Background:Up to 8% of renal tumors have a monogenic cause, yet hereditary renal cell carcinoma (hRCC) syndromes such as von Hippel-Lindau (VHL), Tuberous Sclerosis Complex (TSC), Birt-Hogg-Dubé (BHD), and Hereditary Leiomyomatosis and Renal Cell Cancer remain underdiagnosed. Early diagnosis is critical for patient management, genetic counseling, and family screening. We developed and prospectively validated a structured risk assessment tool (hRCC score) for identifying patients at risk of hereditary renal tumors. Methods:A prospective single-center study was conducted at the University Hospital Cologne (2020-2022) including 200 patients with histologically confirmed renal tumors. The hRCC score incorporated age at diagnosis, multifocal/bilateral disease, histology, extrarenal manifestations, and family history. Patients with a score ≥1.5 were referred for genetic testing using a multiplex MLPA (Multiplex Ligand-dependent Probe Amplification)-based panel including TSC, MET, VHL, FH, SDH-A-D, and FLCN. Results:Of 195 eligible patients, 34.4% (n = 67) had a high-risk hRCC score (≥1.5). Overall, 71 (36.4%) underwent genetic testing; a pathogenic or likely pathogenic variant was detected in 50.7% of tested patients, corresponding to 18.5% of the total cohort. The most common diagnoses were TSC (58.3%), VHL (16.7%), and BHD (11.1%). Confirmed hereditary cases had significantly higher mean hRCC scores (4.67 vs 0.48, P < .0001). Extrarenal manifestations and bilateral or multifocal disease were the strongest predictors. The cutoff of 1.5 yielded 97.2% sensitivity and 79.8% specificity. Conclusions:The hRCC score is an effective clinical screening tool for detecting patients at risk for hereditary renal tumors, demonstrating high diagnostic yield and supporting targeted referral for genetic evaluation.

OBJECTIVES:To analyze the type and frequency druggable mutations in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS:From 2018 to 2023, 311 patients with mCRPC underwent molecular panel analysis of archived prostatectomy samples (n=96) or CT-guided biopsies of progressive metastases (n=215).Mutation analysis was performed using NGS with an 18 multiplex PCR amplicon (AR, ATM, AURKA/MYC, BRCA1/2, CDK12, CTNNB1, DLL3, ETS family, FOXA1, FOXO1, MED12, PIK3CA, PTEN, RAD51C, TP53, Wnt-Pathway). Since 2023, we applied the TSO500 panel in selected cases. The HRD score was calculated by combining BRCA1 and BRCA2 mutations (Genomic ScarScore GSS) using the HANDLE HRD Focus Panel. The data were evaluated using the following thresholds: tumor cell content ≥ 30%, GScore positive at ≥ 50, HRD positive: GScore at ≥ 50 or BRCA1/2 category 4/5 mutation. MSI-high and mutations of MSH2, MSH6, PMS2, and MLH1 were analysed. The following databases were reviewed to identify druggable mutations: OncoKB, ClinVar, JAX-CKB, COSMIC, and My Cancer Genome. RESULTS:299/311 (96%) biopsies had sufficient DNA content for NGS. NGS was performed from prostate (31%), lymph node (30%), visceral (15%), and bone (24%) metastases with informative DNA retrival in 95%, 95%, 92%, and 85%, respectively. 157 patients (50.5%) had no or non druggable mutations, while 154 patients (49.5%) exhibited druggable mutations. HRD gene mutations and inactivating p53 mutations were observed in 66 patients (22%). 3 patients had p53 mutations with gain-of-function resulting in ATM inactivation. 50% of HRD gene mutations iwere pathogen and treated with PARPi resulting in a progression-free survival of 3-28 months. Activating AR mutations and inactivating PTEN/activating PIC3Ca mutations were found in 42 (14%) and 24 (8%) patients, respectively. Switch of treatment for AR mutation resulted in PFS of 6-9 months. Mismatch repair deficiency/MSI high mutations were identified in 3 cases who received pembrolizumab with a PFS of 4-8 months. CONCLUSIONS:NGS analysis in mCRPC reveals mutations in two-thirds of patients, of which 41% are already druggable. Only 50% of druggable mutations are based on BRCA1/2 or ATM. NGS analysis should be integrated into the diagnostic armentarium following failure of first-line systemic therapy for mCRPC.

Abstract Introduction Enfortumab vedotin plus pembrolizumab (EVP) is the standard first-line treatment for metastatic or locally advanced urothelial carcinoma (m/laUC). Real-world patients frequently present with unfavorable clinical characteristics, raising uncertainty about whether outcomes mirror those of the pivotal EV-302/KEYNOTE-A39 trial. This study assessed effectiveness and safety of EVP in a real-world cohort of patients with m/laUC. Materials and methods Retrospective multicenter study including patients treated with EVP across 25 German hospitals (between 03/2022 and 08/2025). Treatment delivery and monitoring followed local clinical standards. Adverse events (AEs) were documented per CTCAE v5.0. Responses were assessed locally using RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier methodology. Results A total of 468 patients (median age = 69 years) were included. The overall response rate (ORR) was 50.2% (partial response:37.4%, complete response:12.8%). Median PFS was 10.2 months (95%CI,8.0–12.7). 12-month and 24-month OS rates were 71.9% and 60.6%, respectively. ECOG PS 0–1 and occurrence of skin toxicity were associated with improved outcomes. Any-grade AEs occurred in 81.8% and grade ≥ 3 AEs in 35.8%. Peripheral sensory neuropathy and skin toxicity were the most common AEs. Ten treatment-related fatal events were recorded. Conclusions EVP demonstrated robust effectiveness and manageable toxicity in a large and diverse real-world cohort including patients with divergent histology. Skin toxicity was associated with superior ORR, PFS, and OS. Our findings support EVP as an effective first-line option for patients with m/laUC treated outside clinical trials.

Prostatic ductal adenocarcinoma (PDA) is a rare, aggressive prostate cancer subtype associated with advanced disease and poorer prognosis than acinar adenocarcinoma. Small ductal components influence management and preclude active surveillance. This study analyzed oncologic outcomes and therapeutic patterns in a multicenter German cohort. Retrospective multicenter cohort, seven high-volume German centers. 82 patients with histologically confirmed PDA diagnosed 2014–2024 included. Histopathological data from biopsy and radical prostatectomy (RP) specimens. Clinical data: local/systemic treatments, follow-up until 2025. Primary outcome: time to systemic therapy. Secondary: overall survival. Predictors of adverse outcomes assessed via Cox regression. Most patients presented with d’Amico high-risk (47/82, 57.3

Abstract:Molecular diagnostics and targeted therapies are increasingly evolving towards a personalized medicine approach. This review summarizes recent advances in testicular germ cell tumors (TGCTs) and penile cancer, with a focus on emerging biomarkers and targeted therapeutic strategies. Conventional serum tumor markers such as AFP, β-HCG, and LDH remain important but are limited by suboptimal sensitivity and specificity. Novel biomarkers, particularly microRNA miR-371a-3p, have demonstrated substantially higher diagnostic accuracy and may improve risk stratification, detection of disease recurrence, and treatment decision-making in TGCTs. In addition, the analysis of circulating tumor DNA (ctDNA) has emerged as a promising liquid biopsy procedure. In penile squamous cell carcinoma, molecular classification based on human papillomavirus (HPV) status and comprehensive genomic profiling are becoming increasingly relevant for prognosis and therapeutic selection. The identification of actionable molecular alterations has facilitated the development of immunotherapy, anti-EGFR strategies, and antibody-drug conjugates. Early clinical data also suggest that ctDNA may provide valuable information for treatment monitoring and early relapse detection. Despite these promising findings, further prospective studies and standardized methodologies are required before many of these approaches can be incorporated into routine clinical practice. Overall, these developments highlight the ongoing transition towards biomarker-driven precision oncology and the potential for more individualized management of patients with TGCTs and penile cancer.

BACKGROUND AND OBJECTIVE:In metastatic hormone-sensitive prostate cancer (mHSPC), first-line treatment with either docetaxel + androgen deprivation therapy (ADT) or androgen receptor pathway inhibitors (ARPI) + ADT represented the standard of care. Triplet therapy (docetaxel + ARPI + ADT) has shown superiority over docetaxel + ADT, leading to regulatory approval. However, real-world data directly comparing ARPI + ADT and triplet therapy are lacking. This study evaluates real-world outcomes across 3 treatment regimens using inverse probability of treatment weighting (IPTW). METHODS:We retrospectively analyzed data from 13 centers of men with mHSPC treated with docetaxel + ADT, ARPI (apalutamide or enzalutamide) + ADT, or darolutamide + docetaxel + ADT. The primary endpoint was progression-free survival (PFS); secondary endpoints included adverse events. To address baseline imbalances, IPTW was employed. Time-to-event data were analyzed using weighted Cox proportional hazards regression with robust variance estimation. RESULTS:After excluding incomplete cases, 346 men were analyzed: 58 (16.8%) received docetaxel + ADT, 203 (58.7%) ARPI + ADT, and 85 (24.6%) triplet therapy. Before weighting, triplet patients demonstrated more adverse baseline features. After achieving covariate balance through IPTW adjustment, no significant differences in PFS were observed, with hazard ratios of 1.60 (95% CI: 0.78-3.28, P = 0.20) for docetaxel + ADT and 0.70 (95% CI: 0.36-1.35, P = 0.29) for ARPI + ADT compared to triplet therapy. Grade ≥3 adverse events occurred in 36.2%, 10.9%, and 31.8% of patients, respectively (P < 0.001). CONCLUSIONS:In this IPTW-adjusted real world cohort, triplet therapy was not significantly associated with improved PFS compared to ARPI + ADT or docetaxel + ADT. These findings should be interpreted in the context of limited sample size and follow-up, and further prospective studies are warranted.

Das Urothelkarzinom des oberen Harntrakts (UTUC) erfordert einen komplexen, multimodalen und leitlinienbasierten Therapieansatz. Aufgrund der Seltenheit der Erkrankung, geringer Fallzahlen und diagnostischer Herausforderungen ist die Umsetzung der jährlich aktualisierten EAU-Leitlinien (European Association of Urology) im klinischen Alltag jedoch häufig erschwert. Ziel dieser Studie war die Evaluation der leitliniengerechten Versorgung sowie der Einfluss leitlinienabweichender Therapieentscheidungen auf das onkologische Outcome. In einer retrospektiven Analyse wurden 181 Patient:innen mit UTUC untersucht, die zwischen 2011 und 2024 an unserer Klinik behandelt wurden. Diagnostik, Therapie und onkologisches Outcome wurden anhand der jeweils gültigen EAU-Leitlinien bewertet und die Behandlungsverläufe in Abhängigkeit von der Leitlinientreue analysiert. Eine nicht leitlinienkonforme Diagnostik oder Therapie erhielten 13

176 Background: Local complications due to infiltration and compression of adjacent organs represent significant complications of locally advanced castration sensitive (CSPC) and castration resistant PCA (CRPC) despite the use of life prolonging agents. Methods: 139 patients with locally advanced CSPC/CRPC underwent palliative pelvic surgery: radical cystoprostatectomy in n=105 (75.5%), radical prostatectomy with continent vesicostomy in n=9 (6.5%) and anterior plus posterior exenteration in n=25 (17.6%). All patients underwent local staging via MRI of the small pelvis, cystoscopy and rectoscopy. Systemic staging was done with CT scans of the chest, abdomen, pelvis and bone scans. Perioperative complications were assessed according to Clavien-Dindo classification and symptom-free (SFS), cancer specific survival (CSS) were evaluated using the Kaplan-Meir method. Results: Indications for surgery were lower or upper urinary tract obstruction in 75 (54%) and 55 (39%), resp., hematuria and blood transfusions in 31 (22%), rectal infiltration with/without obstructive ileus in 23 (17%), refractory pelvic pain in 17 (12%). 96 (69%) pts had a combination of various symptoms. Clavien-Dindo grade 2, 3 and 4 complications developed in 32 (23%), 12 (8.6%) and 8 (5.7%), respectively. After a median follow-up of 42.5 (3 – 123) months, the SFS at 1 and 3 years was 90.3% and 66.9%. The median SFS was 27.9 months. CSS at 1 and 3 years was 92.2% and 43.7%, respectively. 78.6% of the patients were symptom-free during their remaining lifetime. Conclusions: Multivisceral prostate surgery is a technically feasible approach in well-selected patients resulting in symptom relief of > 90% of patients which covered almost 80% of the remaining life-time. Adequate preoperative imaging studies, endoscopic evaluation and extensive surgical experience is mandatory to achieving a benefit for the individual patient with improvement of quality of life.

BACKGROUND AND AIMS:Histological grading of renal cell carcinoma (RCC) is an important part of diagnostic evaluation. Reproducibility of RCC grading using whole-slide imaging (WSI) compared to glass-slide microscopy is understudied. The aim of the study was a head-to-head evaluation of WSI-based and glass-based grading approaches in clear-cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) subtypes. METHODS:Four cohorts of patient cases with glass slides and corresponding digitized WSI were included from two institutions (cases n, Institution 1 (I-1): ccRCC 100, pRCC 89; Institution 2 (I-2): ccRCC 97, pRCC 50). Nine board-certified pathologists provided grades, with some pathologists evaluating both glass-based and WSI-based slides in the same cohorts. An interobserver and intraobserver (different modalities) analysis was carried out, including comparisons to majority vote and consensus grades using kappa statistics. Information on prognostic endpoint (overall survival) was available for cases from Institution 1. RESULTS:In ccRCC cases, interobserver pairwise comparison among pathologists showed low to moderate agreement, similar for glass-based (kappa range 0.14-0.77) and WSI-based (0.12-0.83) approaches, with in general similar results for pRCC subtype. Significant differences could be observed for datasets stemming from two institutions: ccRCC kappa average 0.73 and 0.54 for I-1 and I-2, respectively, for glass-based, and 0.66 and 0.48 for the WSI-based approach, revealing staining differences as a potential important confounder. Intraobserver (same pathologist, same cases, glass-based vs. WSI-based) analyses revealed significant differences in assigned grades with trends to both under-grading and over-grading. For ccRCC (I-1: pathologists n = 5, I-2: n = 3), the kappa range was 0.47-0.90 for I-1 and 0.43-0.70 for I-2. In the majority vote/consensus grade analysis, there was a clear general trend to over-grading using the WSI-based approach, with more cases scored as G4. Prognostic analysis showed the value of both WSI-based and glass-based approaches. CONCLUSIONS:WSI-based grading approach for RCC results in divergent grading outcomes, with a trend to over-grading. The interobserver and especially intraobserver agreement present in low to moderate areas for both modalities warrants more standardization and exploring the potential of artificial intelligence for grading objectivization. Institute-specific staining differences might be a confounder for less reproducible RCC grading. We open-source all digital datasets and grades for education and research purposes.

157 Background: Cytoreductive radical prostatectomy (cRP) has emerged as an alternative treatment option to radiation therapy in men with low risk metastatic hormone sensitive prostate cancer (mHSPC). It was the purpose of our analysis to evaluate if different combinations of androgen deprivation therapy have an impact on pathohistological findings and oncological outcome in men undergoing cRP. Methods: We performed a retrospective analysis of 104 patients who underwent cRP and pelvic lymph node dissection for low volume mHSPC. Prior to cRP, all patients underwent at least 6 months of neoadjuvant systemic therapy with ADT (n=15, 14.4%), ADT + Abi (n=26, 25%), ADT+Apalutamide (n=37, 35.6%), ADT+enzalutamide (n=10, 9.6%), ADT+docetaxel (n=18, 17.3%). We analyzed pathohistology of the cRP and lymphadenectomy specimens and we assessed cancer specific survival (CSS), progression-free survival (PFS), metastatic PFS and overall survival (OS). In addition, surgery related complications and continence were assessed. Results: Mean age was 63 (45-76) years. Median follow-up was 62.1 (2-186) months. Median initial PSA and median PSA at time of surgery was 110 (25-465) ng/ml and 1.25 (<0.01-5.6) ng/ml, resp. Pathohistology of the total group revealed pT0 in 5 (4.8%) pts and pT2a-c, pT3a/b in 16(15.4%) and 83 (79.8%), resp. Pathohistology depending on the type of ADT is given in table 1. pN+ was observed in 45 (43.2%) patients with 1-19 positive lymph nodes and positive surgical margins were identified in 36 (34.6%). Local recurrence was observed in 2 (1.9%) pts. We observed Clavien-Dindo grade III-IV complications in 16 (15.4%) patients. With regard to continence, no, mild (1-2 pads/day) or severe incontinence was observed in 67.7%, 18.2%, and 14.1%, resp. Median OS was 84 months, median clinical progression free survival was 72 months. Conclusions: Based on our data, 75% of patients demonstrate viable and significant prostate cancer despite optimal PSA response to combined neoadjuvant ADT making this a strong argument for local surgical treatment in well selected patients with mHSPC. ADT/apalutamide and ADT/docetaxel are associated with the lowest risk of lymph node metastases making this the preferrable combination. Analysis of CSS, OS and PFS are under way to assess if those findings translate into superior oncological outcome. Surgery related side effects are low if cRP is performed in experienced hands. cRP should be discussed as one option of local treatment in multidisciplinary tumor boards. Pathology dependent on type of ADT. n pT0n (%) pT2a/bn (%) pT2cn (%) pT3a/bn (%) pN+n (%) R1n (%) ADT 15 1 (0.7) 0 2 (13.3) 12 (75) 9 (60) 5 (33.3) ADT + Abi/Pred 26 1 (0.4) 1 (0.4) 3 (11.5) 21 (80.8) 13 (50) 11 (42.3) ADT + Apalutamide 37 2 (0.5) 2 (0.5) 5 (13.5) 27 (73) 7 (19) 7 (19) ADT + enzalutamide 8 0 1 (0.12) 0 7 (87) 6 (75) 3 (37.5) ADT + docetaxel 18 1 (0.5) 1 (0.5) 1 (0.5) 15 (83.3) 7 (38.9) 9 (50)

626 Background: Still, standard treatment of low-volume metastatic semimoma is either systemic chemotherapy or radiotherapy. Both options are associated with significant acute and long-term toxicities including mortality due to secondary malignancies in long-term follow-up. We calculated the number of potentially unnecessary chemotherapy cycles per hundred patients undergoing primary RPLND or Chemotherapy. Methods: In long-term follow-up of the COTRIMS-trial, 34 (12%) patients developed outfield relapses after a median follow-up of 41 months. All relapsing patients were cured by salvage PEB-chemotherapy. The base of our calculation are 12 recurrences on 100 Pts compared to 100 patients receiving chemotherapy upfront. Short term side effects of chemotherapy are from a historic patient cohort. Results: 12 relapsing patients received 36 cycles of PEB instead of 300 cycles of chemotherapy if given as first-line treatment. Significant PEB-associated acute toxicities mostly affect haematoxicity with neutropenia in 4 and 37 patients, resp., and febrile neutropenia in 1.7 and 14 patients, resp.. Based on our previous studies (Paffenholz P et al., World J Urol 2019; 37:1907), thrombembolic venous or arterial events are expected in 1.2 and 0.8 , resp. versus 10 and 7 patients, resp.. Therapy associated mortality would be expected in 0.2 and 2 patients, resp.. No data on long-term toxicities are available. Conclusions: All patients with relapses after primary RPLND can be cured by salvage chemotherapy. The number of chemotherapy cycles can be reduced by 88% without impairing oncological efficacy if surgery is performed in an experienced reference center. Thus overall acute toxicity rate affecting patients quality of life and even treatment associated deaths can be reduced dramatically. Although the reduction of long-term toxicities associated with cytotoxic therapy cannot be anticipated today, we strongly recommend to include primary nsRPLND in the therapeutic armentarium of clinical stage IIA/B seminomas.

498 Background: IO-based combination therapies - either in combination with tyrosine kinase inhibitors (TKI) or as double checkpoint inhibition - have revolutionized first-line treatment of ccRCC patients. We compared tolerability and effectiveness of ipilimumab plus nivolumab (ipi/nivo), cabozantinib plus nivolumab (cabo/nivo), axitinib plus pembrolizumab (axi/pem), and lenvatinib plus pembrolizumab (len/pem) as first-line treatment in real-world cohorts. Methods: Data from retrospective, multicenter cohorts of advanced ccRCC patients were analyzed. Best response was evaluated by local investigators. Adverse events (AE) were assessed according to CTCAE v5.0. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to calculate statistical differences between the cohorts. Results: A total of 543 patients were included in this analysis. Median age of all patients was 65 years (range 21-88), most patients were male (70%). Median number of affected organs were 2 and sites of metastases were comparable between treatment regimens. Key data on IMDC risk group distribution, median follow-up (FU), best response, disease control rate, median PFS, median PFS by IMDC risk group, 1-year OS-rate and occurrence of AEs by treatment regimens are depicted in the table. PFS was significantly superior for IO/TKI combinations compared to Ipi/Nivo (p=0.021). At a median FU of 21.2 months (95%CI 19.7-22.7) for all patients, 51% of patients had disease progression and 26% of patients died. Conclusions: IO/TKI combinations demonstrated significantly better PFS compared to IO/IO as first-line treatment for ccRCC patients. However, no specific IO/TKI regimen showed clear superiority over others, and 1-year OS rate was encouraging across all cohorts. Factors such as IMDC risk, comorbidities, AE profiles and individual treatment goals should be considered when tailoring therapy. Key limitations include the retrospective design, which introduces potential selection and recall biases, varying cohort sizes, the different and limited follow-up time between cohorts and limited OS events. Ipi/Nivo(n=251) Cabo/Nivo(n=47) Axi/Pem(n=118) Len/Pem(n=127) IMDC risk group- fav. risk- int./poor risk 8%92% 34%60% 24%72% 27%73% Median FU in mo. (95%CI) 32.1 (27.5-36.7) 14.0 (10.1-17.8) 22.5 (19.7-25.3) 14.7 (11.3-18.1) Best Response (CR rate) 40% (10%) 49% (2%) 64% (7%) 67% (7%) Disease control rate 64% 68% 86% 78% Median PFS (95%CI)- IMDC fav. risk- IMDC int./poor risk 9.0 (5.8-12.2)7.3 (6.9-7,7)9.7 (6.3-13.1) 16.1 (4.9-27.3)13.0 (6.8-19.2)10.7 (n.e.) 16.8 (10.4-23.2)25.4 (10.0-40.8)12.9 (9.4-16.4) 22.2 (11.7-23.7)22.2 (15.6-28.8)12.2 (0-24.6) 1 y OS rate (95%CI) 81.0 (75.8-86.2) 78.0 (63.8-92.2) 90.6 (84.8-96.4) 78.7 (70.5-86.9) AEs any grade 78% 79% 92% 95% AEs ≥ grade 3 40% 47% 47% 61%

BACKGROUND:Testicular tumors are rare in childhood but differ significantly from adult forms in terms of etiology, histology, and prognosis. Early diagnosis and appropriate treatment are crucial for the prognosis and quality of life of affected children. OBJECTIVE:The aim of this article is to provide an overview of the etiology, classification, clinical presentation, diagnostic tests, and treatment of pediatric testicular tumors. MATERIALS AND METHODS:This article is based on an analysis of current literature. RESULTS:Pediatric testicular tumors are benign in 60-75% of cases, most commonly teratomas or Leydig cell tumors. Malignant tumors such as yolk sac tumors are rare and show low metastatic potential. Diagnostics include ultrasound, tumor markers (AFP, hCG, LDH), and imaging (MRI, CT). Treatment consists of organ-sparing surgery in suspected benign cases and orchiectomy in malignant cases. Chemotherapy is reserved for metastatic tumors. In localized stage I disease, surveillance is often sufficient. CONCLUSION:Pediatric germ cell tumors differ from adult testicular tumors in terms of incidence, malignancy, and histology. Treatment decisions should always be made within an interdisciplinary framework.

INTRODUCTION:Prostate cancer guidelines recommend molecular analysis of biomaterial following resistance to first-line systemic therapy in order to identify druggable mutations. We report on our results of molecular analysis of tissue specimens via next generation sequencing (NGS) in men with metastatic castration resistant prostate cancer (mCRPC). PATIENTS AND METHODS:In all, 311 mCRPC patients underwent NGS analysis from biopsy samples of progressive metastatic lesions or archival radical prostatectomy specimens. NGS analysis was either performed using a panel of 18 prostate cancer-specific amplicons or via the TS0500 panel. RESULTS:Of the 311 biopsies, 299 (96%) revealed sufficient DNA content for NGS analysis independent on the specimen origin. Biopsies were taken from prostate (31%), lymph nodes (26%), visceral (17%) or osseous (18%) metastases. In 223 (75%) and 76 (25%) patients activating/inhibiting and no mutations were identified, respectively. Most frequently, mutations of HRD genes including a positive HRD score and p53 were identified in 22% of patients each. About 50% of HRD gene mutations were pathogenic and treatment with PARP inhibitors was initiated. Although the majority of p53 alterations were inactivating mutations, 3 patients demonstrated gain-of-function mutations resulting in an inactivation of ATM. Activating androgen receptor mutations and inactivating PTEN mutations were identified in 42 (14%) and 24 (8%) patients, respectively. Specific AR mutations resulted in a switch of hormonal therapy. Mutations of mismatch repair deficiency genes/MSI high were identified in 5 patients resulting in the administration of pembrolizumab. Addition of the TSO 500 panel identified additional mutations in 4.5% of patients and only 2% of the total cohort would have benefitted from this large panel with the identification of druggable mutations. CONCLUSION:Druggable mutations were identified in one third of mCRPC patients using an 18 amplicon-panel analyzed via NGS. Based on our data, molecular analysis of AR mutations or mutations of the HRD genes should be performed following progression after first-line hormonal therapy. A more extensive molecular analysis seems to be useful following progression to the standard sequential hormonal, cytotoxicand radioligand therapies. Use of the expensive TSO 500 panel seems to be of additional therapeutic value in only a minority of patients.

e16548 Background: Patients with terminal renal failure (GFR <30 ml/min or dialysis), poor performance status (ECOG ≥2), and/or age ≥80 are often excluded or underrepresented in pivotal clinical trials evaluating enfortumab vedotin and pembrolizumab (EV/P) as first-line (1L) treatment in metastatic urothelial carcinoma (mUC). Consequently, data on safety and efficacy in these populations are limited. This study evaluates EV/P outcomes in this high-risk group. Methods: This multicenter, real-world, retrospective study included mUC patients receiving EV/P as 1L treatment who were underrepresented (age ≥ 80) or ineligible for the EV-302 trial due to GFR <30 ml/min, ECOG ≥2. Endpoints included overall and progression free survival (OS, PFS), objective response rate (ORR), and treatment-related adverse events (AE). Descriptive and survival analyses evaluated safety and efficacy in frail patients. Results: A total of 116 patients from 18 German tertiary care centers were treated between May 2022 and December 2024. The median age was 79 years (IQR 68–83), with 20.7% having a GFR <30 ml/min, 44.8% presenting with ECOG ≥2, and 49.1% aged ≥80. The median age-adjusted Charlson Comorbidity Index was 6 (IQR 4–8), highlighting the high burden of comorbidities in this population. The ORR was 54.1%, including an 8.1% complete response rate. The mPFS was 7.5 months (95% CI 5.9–NR), and the mOS was not reached. Any-grade AEs were reported in 72.2% of patients, with ≥grade 3 AEs in 31.3%. The most common treatment-related AEs were peripheral neuropathy (33.0%) and skin toxicity (23.3%). Among patients aged ≥80, 39% required dose reductions, compared to 31% in the overall cohort, occurring after a median of 68 days (IQR 42–137). Of all patients, 18.1% discontinued treatment due to progressive disease, with only 31.3% of them receiving subsequent anti-cancer therapy. In contrary a total of 26.7% of patients permanently discontinued EV/P due to toxicity or non-specified reasons, with a median treatment duration of 89 days (IQR 40–180). Conclusions: This retrospective real-world analysis suggests that EV/P demonstrates promising oncological efficacy, even in highly frail patients, including those with a GFR <30 ml/min, ECOG ≥2, or aged ≥80 years. However, frequent discontinuations in absence of disease progression underscore the need for prospective studies to evaluate more tolerable regimens and treatment interruptions strategies.