrated tumor subtypes are less. In the context of neoadjuvant immunotherapy, programmed death-ligand 1 (PD-L1) status and ctDNA remain the only biomarker with possible value as the clinical utility of tumor mutational burden remains controversial/poor. Summary Biomarker approach is a necessary step to usher the age of precision/personalized medicine for muscle-invasive UCB with the overarching good to prevent both over- and under-therapy. The present review may offer a robust framework to compare and assess current and future molecular biomarkers for the selection of NAST in muscle-invasive UCB.

PURPOSE OF REVIEW Urinary tract infection (UTI) is one of the most common pediatric infections worldwide. Recently introduced 16S rRNA sequencing allows detailed identification of bacteria involved in UTI on a species-based level. The urogenital microbiome in children is scarcely investigated, with underlying conditions differing from adults. Improvement in diagnostic and therapeutic approaches can help to minimize unnecessary antibiotic treatments, thereby protecting the physiological microbiome. RECENT FINDINGS Healthy bladders of children display a distinct microbiome than those of adults. UTI is characterized by changes in bacterial composition, with a high prevalence of Enterobacterales. There is a correlation between bacterial species and the pH of the urine, so a characteristic age-related pathogen pattern can be found due to the acidic urine in infants and more alkaline urine in older children. Recently, new methods were proposed to overcome the suboptimal diagnostic performance of urine cultures and urine dipstick test. This allows precise treatment decisions and helps to prevent chronification of UTI, related voiding dysfunctions and renal scaring, systemic abiosis, and the development of antibiotic resistance. SUMMARY Uropathogens involved in UTIs in children should be identified with precision to allow targeted therapeutic decisions. This can also help preventing the destruction of the microbiome homeostasis, which could result in a life-long dysbiosis. New treatment approaches and recolonization with probiotics are necessary due to increasing intrinsic antibiotic resistance of bacteria.

Purpose of review Testicular germ cell tumours (TGCTs) exhibit, in contrast to other cancer types, a relatively low mutational burden. However, numerous epigenetic alterations have been shown to impact TGCT. In this review, we summarize the most relevant findings of the past 2 years. Recent findings Recent studies focused on the functions of microRNAs and the impact of aberrant DNA methylation. Moreover, several epigenetic drugs with antineoplastic effects in TGCTs were identified. Summary Aberrant DNA methylation and differentially expressed microRNAs have an important effect on TGCT pathogenesis. Moreover, differential DNA methylation patterns were found to be specific for different TGCT subtypes. Various microRNAs, such as miR-371a-3p, were found to be highly sensitive and specific biomarkers for TGCT. The epigenetic drugs guadecitabine, animacroxam, and JQ1 showed promising effects on TGCT in preclinical in-vivo and in-vitro studies.

Purpose of review The aim of the article to summarize recent changes of treatment options in metastatic renal cell carcinoma (mRCC) with a special emphasis on immune checkpoint inhibition. Recent findings The introduction of checkpoint inhibitor (CPI) therapy has led to a paradigm change in advanced renal cell carcinoma (RCC). Dual immune checkpoint inhibition or the combination of CPI and tyrosine kinase inhibitors (TKIs) was shown to improve survival when compared with the former standard of care sunitinib. Moreover, these novel strategies were shown to enable unprecedented rates of complete and durable responses, particularly with dual checkpoint inhibition. Although the treatment landscape has rapidly evolved, it remains unknown which combination is the best for the individual patient. Pivotal trials have used sunitinib as a comparator but no head to head comparisons have been conducted between novel agents so far. Moreover, no predictive biomarker has been identified yet to bring the best treatment to the individual patient. Summary The aim of this review is to summarize the findings of CPI-based trials conducted in RCC and to discuss the future of mRCC treatment.

Purpose of review The aim of this article is to give an overview of poly(ADP-ribose) polymerase inhibitors (PARPis) trials in prostate cancer and to discuss emerging approaches with potential future clinical implementation in both prostate and urothelial cancer. Recent findings PARPis are a class of drugs that can be applied for the treatment of homologous recombination repair (HRR)-deficient tumors. Tumors are potentially sensitive to PARPi harbor mutations in genes relevant for DNA damage repair, such as BRCA1/2 or ATM, which are present to a significant degree in metastatic prostate and urothelial cancer patients. Several PARPis have been successfully tested in clinical trials for HRR-deficient metastatic castration-resistant prostate cancer (mCRPC), and olaparib and rucaparib have recently received breakthrough approval in BRCA1/2 mutated mCRPC. Combination treatment of PARPis with androgen-receptor inhibitors or with checkpoint inhibitors and earlier frontline applications are currently being evaluated, and clinical trials enrolling bladder cancer (BCa) patients with HRR deficiency have recently been initiated. Summary Approximately 10% of mCRPC patients and 34% of metastatic BCa patients have tumors with HRR deficiency and may benefit from PARPi treatment. Correct identification of these patients as well as determining the most adequate time point for drug administration will be key to successful clinical implementation.