AbstractMale germ cell tumors (GCT) have excellent survival. Long-term sequelae in cancer survivors are an evolving field. We evaluated the risk of patients with GCT to develop primary hypogonadism and adherence to guideline-recommended therapy in a real-world cohort. Monocentric study at a tertiary cancer centre to evaluate treated GCT-patients (2001–2019). Post therapeutic male endocrine function, International Index of Erectile Function (IIEF)-5 and The aging males’ symptoms rating scale (AMS) questionnaires were assessed. The overall response rates were low, with 44 of 402 contacted patients participating in the study. From these, 32(73%) underwent blood analysis, 42(95%) answered the IIEF-5 and 43(98%) the AMS. Latent hypogonadism (serum testosterone 8–12 nmol/l) was found in n = 9 (28%) and manifest hypogonadism (testosterone < 8 nmol/l) in n = 8 (25%). 50% (n = 21) indicated erectile dysfunction on IIEF-5 (cut off ≤ 21 pts.) and 62.8% (n = 27) reported symptomatic affection on AMS (cut off ≥ 27 pts.). Majority of tested patients revealed different degrees of hypogonadism. Standard instruments were able to detect gonadal damage in > 50%, which underscored the clinical need to evaluate endocrine function in cancer survivors. We further indicated the difficulties of today’s research and provided starting points to assess barriers for study participations.

e16562 Background: Enfortumab vedotin (EV) is an antibody drug conjugate targeting Nectin-4. It was approved by EMA/FDA in patients (pts) with metastatic/ locally advanced urothelial cancer post platinum and immune check point inhibitors (ICI) following the results of the EV-301 trial. We report updated efficacy data of EV in a large European cohort of real-world pts (GUARDIANS consortium) treated in hospitals and private practices. Methods: Retrospective data were collected from 25 German and Swiss hospitals and private practices for pts who received EV. Objective responses were evaluated by local investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Cox proportional hazard model was used to analyze risk patterns. Correlation was assessed using spearmen’s rank correlation coefficient. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: We identified 188 pts (32.4% female) with a median age of 66 yrs (range 31-89; 22.3% ≥ 75 yrs). Median OS (mOS) was 12.0 months (mo) (95% CI 9.65-14.35) and median PFS (mPFS) was 7.0 mo (95% CI 5.43-8.57). Overall response rate was 46.3% (partial remission: 42.0%, complete response 4.3%). Median follow up was 11 mo (IQR: 6.0-17.0 mo). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1/ 2-4/ unknown in 75/14/11%. With decreasing ECOG-PS ≥2, there was also a decrease in OS 4.95 (95 CI 3.0-8.3; p<0.001) and PFS 2.1 (95 CI 1.14-3.92), resulting in a significant Spearman coefficant for death 0.31, OS -0.36 and PFS -0.31 (p<0.001). Median EV line was 3 (IQR: 3-4). Bellmunt Risk Score (BRS) >1 prior to EV initiation significantly predicts poorer OS and PFS with 3.3 (95 CI 1.82-5.72, p<0.001) and 1.9 (65 CI 1.15-3.25, p=0.013), respectively. Regarding metastases localization, liver and bone involvement correlated with poorer OS with 1.3 (95 CI 0.9-2.1; p=0.01) and 1.5 (95 CI 1.01-2.36; p=0.04). In addition cancer of the Upper Urinary Tract showed a poorer OS 1.4 (95 CI 0.89-2.19; p=0.027). Prior definitive local intervention demonstrated improvement in OS 0.6 (95 CI 0.32-1; p=0.048). Response to ICI-therapy, IC or CPS did influence neither OS nor PFS. Limitations are retrospective design and short follow-up. Conclusions: Anti-tumor activity of EV in real-world pts including difficult-to-treat subgroups is comparable to the results of the pivotal EV-301 trial. Frail pts. have a significant higher risk for death and progression. BRS is a predictive indicator for treatment with EV in heavily pretreated patients. Liver and bone metastases have a poorer OS. The improvement in prognosis after local definitive therapy in connection with EV therapy should be investigated further in the future.

392 Background: Papillary (pRCC), chromophob (chRCC) and predominantly sarcomatoid renal cell carcinoma (sRCC) as well as RCC with sarcomatoid features are rare cancers. We evaluated real-world treatment outcomes of 1st line treatment in these cohorts in Germany. Methods: We retrospectively analyzed patients with non-clear cell RCC treated at 17 German tertiary cancer centres. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to RECIST 1.1. Progression free survival (PFS) and overall survival (OS) were calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 189 patients with a median age of 63 years (IQR 54-72). Of these, 49% were pRCC, 12% chRCC, 12% sRCC. 17% of all RCC had a sarcomatoid features. 87% had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 15/54/31%. 74% received prior nephrectomy. Lymphatic (63%) and pulmonary (51%) metastases were the most common metastatic sites. 72% patients received first-line IO-combinations (IO-IO: 36%, TKI-IO: 64%) and 28% patients TKI-monotherapy, predominantly sunitinib. AE of all grades occurred in 86% and 72% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 46% or 36%, of which led to discontinuation of treatment in 42% or 29% of patients, respectively. ORR and survival outcomes with median follow-up of 17 months (IQR 9-30) are described in the table. Conclusions: IO-combinations are frequently applied in pRCC, chRCC and sRCC. Our data suggests that first-line IO-combinations yields higher ORR compared to single agent TKI in sRCC, but not in chRCC. However, the retrospective nature and small sample size are major limitations of our analysis. Additional analyses to tailor treatment strategies in patients with metastatic nccRCC or sRCC is warranted. [Table: see text]

387 Background: Brain (BM) and bone metastases (BOM) in renal cell carcinoma (RCC) are associated with poor outcome. We evaluated real-world treatment paradigms of RCC patients with BM and BOM. Methods: We retrospectively analyzed RCC patients with BM and/or BOM treated at 18 German tertiary cancer centres from 2003 to 2023. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to local standard. Overall survival (OS) was calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 453 patients with a median age of 64 years (IQR 56-71). 93% of all patients had BOM, 15% BM and 8% both. Most patients (79%) had clear cell RCC, 7% of all patients had sarcomatoid differentiation. 82% of patients had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 20/56/24%. 64% received prior nephrectomy. Patients with BOM received first-line IO-combinations in 61% (IO-IO: 38%, TKI-IO: 62%), TKI-monotherapy in 39%, while patients with BM received IO-combinations in 68% (IO-IO: 37%, TKI-IO: 63%) and TKI in 32%. IO-based first-line therapy increased from 2003 to 2023. AE of all grades occurred in 87% and 69% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 42% or 25%. Best ORR and survival outcomes with median follow-up of 23 months (IQR 9-42) are described in table 1. 56% and 58% of all patients with BOM and BM received second-line treatment, with Cabozantinib (34%; 34%) and Nivolumab (17%, 23%) being the most common treatment options. In the subgroup of RCC with sarcomatoid features (n=36), 34 patients had BOM and 7 had BM, of which were treated with IO-combinations in 88% (BOM; IO-IO: 41%, TKI-IO: 59%) or 66% (BM; IO-IO: 50%, TKI-IO: 50%) and TKI-monotherapy in 12% (BOM) or 34% (BM) of all patients. Response rates (ORR/SD/PD) were 48%/28%/24% for IO-based therapy and 0%/50%/50% for TKI-monotherapy in RCC with sarcomatoid features, mOS was 41 months (95% CI 16.7-65.3). Conclusions: RCC patients with BOM and BM are increasingly treated with IO-combinations but lead to higher rates of AE grade ≥ 3. In patients with BOM, IO-TKI revealed higher ORR compared to IO-IO combination, but not in patients with BM. However, the small sample size and retrospective design are major limitations of our analysis. Prospective studies evaluating treatment options for BOM and BM in patients with RCC is critical. [Table: see text]

553 Background: Enfortumab vedotin (EV) is an antibody drug conjugate targeting Nectin-4. It was approved by EMA/FDA in patients (pts) with metastatic/ locally advanced urothelial cancer post platinum and immune check point inhibitors following the results of the EV-301 trial. We report updated efficacy and safety data of EV in a large European cohort of real-world pts (GUARDIANS consortium) treated in hospitals and private practices. Methods: Retrospective data were collected from 25 German and Swiss hospitals and private practices for pts who received EV. Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated by local investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Weidentified 188 pts (32.4% female) with a median age of 66 yrs (range 31-89; 22.3% >/= 75 yrs). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2/3-4/unknown in 36/39/11/3/11%. EV was administered in the fourth or later line in 43% of pts. Overall response rate (ORR) was 46.3% (partial remission: 42.0%, complete response 4.3%), disease control rate was 58.0%. Median OS (mOS) was 12.0 months (mo) (95% confidence interval 9.65-14.35) and median PFS (mPFS) was 7.0 mo (95% confidence interval 5.43-8.57). Any-grade AEs were observed in 71% and CTCAE grade ≥3 AEs in 32% of pts. Most common AEs were peripheral sensory neuropathy (33.5% any grade), skin toxicity (24.5%) and fatigue (22.9%). In pts >/= 75 yrs, females, and pts treated in >/=4 th line mOS, mPFS, ORR, and toxicities were comparable to younger and male counterparts and pts treated in <4th line, respectively. Limitations are retrospective design and short follow-up. Conclusions: Anti-tumor activity of EV in real-world pts including difficult-to-treat subgroups is comparable to the results of the pivotal EV-301 trial. No new safety signals were observed.

436 Background: The standard first-line treatment for metastatic renal cancer (mRCC) combines immune checkpoint- (ICI) and tyrosine kinase inhibitors (TKI). While TKI therapy continues until disease progression, ICI treatment is typically stopped after 24 months or 35 cycles, aligning with approval study criteria. However, in real-world practice, the decision to discontinue ICI therapy upon achieving a positive response can be distressing for both patients and healthcare providers; thus ICIs are not stopped. We conducted an initial analysis of prolonged pembrolizumab (Pem) use in axitinib-pembrolizumab (Axi-Pem) combination therapy to evaluate its effects and toxicity. Methods: We retrospectively analyzed data from mRCC patients treated with first-line Axi-Pem in 10 German tertiary care centers between 2019 and 2023. After completing 35 cycles or 24 months of Pem, patients were offered continued ICI therapy if positive response was assessed. We calculated objective response rate (ORR) and progression-free survival (PFS) from the treatment start to achievement of 36 therapy months. Adverse events (irAEs) were reported following CTCAE 5.0 criteria. Results: Out of 72 patients, 27 met strict eligibility criteria from the Keynote-426 study (NCT02853331), with a response at 24 months and continuous Pem therapy. Patients had a median age of 65.7 years (range: 34-84), and IMDC risk was favorable/intermediate/poor in 22.2%/55.5%/18.5%. Median follow-up was 33.2 months (range: 25.3-48.4). At the 36-mos landmark, median PFS was not reached (PFS 64.7%), ORR was 63.6%, with complete response, partial response, and stable disease observed in 9.1%(1)/54.5%(6)/9.1%(1) of cases, respectively. Permanent Pem discontinuation occurred due to progressive disease in two cases and complete response in one case. Another case led to Pem discontinuation due to immune-related toxicity. Conclusions: In our selected real-world patient cohort seeking prolonged ICI therapy, responders who received continuous Pem beyond 24 months achieve sustained efficacy in first-line treatment. Furthermore, the incidence of irAEs does not increase with prolonged exposure to ICI therapy. Additional results beyond the 36-month landmark are urgently needed to further support the clinical necessity and feasibility of ongoing ICI treatment in light of its impact on the overall financial burden of cancer care.

Zusammenfassung Hintergrund Immunmodulatorische Therapien gewinnen immer größere Bedeutung in der Uro-Onkologie. Aus diesem Grund werden wir vermutlich immer häufiger mit Nebenwirkungen konfrontiert werden. Hinzu kommt eine immer größere Zahl an Kombinationen mit anderen Wirkmechanismen. Als Folge dieser Therapie können immun-vermittelte Nebenwirkungen auftreten. Diese unterscheiden sich von den Nebenwirkungen einer Chemotherapie und anderen zielgerichteten Therapien und erfordern daher andere Behandlungsstrategien. Ziel der Arbeit Anhand der aktuellen Literatur werden die Daten zur Graduierung und stadienabhängigen Management dargelegt sowie mit Beispielen aus der Praxis anschaulich dargestellt. Material und Methoden Literaturrecherche zur Detektion und Therapiemanagement von im Rahmen der immunonkologischen Therapie vermittelten Nebenwirkungen. Ergebnisse Die behandlungsbezogenen Ereignisse können prinzipiell alle Organsystem betreffen, häufig sehen finden sich Toxizitäten im Bereich der Haut, wie Ausschlag oder Pruritus, Hypo- oder Hyperthyreosen, Arthritiden, Muskelschmerzen und gastrointestinale Symptome. In der Häufigkeit sind die meisten Nebenwirkungen Grad 1 bis 2 zuzuordnen, jedoch auch Grad 3 bis 4 Toxizitäten sind grundsätzlich gut zu therapieren, sofern sie frühzeitig erkannt werden. Seltene Komplikationen wie neurologische Toxizitäten, Pneumonitis oder auch Karditis können bei zu später Diagnose einen fulminanten Verlauf entwickeln. Diskussion Selbst Notfälle sind gut zu managen, wenn wir die wichtigsten Nebenwirkungen und therapeutischen Optionen kennen. Dabei kommt den immunvermittelten Nebenwirkungen ein besonderer Stellenwert zu, weil sie grundsätzlich jedes Organsystem betreffen können. So lange wir jedoch bei Patienten, die Symptome zeigen, an die Möglichkeit einer Toxizität durch Checkpointinhibitoren denken, sind die meisten Nebenwirkungen gut zu therapieren und daher kontrollierbar.

Rationale 177Lu-PSMA ([177Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant 177Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and 177Lu-PSMA therapy efficacy is poorly understood.Methods Between March 2018 and December 2021, a total of 168 patients were referred to 177Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication.Results In the subset of patients who received 177Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=−0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01).Conclusion Higher PD-L2 signature might be associated with a better response to 177Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.

Background Immunomodulatory therapies are becoming increasingly important in uro-oncology. For this reason, we will probably be increasingly confronted with side effects. In addition, there is an increasing number of combinations with other mechanisms of action. Immune-mediated side effects may occur as a consequence of this therapy. These are different from the side effects of chemotherapy and other targeted therapies and therefore require different treatment strategies.Aim Based on the current literature, the data on graduation and stage-dependent management will be presented as well as illustrated with examples from practice.Materials and methods Literature review on the detection and therapeutic management of adverse events mediated in the setting of immuno-oncologic therapy.Results Treatment-related events can in principle affect all organ systems. Toxicities in the area of the skin, such as rash or pruritus, hypo- or hyperthyreosis, arthritis, muscle pain and gastrointestinal symptoms are frequently seen. In terms of frequency, most side effects are grade 1 to 2, but grade 3 to 4 toxicities are also generally well treatable if detected early. Rare complications such as neurological toxicities, pneumonitis or carditis can develop a fulminant course if diagnosed too late.Conclusions Even emergencies are manageable if we know the most important side effects and the therapeutic options. Immune-mediated side effects are of particular importance because they can affect any organ system. However, as long as we consider the possibility of toxicity from checkpoint inhibitors when the patient presents with symptoms, most side effects are easy to treat and therefore manageable.

Purpose To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [ 68 Ga]Ga-FAPI-04 PET/CT imaging in patients with castration-resistant PC (CRPC). Methods Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [ 68 Ga]Ga-FAPI-04 PET/CT, and PET positivity was analyzed. Results The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [ 68 Ga]Ga-FAPI-04 PET/CT was highly positive in men with advanced CRPC. Conclusion Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC.