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Background: There is a lack of published data on real-world cabozantinib use in patients with advanced renal cell carcinoma after prior vascular endothelial growth factor (VEGF)-targeted therapy., Methods: CASSIOPE was a real-world, prospective, multicenter, non-interventional postauthorization safety study of cabozantinib in adult patients with advanced renal cell carcinoma in Europe following prior VEGF-targeted treatment (NCT03419572). Endpoints included cabozantinib utilization (dose modifications due to adverse events [AEs; primary endpoint], dose, dose modifications, and treatment duration), safety, effectiveness (progression-free survival [PFS], overall survival [OS], best overall response [BOR]), and healthcare resource utilization., Findings: Full analysis set (FAS)/safety population comprised 679 patients; 433 of these initiated cabozantinib at 60 mg/day (recommended dose) (primary safety population). Median age (FAS) was 67 (range, 29-93) years; most were male (73·0%), had clear-cell histology (85·7%), metastatic disease at cabozantinib initiation (97·8%), and prior nephrectomy (80·3%). In the primary safety population, 77·1% experienced dose modification owing to an AE. In the safety population, the median daily dose was 40·0 (range, 7·8-60·0) mg/day and the median treatment duration was 7·8 (< 0·1-15·2) months. Treatment-emergent and treatment-related AEs were experienced by 95·9% and 90·4% of patients, respectively. Median PFS (FAS) assessed by the local investigator using any method was 8·3 months, and 1-year OS rate was 74%. Approximately one-third of all patients had a BOR of partial response and 6 had a complete response., Interpretation: Second- or later-line cabozantinib was effective and manageable in a real-world setting and had a safety profile consistent with previous studies., Competing Interests: Disclosure MS: Consulting or advisory role—Apogepha, Bristol-Myers Squibb, Eisai, EMD Serono, EUSA Pharma, Exelixis, Ipsen, Merck Sharp & Dohme, Novartis, Oncorena, Pfizer; Speakers’ bureau—Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Novartis, Pfizer; Travel, accommodations, expenses—Bristol-Myers Squibb, Eisai, EMD Serono, EUSA Pharma, Ipsen, MSD Oncology, Novartis, Pfizer; Honoraria—Astellas Pharma, Bayer, Bristol-Myers Squibb, Incyte, EMD Serono, EUSA Pharma, Exelixis, Ipsen, MDS Oncology, Novartis, Pfizer, Roche; Research funding—Bayer, Bristol-Myers Squibb, Eisai, Exelixis, Novartis, Pfizer, Roche/Genentech. UB: Consulting or advisory role—AAA Novartis, AstraZeneca, Bristol-Myers Squibb, Pfizer; Research funding—Ipsen; Travel, accommodations, expenses—Astellas Pharma, Bayer, Bristol-Myers Squibb, Janssen Oncology, Ipsen, Merck/Pfizer, MSD Oncology; Other relationship—Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen Oncology, Ipsen, Merck/Pfizer, MSD. J-CE: Honoraria—Bristol-Myers Squibb, Ipsen, Pfizer; Consulting or advisory role—Bayer, Pfizer; Travel, accommodations, expenses—Janssen, Pfizer. PhB: Consulting or advisory role—AAA/Endocyte/Novartis, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead Sciences, Ipsen, Janssen-Cilag, Merck KGaA, MSD Oncology, Pfizer; Travel, accommodations, expenses—Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck/Pfizer, MSD, Pfizer; Honoraria—Astellas Pharma, Bayer, Bristol-Myers Squibb, Gilead Sciences, Ipsen, Janssen-Cilag, Merck KGaA, MSD, Novartis, Pfizer, Seattle Genetics. PiB: Honoraria—MSD; Consultancy or advisory role—Bristol-Myers Squibb, Ipsen, MSD. ML: Consulting or advisory role—Amgen, AstraZeneca, Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer; Speakers’ bureau—AstraZeneca, Ipsen; Travel, accommodations, expenses—Ipsen, MSD, Pfizer. MR: Consulting or advisory role—AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, Ipsen Pharma, MSD, Novartis, Pfizer, Roche; Honoraria—AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, Ipsen Pharma, MSD, Novartis, Pfizer, Roche; Speakers’ bureau—Bayer Healthcare, Bristol-Myers Squibb, EUSA Pharma, Ipsen Pharma, Novartis, Olympus, Pfizer, Roche. CS: Consulting or advisory role—Astellas Pharma, Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Merck Sharp & Dohme, Pfizer, Roche/Genentech; Speakers’ bureau—Bristol-Myers Squibb, Eisai, Ipsen, Merck Sharp & Dohme, Pfizer, Roche/Genentech; Travel, accommodations, expenses—Bristol-Myers Squibb, Ipsen, Roche; Research funding—AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Exelixis, GlaxoSmithKline, Novartis, Pfizer, Roche/Genentech, Sanofi Aventis GMbH. AG: Nothing to disclose. JB: Consulting or advisory role—Apogepha, Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen, Merck Serono, MSD, Pfizer, Roche; Speakers’ bureau—Astellas, BMS, Ipsen, Merck Serono, MSD, Pfizer, Roche, Seagen; Research funding—Astellas, AstraZeneca, BMS, Eisai, Ipsen, MSD, Nektar, Novartis, Pfizer, Roche, Seagen; Travel, accommodations, expenses—Merck. PH: Consulting or advisory role—Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, MDS, Pfizer. RDV: Honoraria—AstraZeneca, Bayer, Ipsen, Janssen, MDS, Pfizer; Travel, accommodations, expenses—AAA Novartis. PG: Consulting or advisory role—Astellas, Bristol-Myers Squibb, Ipsen, Merck, MSD, Pfizer, Roche; Speakers’ bureau—Astellas, Bristol-Myers Squibb, Ipsen, Merck, MSD, Pfizer, Roche; Travel, accommodations, expenses—Ipsen, Merck, Pfizer. ML-Q: Consulting or advisory role—Astellas, AstraZeneca, Bayer, MSD, Pfizer; Speakers’ bureau—Astellas, AstraZeneca, BMS, Eisai, Ipsen, MSD, Pfizer; Research funding—AstraZeneca, BMS, Gilead, Ipsen, MSD, Roche; Travel, accommodations, expenses—Ipsen, MSD, Pfizer. PR: Employment—Ipsen. VP: Employment—Ipsen; Stockholder—Ipsen; Travel, accommodations, expenses—Ipsen. BQ: Employment—Ipsen; Stockholder—Ipsen; Honoraria—Ipsen; Travel, accommodations, expenses—Ipsen. PD: Employment—Ipsen. EV: Consulting or advisory role: AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck Sharp & Dohme, MSD Oncology, Novartis, Pfizer. GP: Consulting or advisory role—Accord, Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen, Lilly, Merck Sharp & Dohme, MSD Oncology, Novartis, Pfizer, Roche Genentech; Research funding—Astellas Pharma, Gilead, Ipsen, Janssen Oncology, MSD; Travel, accommodations, expenses—AAA/Novartis, Ipsen, Janssen, Recordati., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Over the years, several prognostic models were developed in patients receiving chemotherapy for metastatic castration resistant prostate cancer (mCRPC), while data on androgen-receptor signaling inhibitors (ARSI) in a real-world setting are limited., Patients and Methods: We compared a consecutive series of 565 mCRPC patients receiving first-line ARSI at 4 high-volume Italian Centers (development set) to an external series of 180 patients receiving the same treatment at another Italian high-volume Center (training set), between 2011 and 2022. Sixteen clinical and baseline laboratory variables were selected to develop a prognostic model. Patients were categorized into risk groups according to the number of independent factors positively associated with overall survival (OS)., Results: In the development cohort, after a median follow-up of 21.1 months, the median OS was 30.4 months (95% CI 27.5-33.4). At the multivariate analysis, 7 variables [age, prostate specific antigen (PSA) doubling time, baseline levels of hemoglobin, PSA, time to castration resistance, ECOG PS and bone metastases number) were included into the final model. The median OS was 13.4, 25.7 and 46.4 months in poor (0-2 factors), intermediate (3-4 factors) and good (≥ 5 factors) prognosis group, respectively. The application of the model to the validation set confirmed its ability to prognosticate for OS. The model c-indexes were 0.68 (95% CI 0.64-0.72) and 0.75 (95% CI 0.68-0.81) in the development and validation cohort, respectively., Conclusions: Our model, based on clinical and laboratory variables readily assessable in clinical practice, might prognosticate the OS of mCRPC patients receiving first-line ARSI., Competing Interests: Disclosure Consuelo Buttigliero has received honoraria for advisory board and speaker engagements from Janssen, Astellas, Merk Sharp & Dohme (MSD), Pfizer, Ipsen, Bristol Meyer Squibb, Astra Zeneca and Bayer. Paola Ermacora. Janssen: Travel Grant, Astellas, BMS, MSD: Spiker, Tripla AAA, MSD: Advisory Board. Orazio Caffo Advisor: AAA, Astellas, Bayer, Janssen, Ipsen, MSD, Pfizer, Astra Zeneca. Speaker: Astellas, Bayer, Janssen, MSD, Recordati Francesco Pierantoni: Advisory board: Eli Lilly; speaker or travel fees: Ipsen, Takeda, Pfizer, MSD, BMS, Merck, Astellas, Janssen, AstraZeneca. Marco Maruzzo Advisor per Jassen, Astellas, MSD, BMS, Merck Serono, Eisai ed Exelixis. Umberto Basso Advisory role: BMS, Novartis, Pfizer AZ, Ipsen Travel accommodation: Bristol-Myers Squibb, Astellas Pharma, Ipsen, MSD Oncology, Merck/Pfizer, Bayer. Other relationship: Jannsen Oncology, Ipsen, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Bayer, Merck/Pfizer. The other authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The present study aimed to investigate the prognostic and predictive roles of Hb/RDW ratio in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI)., Materials and Methods: We performed a sub-analysis of a multicenter retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations., Results: Three hundred and twenty-nine patients were enrolled, 244 males and 85 females. Median age was 65.5 years. The prognostic impact of the Hb/RDW ratio on PFS and OS was observed in the whole population examined. Hb/RDW ratio had a correlation with neutrophil-to-lymphocyte ratio (NLR), a blood inflammatory parameter., Conclusion: Hb/RDW ratio is a new inflammatory prognostic factor, easy to use in daily clinical practice.

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First-line immunotherapy (IO)-based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real-world data confirming the adequate first-line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO-based combinations within the ARON-1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non-sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first-line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non-sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6-44.2) in sRCC and 35.3 months (95%CI 30.2-40.4) in non-sRCC patients (p = .013). The median progression-free survival (PFS) was longer in non-sRCC patients compared to sRCC (14.5 vs. 12.3 months, p = .064). In patients treated with first-line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p = .729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p = .606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO-based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Pembrolizumab/Axitinib combination is approved as first-line therapy in mRCC. The aim of this study is to evaluate outcomes of PAXI combo in the real-world in Italy., Methods: This is a prospective study including patients diagnosed with mRCC who received combination as first-line therapy in recruiting Italian Centers. Data about patient characteristics, safety and outcome were collected., Results: 170 pts have been treated from December 2020 to September 2023. The majority had clear-cell histology (83%). Sarcomatoid feature was present in 33%of available cases. About one half of patients (55%) had synchronous metastasis. In 58% of cases nephrectomy was performed, of which 27% were cytoreductive and 4% were deferred nephrectomies. Lung metastases were identified in 106 patients (62%), bone and liver involvement in 66 and 29 patients (38.8% and 17.1%) respectively. Stratifying by IMDC criteria, 32 patients (18.8%) were at favorable-risk, 106 (62.4%) at intermediate-risk, and 32 (18.8%) at poor-risk. At time of analysis, treatment was ongoing in 49% of patients. Progression occurred in 45% of patients. Median PFS was 19.2 months (95% CI: 15-NR). With a median follow-up of 19.3 months (range 1.3-34.5), at 24-months and 36-months landmark analysis 62% (95% CI, 53-70) and 58% (95% CI, 47-69) of treated patients are still alive respectively. Disease control rate was achieved in 84.6% of patients: 4.3% reached a complete response, 52% had a partial response and 28.8% a stable disease. Primary progression was observed in 15.3% of patients. In the multivariate analysis, the prognostic significance of age ≥ 65 years, non-clear cell histology, IMDC score, and adverse events and gender interaction as predictors of worse OS were confirmed., Conclusion: This is the first available prospective study on first-line Pembrolizumab/Axitinib combination in real world scenario. Our findings support the effectiveness and safety of first-line this combination in mRCC and reveal that gender emerged as a prognostic factor in relation to the occurrence of adverse events., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objective: Apalutamide (APA) is a treatment for metastatic castration-sensitive prostate cancer (mCSPC). In the ARON-3 study we investigated real-world experiences with APA treatment for mCSPC., Methods: We retrospectively assessed real-world clinical outcomes for patients with mCSPC treated with APA in the ARON-3 study. Overall survival (OS) was calculated from APA initiation to death from any cause. PSA 90 was defined as a prostate-specific antigen decline of ≥90% from baseline, and PSA 0.2 as achievement of a PSA level ≤0.2 ng/ml. Data for adverse events were retrospectively collected from electronic and paper charts and categorized according to Common Terminology Criteria for Adverse Events v5.0., Key Findings and Limitations: We included 531 patients with mCSPC treated with APA. High-volume disease was reported for 214 patients (40%), and 56 (11%) had visceral metastases. Median OS was not reached. PSA 90 was experienced by 461 patients (87%) and PSA 0.2 by 368 (69%). Median OS was significantly longer for patients with PSA 90 or PSA 0.2 than for subjects without these responses (p < 0.001). The incidence of grade 3-4 fatigue was higher among elderly patients (≥80 yr) than among younger patients (19% vs 5%), but the incidence of other adverse events was comparable between the age groups., Conclusions and Clinical Implications: APA is an effective and tolerable treatment for mCSPC in the real-world setting., Patient Summary: The ARON-3 project collects data for patients with prostate cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic hormone-sensitive prostate cancer receiving apalutamide. Our results show that apalutamide is a safe and effective drug in the real-world setting as well as in clinical trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy., Objective: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2 EV study., Patients and Methods: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models., Results: Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia., Conclusions: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab., Competing Interests: Declarations Funding No external funding was used in the preparation of this manuscript. Conflicts of Interest Ondřej Fiala received honoraria from Roche, Janssen, GSK, and Pfizer for consultations and lectures unrelated to this project. Francesco Massari has received research support and/or honoraria from Advanced Accelerator Applications, Astellas, Astra Zeneca, Bayer, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. Umberto Basso received honoraria for Bristol-Myers Squibb, Novartis, and Astra Zeneca; research funding from Ipsen; and travel grants from Bristol-Myers Squibb, Janssen Oncology, Astellas Pharma, MSD Oncology, Merck/Pfizer, and Bayer, all unrelated to this project. Sebastiano Buti received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, and Astellas, all unrelated to the present paper. Yüksel Ürün has served on advisory board for Abdi-İbrahim, Astellas, AstraZeneca, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen ilaç, Gilead, GSK, Janssen, Merck, MSD, Novartis, Pfizer, and Roche and received travel grants, honoraria, or consultation fees from Abdi-İbrahim, Astellas, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen İlaç, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, and Roche, all unrelated to the present paper. Maria T. Bourlon is a consultant of Bristol Myers Squibb, Merck, MSD, Gilead, Astellas, and Asofarma and a speaker for Janssen Pharmaceuticasl, MSD, Merck, and Astellas, all unrelated to the present paper. Mimma Rizzo has received honoraria as a speaker/consultant by MSD, Merck Serono, Astrazeneca, Bristol Myers Squibb, Eisai, and Gilead, all unrelated to the present paper. Linda Cerbone has received honoraria for advisory boards, speaker engagements, and scientific consultancy for educational purposes from AstraZeneca, EISAI, MSD, Ipsen, BMS, and A.A.A.; and is a past MSD employee in Medical Affairs. Javier Molina-Cerrillo reports research funding from Roche, Ipsen, Pfizer, and Janssen; travel support from Pfizer, Janssen, Ipsen, and BMS; and a consulting or advisory role with Ipsen, Roche, BMS, Pfizer, Sanofi, Janssen, Astellas, Eisai, Adium, and MSD, all unrelated to the present paper. Álvaro Pinto is a member of advisory boards of Pfizer, Novartis, Ipsen, BMS, Janssen, Astellas, Sanofi, Bayer, Clovis, Roche, MSD, Pierre Fabre, and Merck; has received research support from Pfizer and BMS; clinical trial payments from Pfizer, Bayer, Janssen, MSD, Clovis, Pharmacyclics, BMS, Sanofi, Astra Zeneca, Roche, Eisai, and Aveo; and travel arrangements from Janssen, Roche, Pfizer, BMS, and Ipsen, all unrelated to the present paper. Andrey Soares reports honoraria from Janssen, Pfizer, Bayer, AstraZeneca, Astellas Pharma, Merck Serono, Sanofi, Ipsen, and Adium; consulting or advisory role from Astellas Pharma, Janssen, Roche, Bayer, AstraZeneca, MSD, Bristol-Myers Squibb, Adium, Ipsen, Pfizer, and Novartis; research funding from Bristol-Myers Squibb (Inst), Astellas (Inst), and AstraZeneca (Inst); travel, accommodations, and expenses from Bayer, Janssen, Ipsen, Adium, MSD, and Merck Serono; and ownership in BIO, Brazilian Information Oncology; all unrelated to this study. Alexandr Poprach has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Ipsen, Roche, Astellas, Merck, Eisai, MSD, Novartis, and Pfizer, unrelated to this project. Gian Paolo Spinelli has received payment or honoraria for advidory boards from Novartis, Roche, and Bayer, unrelated to this project. Martin Angel received honoraria from Roche, Johnson & Johnson, Raffo, and Pfizer for consultations and lectures unrelated to this project. Fernando Sabino M. Monteiro reports research support provided by Merck Sharp Dome; honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome; and ownership in BIO, Brazilian Information Oncology, all unrelated to this study. Camillo Porta acted as a remunerated consultant and/or speaker for Angelini Pharma, AstraZeneca, BMC, Eisai, Exilixis, Genenta, Ipsen, Merck Serono, and MSD; as a protocol steering committee member for Eisai and MSD; and as an Independent Review Board member for Genenta. Shilpa Gupta is a consultant for Bristol Myers Squibb, Merck, Pfizer, Gilead, Bayer, and Seattle Genetics; is a speaker for Bristol Myers Squibb; and has institutional research funding from Seatte Genetics, Pfizer, Merck, Bristol Myers Squibb, Roche, Novartis, and Tyra Biosciences. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas, and Bayer, all unrelated to the present paper. Patrizia Giannatempo, Enrique Grande, Zin W. Myint, Ugo De Giorgi, Renate Pichler, Francesco Grillone, Fabio Calabrò, Luca Galli, Ravindran Kanesvaran, Giandomenico Roviello, Jakub Kucharz, Se Hoon Park, Emmanuel Seront, Carlo Messina, Daniele Santini, Akihiro Yano, Lorena Incorvaia, Martina Catalano, Luigi Formisano, Gaetano Facchini, Giuseppe Fornarini, Sara Elena Rebuzzi, Cecilia Nasso, Marco Stellato, Deniz Tural, Gaetano Aurilio, Ilana Epstein, Francesco Carrozza, Giovanni Benedetti, Tomáš Büchler, Cinzia Ortega, Roubini Zakopoulou, Nicola Battelli, and Joaquin Bellmunt declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Tomáš Büchler and Camillo Porta are Editorial Board members of Targeted Oncology. Tomáš Büchler and Camillo Porta were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics Approval The study protocol was approved on 28 September 2023, by the Ethical Committee of the coordinating center (Marche Region – Italy – no. 2022 39/7875, Study Protocol “ARON 2 Study” NCT05290038) and by the Institutional Review Boards of participating centers. Consent to Participate Informed consent with subsequent analysis of the follow-up data was obtained from all participants. Consent for Publication Not applicable. Availability of Data and Material The datasets generated and/or analyzed during the current study are not publicly available due to patient data security but are available from the corresponding author on reasonable request. Code Availability Not applicable. Author Contributions Study concept and design: all authors; acquisition of data: all authors; analysis and interpretation of data: all authors; drafting of the manuscript: Fiala, Massari, Gupta, and Santoni; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: Santoni; obtaining funding: none; administrative, technical, or material support: none; and supervision: Gupta and Santoni., (© 2024. The Author(s).)

Background: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (P ref ), face dismal outcomes., Objective: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of P ref patients., Methods: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve., Results: In our study, the P ref rate was 19%. Nivolumab/ipilimumab showed the highest P ref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-P ref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for P ref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of P ref . This study presents limitations, mainly because of its retrospective design., Conclusions: The ARON-1 study provides valuable insights into P ref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches., Competing Interests: Declarations Funding No external funding was used in the preparation of this article. Conflicts of Interest/Compting Interests Ondrej Fiala received honoraria from Novartis, Janssen, Merck, BMS, MSD, Pierre Fabre, and Pfizer for consultations and lectures unrelated to this project. Sebastiano Buti has received honoraria for speaking at scientific events and advisory roles from Astra Zeneca, BMS, Ipsen, Merck, Eisai, MSD, Novartis, and Pfizer and research funding from Novartis and Pfizer unrelated to this project. He has also been on the advisory board for Gentili. Francesco Massari has received research support and/or honoraria from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. Enrique Grande has received honoraria for speaker engagements and advisory roles or received funding for continuous medical education from Adacap, Amgen, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, Ipsen, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific and research grants from Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. All of the above are unrelated to the present paper. Alexandr Poprach has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Ipsen, Roche, Astellas, Merck, Eisai, MSD, Novartis, and Pfizer, unrelated to this project. Javier Molina-Cerrillo declares consultant, advisory, or speaker roles for Ipsen, Roche, Pfizer, Sanofi, Janssen, and BMS unrelated to this project. Zin W. Myint has received research support from Merck unrelated to the present paper. Ray Manneh Kopp has received research support and/or honoraria from Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Janssen, MSD, Pfizer, Tecnofarma and Roche, unrelated to this project. Jakub Kucharz has received honoraria from Angelini, Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, and Pfizer, and research funding from Novartis, all unrelated to the present paper. Fernando Sabino M. Monteiro has received research support from Janssen and Merck Sharp Dome and honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome, all unrelated to the present paper. Ravindran Kanesvaran has received fees for speaker bureau and advisory board activities from the following companies; Pfizer, MSD, BMS, Eisai, Ipsen, Johnson and Johnson, Merck, Amgen, Astellas, and Bayer, unrelated to this project. Tomáš Büchler has received research support from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer, all unrelated to the present paper. Andrey Soares has received honoraria from Janssen, Pfizer, Bayer, AstraZeneca, Astellas Pharma, Merck Serono, Sanofi, Ipsen, Adium. Consulting or Advisory Role from Astellas Pharma, Janssen, Roche, Bayer, AstraZeneca, MSD, Bristol-Myers Squibb, Adium, Ipsen, and Pfizer, research Funding from Bristol-Myers Squibb (Inst), Astellas (Inst), and AstraZeneca (Inst), travel, accommodations, and expenses from Bayer, Janssen, Ipsen, Adium, MSD, and Merck Serono, and ownership in BIO, Brazilian Information Oncology. All are unrelated to this study. Camillo Porta has received honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, Exelixis, Genenta, Ipsen, Merck Serono, and MSD and acted as a Protocol Steering Committee Member for Eisai and MSD, unrelated to this project. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas, A.A.A. and Bayer, all unrelated to the present paper. Daniele Santini, Haoran Li, Giandomenico Roviello, Se Hoon Park, Umberto Basso, Martina Catalano, Emmanuel Seront, Jawaher Ansari, Marwan Ghosn, Fabio Calabrò, Dipen Bhuva, Maria T. Bourlon, Michela Roberto, Mattia Alberto Di Civita, Veronica Mollica, Andrea Marchetti, Nicola Battelli, Marco Ricci, and Aristotelis Bamias have no conflicts of interest that are directly relevant to the content of this article. Tomas Buchler and Camillo Porta are Editorial Board members of Targeted Oncology. Tomas Buchler and Camillo Porta were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics Approval The “ARON-1” project obtained approved from the Ethics Committee of the Marche Region (2021-492) and adhered to the principles outlined in the Declaration of Helsinki. Consent to Participate Informed consent was obtained from all individual participants included in the study. Consent for Publication Not applicable. Availability of Data and Material The datasets generated during and/or analyzed in the current study are available from the corresponding author on reasonable request. Code Availability Not applicable. Authors’ Contributions Conception and design: DS, MS, FM; acquisition of data: DS, MS, FM; analysis and interpretation of data: DS, MS, FM; drafting of the manuscript: DS, MS, FM; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: MS; supervision: MS, FM., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Rationale: Metastatic castration-resistant prostate cancer has a poor prognosis especially when harboring DNA damage repair gene mutations, nevertheless, in the case of pathogenic BRCA gene mutations, PARPi demonstrated a survival benefit and is a validated treatment. Nowadays, there is no data regarding unusual metastases after these drugs. Cutaneous metastases appear rarely in prostate cancer and were associated with a worse prognosis. Moreover, there are no consolidated data concerning skin tropism of prostate cancer cells, neither in the case of BRCA-associated cancers., Patient Concerns: Here, we report the case of a patient with a long history of BRCA1-mutated metastatic castration-resistant prostate cancer who developed a skin lesion on the scalp while on his fifth line of systemic therapy with olaparib. After a complete radical surgical excision, the pathology report showed prostate cancer localization., Diagnoses: A diagnosis of skin metastasis from prostate cancer was reported., Outcomes: The patient then continued olaparib therapy; after 7 months from excision, he experienced further bone and biochemical progression but not cutaneous progression., Lessons: A literature review of all reported cases of cutaneous metastasis in prostate cancer was conducted to shed light on the incidence, clinical presentation, diagnosis, treatment, and prognosis of this entity. We also reviewed published cases of skin metastasis in BRCA-associated cancers with an effort to correlate skin involvement with PARPi treatment, BRCAness status, and prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/aim: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC). However, they could be associated with immune-related adverse events (irAEs), which may be clinically significant. Identifying clinical characteristics that may be associated with a higher risk of irAEs is of great importance., Patients and Methods: We retrospectively collected data from all patients who received anti-PD1 or anti-PD-L1 for metastatic UC at our Institution from January 2017 to December 2022. Patients were dichotomized according to baseline neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR) values. We performed univariate and multivariate logistic regression to determine the association between baseline characteristics and the development of irAEs., Results: A total of 119 patients were identified. At a median follow-up of 29.6 months, 96 patients progressed and 82 died. Forty-five patients developed irAEs of any grade, 8 patients developed grade 3 toxicities. In the univariate analysis PS of 0 (p<0.01), baseline NLR <3.52, baseline PLR <194 (p=0.04) and baseline SII <906 (p=0.01) were significantly associated with a higher risk of developing irAEs, whereas in the multivariate analysis only PS=0 (p<0.01) and NLR <3.52 (p=0.03) maintained their correlation. Median progression-free survival (mPFS) and overall survival (mOS) were significantly longer in patients with NLR <3 (mPFS 3.8 vs. 2.6 months, p=0.01; mOS 15.3 vs. 5.6 months, p=0.002) and PS=0 (mPFS 4.8 vs. 2.1 months, p<0.001; mOS 15.3 vs. 3.8 months, p<0.001)., Conclusion: Low baseline NLR, PLR, and SII and good PS are associated with a higher risk of developing irAEs in patients treated with ICIs for mUC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear., Methods: The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile., Discussion: Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity., Trial Registration: CESC IOV 2023-78., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy., Patients and Methods: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors., Results: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001)., Conclusions: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy., (© 2024. The Author(s).)

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling., (© 2024. The Author(s).)

Background: The addition of neutrophil to lymphocyte ratio (NLR) and bone metastases to the IMDC classification provided by the Meet-URO score, resulted in higher prognostic accuracy in metastatic renal cell carcinoma (mRCC) patients receiving ≥2nd line nivolumab or cabozantinib in 2 retrospective analyses and 1st line nivolumab-ipilimumab in an expanded access programme. Prognostic estimates for older mRCC patients might be key for clinical decision-making., Methods: The outcome of real-world older (≥70 years) mRCC patients treated with any line cabozantinib within the multicenter observational prospective ZEBRA (Meet-URO 9) study was analyzed according to the baseline Meet-URO score. The primary endpoint was overall survival (OS). The discriminative ability by Harrell's c-index and calibration were assessed to compare the Meet-URO and IMDC scores., Results: A total of 104 mRCC patients received cabozantinib as 1st (38%), 2nd (20%), or ≥3rd (41%) line. With a median follow-up of 11.2 months, the median OS (mOS) was of 18.4 months. According to the IMDC score, favorable (15%), intermediate (65%) and poor-risk (19%) patients had a mOS not reached, of 15.6 and 5.7 months respectively (p = .011). According to the Meet-URO score groups, mOS was not reached in both group 1 (10%) and group 2 (25%), while in group 3 (33%), group 4 (25%) and group 5 (8%) mOS was of 13.6, 12.5, and 3.7 months, respectively (p < .001). The discriminative ability of the Meet-URO score was maintained by merging groups 1 to 2 vs. 3 to 4 vs. 5 (p < .001). The Meet-URO score (with either the original 5-group stratification or the modified 3-group one) showed higher accuracy than the IMDC score (c-index of 0.686 and 0.676 vs. 0.622)., Conclusion: This analysis confirmed the prognostic accuracy of the Meet-URO score in older mRCC patients treated with cabozantinib and its role as a convenient tool for informing the patient and clinical decisions., Competing Interests: Disclosure SR received honoraria as a speaker at scientific events and travel accommodation from Amgen, GSK, BMS, and MSD. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accomodation from Astellas, Janssen, Bayer. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. MS services advisory boards/consulting for Janssen, received research funding from Janssen and received travel accomodation from Ipsen, BMS, Janssen, Pfizer, Astellas Pharma. PR services advisory boards for MSD, AstraZeneca and Janssen. GLB reports personal fees from AstraZeneca and Astellas and non-financial support from Janssen. DS received honoraria for the advisory board from Amgen, Jansen, MSD, BMS, Bayer, Astra Zeneca, Ipsen, Novartis, and Merck. CN received honoraria as a speaker at scientific events from Astellas and BMS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Treatment with a combination of immune checkpoint inhibitors (ICIs) (pembrolizumab or nivolumab) and oral Tyrosine Kinase Inhibitors (TKI) targeting angiogenesis (axitinib, cabozantinib or lenvatinib) has shown benefits in terms of efficacy and survival in metastatic renal cell carcinoma (mRCC), with a favorable toxicity profile. However, some rare and serious treatment-related adverse events can be difficult to manage., Patient Concerns: Here we report the first case of an mRCC patient who, after only 2 administrations of pembrolizumab-axitinib, experienced severe multiorgan failure (MOF) with heart failure, oliguria and acute hepatitis requiring aggressive supportive treatment in intensive care unit., Diagnoses: A diagnosis of severe MOF induced by pembrolizumab plus axitinib was considered., Interventions: The patient was treated with dobutamine, levosimendan along with high-dose steroids under continuous cardiologic monitoring., Outcomes: After treatment, the patient had a full recovery and was discharged from the hospital., Lessons: We reviewed all the other cases of MOF reported during treatment with combined ICI-TKI in cancer patients in order to summarize incidence, clinical manifestations and management with a specific focus on the need for prompt recognition and aggressive management under multidisciplinary care., Competing Interests: U.B.: advisory board for BMS, NOVARTIS, MSD, ASTRA ZENECA, PFIZER; speaker’s fees and/or travel grants from Janssen, Astellas, Ipsen, Merck, Bms, MSD, Astra Zeneca. For the remaining authors, there are no conflicts of interest., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification., Significance: Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384., (©2023 The Authors; Published by the American Association for Cancer Research.)

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis., (© 2024. The Author(s).)

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients' IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5-ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28-37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs., (© 2024. The Author(s).)

Background: The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) genes in the Italian population is unknown., Objective: In this prospective multicenter cohort study, we evaluated the prevalence of gDDR alterations in the Italian population affected by metastatic prostate cancer (mPCa) and analyzed the impact on response to therapy, survival, and time to castration resistance., Design Setting and Participants: In an observational prospective trial, 300 consecutive Italian mPCa patients, enrolled in the Meet-Uro-10 trial from three academic Italian centers, were recruited between 2017 and 2019 and were screened for gDDR mutations in 107 genes., Outcome Measurements and Statistical Analysis: The primary endpoint was to assess the prevalence of gDDR mutations in the Italian population of patients with mPCa. The secondary endpoints included the association of gDDR subgroups with metastatic onset, Gleason score, and time to castration resistance., Results and Limitations: We identified 297 valuable patients. Forty-six patients had a pathogenic/likely pathogenic variant (15.5%, 95% confidence interval: 11.4-19.6): the more frequent was gBRCA2 found in nine cases (3%), followed by gATM in five cases (1.7%). In patients without mutations, longer median overall survival was observed with the sequence docetaxel-androgen receptor signaling inhibitor (ARSI) than with the sequence ARSI-docetaxel (87.9 vs 42 mo, p  = 0.0001). In a univariate analysis, the median time to castration resistance in gDDR mutated patients was 19.8 mo, versus 23.7 mo in no mutated patients ( p  = 0.024). There were no associations of gDDR subgroups with metastatic onset and Gleason score ≥8. In our cohort, variants of unknown significance in gDDR genes were found in 80 patients and might have a prognostic relevance., Conclusions: The study reported the prevalence of gDDR in the Italian population. The presence of gBRCA2 mutations correlates with a shorter time to the onset of castration resistance disease., Patient Summary: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to that in the Spanish population, identifying similarities between people of the Western Mediterranean area., (© 2024 The Authors.)

Background: Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis., Objectives: Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes., Methods: In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7., Results: From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1-2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively., Conclusion: The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites., Trial Registration: ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017., (© The Author(s), 2024.)

Background: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC., Patients and Methods: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety., Results: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death., Conclusions: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population., Competing Interests: Disclosure AOS has received honoraria from Astellas, AstraZeneca, Bavarina Nordic, Basilea, Bicycle Therapeutics, Bristol Myers Squibb, G1 Therapeutics, Genentech, Gilead, Ideeya Biosciences, Immunomedics, Janssen, Loxo, Merck, Mirati, Nektar, Seattle Genetics, and Taiho and research funding (institutional) from Basilea Pharmaceutica, Bristol Myers Squibb, Janssen, Loxo, Merck, Millennium, and Nektar. NM has received honoraria (personal) from Sanofi; research funding (institutional) from Amgen, Astellas Pharma, AstraZeneca, Bayer, Chugai Pharm, Eisai, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; and has been reimbursed for travel, accommodations, or expenses (personal) from Pfizer. SHP has received honoraria from Merck, Ono Pharma Korea, and Pfizer; served as a consultant for Janssen Oncology; and received institutional research support from Merck Sharp & Dohme. RAH has received personal fees from Aspen Parkside Hospital, Merck, and Pfizer; consulting fees from Bristol Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, and Bayer; honoraria from Janssen Oncology; has been reimbursed for travel, accommodations, or expenses from Janssen Oncology, Roche/Genentech, MSD Oncology, and Nektar; has other financial or non-financial interests with Merck Sharp & Dohme, Roche, Bristol Myers Squibb, and Janssen; and has a leadership or fiduciary role at Cancer Clinic London Liability Partnership, outside of the submitted work. EFB has received honoraria from Exelixis, Janssen, Merck, Novartis, and Pfizer; research funding (personal) from Astellas and Pfizer; and research funding (institutional) from Astellas, Bristol Myers Squibb, Janssen, Merck, Pfizer, Roche/Genentech, and Seagen. NH has received consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Merck, and Pfizer. MO has served as a consultant for Sanofi, Astellas, and Bayer; has participated in a speaker’s bureau for Regeneron; and has been reimbursed for travel, accommodation, and expenses by Sanofi and Regeneron. BPV has served as a consultant for Astellas Pharma, Astra Zeneca, Bayer, Bristol Myers Squibb, and Novartis; has received honoraria from Astellas, Bristol Myers Squibb, Eusa Pharma, Ipsen, Merck Sharp & Dohme, Pierre Fabre, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or expenses by Bristol Myers Squibb, Janssen-Cilag, Merck, Novartis, and Pfizer. BL has received honoraria from Janssen and has been reimbursed for travel, accommodations, or expenses by Astellas, Jassen, and Pfizer. UB has participated in a speaker’s bureau for and/or received travel and accommodation grants from Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, and Merck Sharp & Dohme and has received research funding (institutional) from Ipsen. YK serves as a functional service provider for Janssen. ST, SA, KD, and SM are employed by Janssen Research & Development and have stock or stock options with Johnson & Johnson. YL has received consulting fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Immunomedics, Janssen (and institutional), MSD Oncology (and institutional), Loxo/Lilly, Pfizer/EMD Serono, Roche, and Taiho Pharmaceutical; has been reimbursed for travel, accommodations, or expenses from Astellas, AstraZeneca, Janssen Oncology, MSD Oncology, and Roche; and has received research funding (institutional) from Astellas Pharma, AstraZeneca, Basilea, Bristol Myers Squibb, Exelixis, Gilead Sciences, Incyte, Janssen Oncology, Merck KGaA, MSD Oncology, Nektar, Pfizer, Roche, Sanofi, and Taiho Pharmaceutical., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Evaluation of tumor response according only to dimensional criteria may underestimate treatment benefit in patients treated for metastatic renal cell carcinoma (RCC). In this study we evaluated the role of lesion enhancement modifications and Choi criteria in patients affected by renal cell carcinoma treated with immunotherapy., Methods: We collected data of 60 consecutive patients (with a total of 154 measurable lesions) treated with immunotherapy (nivolumab or ipilimumab plus nivolumab) at a single Institution. We evaluated tumour response using both RECIST1.1 criteria and Choi criteria at the first radiological assessment; we subsequently associated response with progression free survival and overall survival., Results: Choi criteria found a higher rate of objective response compared to RECIST criteria (38.3% vs 18.3%). An objective response according to both criteria was associated with longer progression free survival and overall survival. Response rate for Choi did not vary according to lesion site., Conclusion: Choi criteria seemed to be able to predict clinical benefit in a higher proportion of patients with renal cell carcinoma treated with immunotherapy than RECIST criteria. Partial response according to RECIST was confirmed as a predictor of longer progression-free survival and overall survival., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: A low fT3/fT4 ratio has been associated with a poorer prognosis in patients treated for different solid malignancies. However, the prognostic role of baseline thyroid function in patients with metastatic urothelial carcinoma (mUC) has not yet been established., Patients and Methods: We analyzed 72 consecutive immunotherapy-treated patients with mUC from a single institution. We recorded clinical data, baseline blood test results, and oncological outcomes. We stratified patients into three groups according to the fT3/fT4 ratio value and analyzed differences in progression-free survival (PFS), overall survival (OS), and radiological response in the three groups. We also conducted univariate and multivariate analyses to identify prognostic factors for PFS and OS., Results: The median PFS in the low, intermediate, and high fT3/fT4 ratio groups was 2.2, 4.1, and 8.2 months, respectively (P < 0.01). The median OS in the low, intermediate, and high fT3/fT4 groups was 3.6, 10.3, and 19.1 months, respectively (P < .01). The low fT3/fT4 ratio maintained its prognostic role independently of other prognostic factors. Patients with a high fT3/fT4 ratio had an increased radiological response., Conclusion: Thyroid hormone impairment, as measured by the fT3/fT4 ratio, is a strong prognostic factor in patients treated with immunotherapy for urothelial carcinoma., Competing Interests: Disclosure This research received “Ricerca Corrente” funding from the Italian Ministry of Health to cover publication costs., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC)., Patients and Methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival., Results: A total of 675 patients were included; BMI was >25 kg/m 2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m 2 versus those with BMI ≤25 kg/m 2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m 2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002)., Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC., Methods: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study., Results: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD., Conclusions: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of cancer. Treatment recommendations are extrapolated from ccRCC and lack solid evidence. Here, we review advanced nccRCC patients treated at our institute., Patients and Methods: We collected retrospective data on all advanced nccRCC pts treated at the Istituto Oncologico Veneto from January 2008. We compared overall response rate (ORR), progression free survival (PFS) and overall survival (OS) according to histological subtypes and type of systemic treatments. Kaplan-Meier method, log-rank test and Cox regression were used to estimate and compare PFS and OS., Results: Of 1370 RCC patients, 289 had a diagnosis of nccRCC and 121 were eligible for the analysis. Fifty-three pts showed papillary histology (pRCC), 15 chromophobe; 37 unclassified RCC (NOS-RCC), 16 other histologies. Pts with chromophobe and other hystologies showed poorer survival rates compared to pRCC and NOS-RCC (mOS 10.7 vs. 20.7 vs. 30.7, p = 0.34). Pts treated with combination regimens achieved a better OS (30.7 vs. 13.7, p = 0.10), PFS (12.7 vs. 6.4, p = 0.10) and ORR (42.4% vs. 13.9%, p = 0.002) than those treated with monotherapy. IMDC and Meet-URO score retained their prognostic value., Conclusion: Our retrospective real-life cohort of advanced nccRCC patients shows that immunotherapy-based combinations could improve ORR, PFS and OS compared to TKI monotherapy. Prospective trials for nccRCC patients utilizing novel therapies are ongoing and their results eagerly awaited.

Background: Renal cell carcinoma (RCC) is the seventh most common neoplasm in high-income countries. New clinical pathways have been developed to deal with this tumor, which includes costly drugs that pose an economic threat to the sustainability of healthcare services. This study provides an estimate of the direct costs of care for patients with RCC by stage of disease (early vs. advanced) at diagnosis, and disease management phase along the pathway recommended by local and international guidelines., Materials and Methods: Considering the clinical pathway for RCC adopted in the Veneto region (north-east Italy) and the latest guidelines, we developed a very detailed "whole-disease" model that covers the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of RCC. Based on the cost of each procedure according to the Veneto Regional Authority's official reimbursement tariffs, we estimated the total and average per-patient costs by stage of disease (early or advanced) and phase of its management., Results: In the first year after diagnosis, the mean expected cost of a patient with RCC is €12,991 if it is localized or locally-advanced and reaches €40,586 if it is advanced. For early disease, the main cost is incurred by surgery, whereas medical therapy (first and second line) and supportive care become increasingly important for metastatic disease., Conclusion: It is crucially important to examine the direct costs of care for RCC, and to predict the burden on healthcare services of new oncological therapies and treatments, as the findings could be useful for policy-makers planning the allocation of resources., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC)., Objective: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients., Patients and Methods: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB)., Results: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001)., Conclusions: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations., Clinical Trial Registration: NCT05287464., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: To assess caregivers' characteristics and influence of the presence or absence of the caregiver on clinical outcomes of older (≥70 years) metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone (ABI) or enzalutamide (ENZ)., Methods: Patients from the Meet-URO 5 ADHERE study were assessed with a 5-item caregiver evaluation questionnaire focusing on the presence, age, degree of kinship, working status and qualification of the caregiver. We investigated the association between the presence of a caregiver and the clinical characteristics and outcomes of enrolled patients., Results: No differences were found in the main clinical characteristics between patients with or without a caregiver, except for a lower median G8 score (p = 0.0453) in the caregiver group. A longer radiographic PFS (rPFS) was observed in the group without a caregiver, with a trend towards more prolonged overall survival (OS) in the same group., Conclusion: Our work suggests a detrimental effect of caregivers in managing older mCRPC patients treated with ABI or ENZ, especially those identified as frail by the geriatric G8 screening score. Further work is needed to identify and address patients' vulnerability areas, which could have a detrimental effect on prognosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Inflammation indexes had been associated with overall survival (OS) and immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs)., Materials & Methods: in 72 patients treated with ICIs for metastatic urothelial carcinoma (mUC) we evaluate differences in OS, response rate and toxicities, according to baseline inflammation indexes values., Results: neutrophil-to-lymphocite ratio (NLR) <3 was associated to longer progression-free survival (PFS; 4.9 vs 3.1 months) and OS (15.7 vs 7.6 months); monocyte-to-lymphocite ratio (MLR) <0.4 was associated to longer PFS (4.6 vs 2.8 months). Overall response rate (ORR), disease control rate (DCR) were higher in these patients. Patients with an irAE had longer PFS and OS., Conclusion: baseline inflammatory indexes are prognostic for mUC patients treated with ICIs., Competing Interests: The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (© 2023 The Authors.)

Background: The current prognostic models for patients with advanced urinary tract cancers were developed and validated in the chemotherapy setting. As immunotherapy has become the backbone of novel treatments, updated prognostic scores are needed., Methods: A comprehensive analysis of inflammatory indexes from peripheral blood and clinical factors was planned on the entire real-world cohort of pretreated patients with advanced urinary tract carcinoma receiving atezolizumab in the prospective, single-arm, phase IIIb SAUL study. Univariable and multivariable analyses with overall survival as the primary endpoint, bootstrap internal validation, Schneeweiss scoring system and calibration test were performed to develop a novel immunotherapy prognostic score., Results: Thirteen clinical variables from 1001 patients were analyzed. The following eight prognostic factors were included in a model: ECOG PS, liver and bone metastases, histology, pre-treatment steroids, systemic immune-inflammatory index (i.e., neutrophils-to-lymphocytes ratio times platelets count), hemoglobin and lactate dehydrogenase. The prognostic model was able to stratify patients into five risk groups with significantly different (P<0.001) median overall survival of NR, 18.0, 8.7, 4.6 and 2.4 months, respectively. The c-index for OS was higher than the Bellmunt Score one (0.702 vs. 0.672)., Conclusions: A novel 5-class prognostic model contemporary to immunotherapy provides robust prognostic discrimination of patients with advanced urinary tract carcinoma homogeneously treated with immunotherapy through baseline affordable and reproducible clinical and laboratory factors. It could be quickly adopted in clinical practice to inform patients about prognosis with immunotherapy and assess the benefit of novel immunotherapy combinations in clinical trials.

Background/aim: Renal cell carcinoma (RCC) constitutes approximately 3% of all cancers. More than 60% of RCCs are detected incidentally; one-third of patients present with regional or distant metastases, and another 20-40% of patients develop metastases after radical nephrectomy. RCC can metastasize to any organ. In contrast, metastatic RCC (mRCC) without evidence of a primary tumor is extremely rare, with only a few reported cases., Case Report: We present a case of mRCC that initially presented with multiple liver and lymph node metastases but no primary renal lesion. An impressive response to treatment was achieved with a combination of immune checkpoint inhibitors and tyrosine kinase inhibitors. A clinical, radiological, and pathological diagnostic strategy, particularly in the context of a multidisciplinary team, are crucial for reaching a definitive diagnosis. This approach allows to select the appropriate treatment, making a huge difference for a mRCC due to its resistance to standard chemotherapy., Conclusion: There are currently no guidelines available for mRCC without primary tumor. Nevertheless, a combination of TKI and immunotherapy could be the optimal first-line treatment if systemic therapy is required., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation., Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed., Results: A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression ( p = 0.059) and CD8+/CD4+ ratio ( p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading., Conclusions: Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned.

Objective: The incidence of Wilms' tumor (WT) among adult individuals accounts for less than 1% of kidney cancer cases, with a prognosis usually less favorable when compared to younger individuals and an overall survival rate of 70% for the adult patients versus 90% for the pediatric cases. The diagnosis and treatment of WT are complex in the preoperative setting; neoadjuvant chemotherapy (NAC) or robotic surgery has rarely been described. This study aimed to review the literature of robotic surgery in WT and report the first adult WT management using both NAC and robotic strategy., Methods: We reported a case of WT managed in a multidisciplinary setting. Furthermore, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses recommendations, a systematic review of the literature until August 2020 of WT treated with a robotic approach was carried out., Results: A 33-year-old female had a diagnosis of WT. She was scheduled to NAC, and according to the clinical and radiological response to a robotic radical nephrectomy with aortic lymph nodes dissection, she was managed with no intraoperative rupture, a favorable surgical outcome, and a follow-up of 25 months, which did not show any recurrence. The systematic review identified a total number of 230 cases of minimally invasive surgery reported in the literature for WT. Of these, approximately 15 patients were carried out using robotic surgery in adolescents while none in adults. Moreover, NAC has not been administered before minimally invasive surgery in adults up until now., Conclusion: WT is a rare condition in adults with only a few cases treated with either NAC or minimally invasive approach so far. The advantage of NAC followed by the robotic approach could lead to favorable outcomes in this complex scenario. Notwithstanding, additional cases of adult WT need to be identified and investigated to improve the oncological outcome., Competing Interests: The authors declare no conflict of interest., (© 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Introduction: Radionecrosis is a consequence of SRS (stereotactic radiosurgery) for brain metastases in 34% of cases, and if symptomatic (8%-16%), it requires therapy with corticosteroids and bevacizumab and, less frequently, surgery. Oncological indications are increasing and appropriate stereotactic adapted LINACs (linear accelerators) are becoming more widely available worldwide. Efforts are being made to treat brain radionecrosis in order to relieve symptoms and spare the use of active therapies., Case Presentation: Herein, we describe a 65-year-old female patient presenting with brain radionecrosis 6 months after stereotactic radiotherapy for two brain metastatic lesions. Being symptomatic with headache and slow cognitive-motor function, the patient received corticosteroids. Because of later lung progression, the patient took cabozantinib. An impressive reduction of the two brain radionecrosis areas was seen at the brain MRI 2 months after the initiation of the angiogenic drug., Discussion: The high incidence of radionecrosis (2/2 treated lesions) can be interpreted by the combination of SRS and previous ipilimumab that is associated with increased risk of radionecrosis. The molecular mechanisms of brain radionecrosis, and its exact duration in time, are poorly understood. We hypothesize that the antiangiogenic effect of cabozantinib may have had a strong effect in reducing brain radionecrosis areas., Conclusion: In this clinical case, cabozantinib is associated with a fast and significant volume reduction of brain radionecrosis appearing after SRS and concomitant immunotherapy. This drug seems to show, like bevacizumab, clinical implications not only for its efficacy in systemic disease control but also in reducing brain radionecrosis. More research is needed to evaluate all molecular mechanisms of brain radionecrosis and their interaction with systemic therapies like third-generation TKIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lolli, Tessari, Berti, Fusella, Fiorentin, Bimbatti, Basso and Busato.)

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P<0.0001), and median progression-free survival of 11.6 (95% CI: 9.1-14.1) months versus 4.8 (95% CI: 2.7-7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0-1) versus the unfavorable (score 2-4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Testicular cancer (TC) is the most common solid tumor in young adults. 95% of patients are cured, but they may experience late adverse effects (anxiety, fear of recurrence, and sexual dysfunction) with an impact on daily life. We attempted to assess Patient Reported Outcomes (PROMs), long-term sexual disorders, and difficulties in achieving fatherhood in a cohort of TC survivors, as well as their possible correlation with previous cancer treatments., Methods: Different questionnaires, such as the Impact of Cancer (IOC) and the Body Image Scale (BIS), were used to investigate the distinct areas of the PROMs. International Index of Erectile Function (IIEF15) and the Premature Ejaculation Diagnostic Tool (PEDT) focused on sexuality and fertility. Patients were prospectively recruited between February 2020 and February 2022., Results: 144 participants completed all the questionnaires. Results showed a good QoL, a moderate fear of TC recurrence, a good satisfaction with their personal body image, low incidence of premature ejaculation and erectile dysfunction. 19.5% of patients who had a testicular implant reported general dissatisfaction. Only 18% of patients had unsuccessfully attempted fatherhood, while the majority had not yet tried, and 23.4% succeeded. A low percentage of patients used procedures assisted reproduction and adoption., Conclusion: This trial supports the use of various questionnaires as a multifactorial tool capable of investigating all the aspects of long-term cancer survivorship. The assessment of medical and psychosocial sequelae is an essential part of patient care and is important for the development of a comprehensive care plan for TC survivors., Competing Interests: Dr Francesco Pierantoni reports personal fees from AstraZeneca, travel fees from Janssen, outside the submitted work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Bimbatti et al.)

Background: The RCC treatment landscape has evolved dramatically over the past decade. The purpose of this study is to present a real-world data estimation of RCC's cost-of-illness for this tumour's clinical pathway., Methods: This investigation is a population-based cohort study using real-world data, which considers all RCC incident cases diagnosed in Local Unit 6 of the Province of Padua in 2016 and 2017 as registered by the Veneto Cancer Registry. Data on drug prescriptions, the use of medical devices, hospital admissions, and visits to outpatient clinics and emergency departments were collected by means of administrative databases. We evaluated the costs of all healthcare procedures performed in the 2 years of follow-up post-RCC diagnosis. The overall and annual average real-world costs per patient, both as a whole and by single item, were calculated and stratified by stage of disease at diagnosis., Results: The analysis involved a population of 148 patients with a median age of 65.8 years, 66.22% of whom were male. Two years after diagnosis, the average total costs amounted to €21,429 per patient. There is a steady increment in costs with increasing stage at diagnosis, with a total amount of €41,494 spent 2 years after diagnosis for stage IV patients, which is 2.44 times higher than the expenditure for stage I patients (€17,037). In the first year, hospitalization appeared to be the most expensive item for both early and advanced disease. In the second year, however, outpatient procedures were the main cost driver in the earlier stages, whereas anticancer drugs accounted for the highest costs in the advanced stages., Conclusions: This observational study provides real-world and valuable estimates of RCC's cost-of-illness, which could enable policymakers to construct dynamic economic cost-effectiveness evaluation models based on real world costs' evaluation., (© 2022. The Author(s).)

Background: Novel androgen receptor signaling inhibitors for prostate cancer (PC) impose the burden of self-administration on older patients overwhelmed by the requirement of many other concomitant medications., Patients and Methods: This study evaluated the proportion of non-adherence in a 12-month follow-up period and the first 3 months to abiraterone (ABI) or enzalutamide (ENZ). In a prospective multicenter observational cohort study, patients with metastatic castration-resistant PC (mCRPC) aged ≥70 years receiving ABI or ENZ pre- or post-docetaxel were enrolled. Treatment monitoring included pill counting, a self-assessment questionnaire, and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting., Results: Overall, 234 patients were recruited with median age of 78 years (range, 73-82); 86 (37%) were treated with ABI, and 148 (63%) with ENZ. The median follow-up for adherence was seven monthly cycles (IQR: 4-12). The two cohorts were well balanced for baseline characteristics. The percentage of non-adherence by pill counting was slightly higher for ABI than ENZ (5.2% vs. 4.2%, P < .001). By self-reporting, patients on ENZ tended to report more frequently than those with ABI forgetfulness as the reason for missing events (42% vs. 17%, P < .001). A lower Geriatric G8 score correlated with non-adherence (P = .004). Overall survival (OS) was 48.8 months. Patients on ABI had radiographic progression-free survival (rPFS) of 28.4 [24.2-32.5], while for ENZ patients, we reported a median rPFS of 23.1 [18.2-28.1] months., Conclusion: Physicians tend to treat older mCRPC patients with ENZ. Non-adherence rate is relatively low overall but can be higher with ABI than with ENZ and correlates with the Geriatric G8 score. Forgetfulness is a potential barrier for ENZ., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The Meet-URO score allowed a more accurate prognostication than the International Metastatic RCC Database Consortium (IMDC) for patients with pre-treated metastatic renal cell carcinoma (mRCC) by adding the pre-treatment neutrophil-to-lymphocyte ratio and presence of bone metastases., Materials and Methods: A post hoc analysis was carried out to validate the Meet-URO score on the overall survival (OS) of patients with IMDC intermediate-poor-risk mRCC treated with first-line nivolumab plus ipilimumab within the prospective Italian Expanded Access Programme (EAP). We additionally considered progression-free survival (PFS) and disease response rates. Harrell's c-index was calculated to compare the accuracy of survival prediction., Results: Overall the EAP included 306 patients, with a median follow-up of 12.2 months, median OS was not reached, 1-year OS was 66.8% and median PFS was 7.9 months. By univariable analysis, both the IMDC score and the two additional variables of the Meet-URO score were associated with either OS or PFS (P < 0.001 for all comparisons). The four Meet-URO risk groups (G) had 1-year OS of 92%, 72%, 50% and 21% for G2 (29.1% of patients), G3 (28.8%), G4 (33.0%) and G5 (9.1%), respectively. OS was significantly shorter in each consecutive G (P = 0.001 for G3, P < 0.001 for both G4 and G5 compared to G2). Similarly, Meet-URO Gs 2-5 showed decreasing median PFS and response rates. The Meet-URO score showed the highest c-index for both OS (0.73) and PFS (0.67). Limitations include the post hoc nature of this analysis and the lack of a comparative arm to assess predictive value., Conclusion: The Meet-URO score appeared to show better prognostic classification than the IMDC alone in patients with mRCC at IMDC intermediate-poor risk treated with first-line nivolumab and ipilimumab., Competing Interests: Disclosure SER received honoraria as a speaker at scientific events and travel accommodation from Amgen, GSK, BMS, MSD. SB received honoraria as a speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis. GLB reported personal fees from Astellas and AstraZeneca. MM reports personal fees from BMS, Pfizer, Merck Serono, Astellas, Janssen, MSD. UDG served as an advisory/board member of Astellas, Bayer, BMS, IPSEN, Janssen, Merck, Pfizer, Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi and travel/accommodations/expenses from BMS, IPSEN, Janssen, Pfizer. GP served as a consultant and/or a speaker for Bayer, BMS, Novartis, Amgen, Pfizer, Janssen, Ipsen, Boehringer. FC has received consulting fees from Merck Sharp & Dohme Oncology and Pfizer. GC works as responsible for research and development at Kerubin Digital Therapeutic. CP served as a consultant and/or a speaker for Ipsen, BMS, MSD, Astra Zeneca, Pfizer, Eisai, EUSA and General Electrics, as an expert testimony for both Pfizer and EUSA and is a protocol steering committee member for BMS, EUSA and Eisai. PR served as an advisory board for MSD and Astra Zeneca Italy. GF served as an advisory board member for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accommodation from Astellas, Janssen, Bayer. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A subset of patients with metastatic renal cell carcinoma (mRCC), deemed as primary refractory, shows progressive disease as the best response to first-line therapy even when treated with novel immune-based combos., Objective: We aimed to assess the outcome of patients treated with second-line cabozantinib for mRCC primary refractory to first-line therapy defined as Response Evaluation Criteria in Solid Tumors (RECIST) progression in the computed tomography scan as the best response to the upfront treatment., Design, Setting, and Participants: We retrospectively collected data from 11 worldwide centers., Outcome Measurements and Statistical Analysis: Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses., Results and Limitations: We collected data from 108 patients with mRCC primary refractory to pembrolizumab plus axitinib (17%), nivolumab plus ipilimumab (36%), or tyrosine kinase inhibitors (TKIs; 31% sunitinib and 16% pazopanib). The median OS with cabozantinib was 9.11 mo, and it was 8.84 and 9.11 mo in patients primary refractory to immunocombinations and TKIs, respectively (p = 0.952). A significant difference was found between patients primary refractory to pembrolizumab plus axitinib (OS not reached) and those primary refractory to nivolumab plus ipilimumab (median OS 8.12 mo, p = 0.024). The median PFS with cabozantinib was 7.30 mo, without significant differences between patients primary refractory to immunocombinations and those primary refractory to TKIs (6.90 vs 7.59 mo, p = 0.435) or between patients primary refractory to pembrolizumab plus axitinib and those primary refractory to nivolumab plus ipilimumab (7.92 and 6.02, p = 0.509). Investigator-assessed overall response rates were 21% and 12% in patients primary refractory to first-line immunocombinations and TKIs, respectively, with a clinical benefit of 48% in the overall population., Conclusions: Our data show that cabozantinib is active in primary refractory mRCC patients regardless of which treatment is received as first-line therapy. Systemic options and prognosis of primary refractory patients with mRCC, particularly those treated with novel immune-based combos, are among the major challenges that we need to face in this field., Patient Summary: Patients primary refractory to first-line therapy are characterized by a poor prognosis. Herein, we aimed to assess the outcome of patients treated with second-line cabozantinib for metastatic renal cell carcinoma (mRCC) primary refractory to first-line therapy. Our results suggest that cabozantinib is active in primary refractory mRCC patients., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73-82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8-29.3) and OS 48.8 mo. (95% CI, 36.8-60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 ( p < 0.001 and p = 0.004) and PSA decline ≥50% ( p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only ( p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only ( p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care.

Background: Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues., Patients and Methods: The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes., Results: Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001)., Conclusion: Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. RI served as consultant for Astellas, BMS, Ipsen; Janssen, Merk, MSD, Novartis; Pfizer; Sanofi and received research grant from Pfizer. SS served as consultant for Astellas, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, Sanofi-Genzyme. EV served as consultant for Ipsen, Janssen, Merck, MSD, Pfizer. Astellas, Novartis. CC served as consultant for Pfizer, BMS, MSD, Janssen. SB served as consultant for Pfizer, BMS, MSD, Roche, Astellas, Janssen, Ipsen, Bayer, Sanofi-Genzyme, Merck, AstraZeneca. Travel accommodation from Pfizer, BMS, Roche, Astellas, Janssen, Ipsen, AstraZeneca. UDG served as consultant for Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer and Sanofi; has received travel support from BMS, Ipsen, Janssen and Pfizer; and has received research funding from AstraZeneca, Roche and Sanofi (Inst). UB served as consultant for Advisory board BMS, MSD, Janssen. He received speaker's fees BMS, Ipsen, Janssen, Astellas. GT served as consultant for BMS and MSD. GP served as consultant for Astellas, Astra-Zeneca, Bayer, BMS, Ipsen, Janssen, Merck, MSD, Pfizer, Novartis, Sanofi. CC, MM. AF, LG, FM, AC, MGM, DB, FMD, MD, FP, FR declared not conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era., Methods: We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups., Results: Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32-0.60, p < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed (p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p < 0.001), but not for groups 4 and 5 (p = 0.54)., Conclusions: Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score., (© 2022. The Author(s).)

Background: Statins are widely used in an ageing population, including subjects with solid malignancies. However, no conclusive evidence is currently available on their potential influence on patients' outcome. We aimed to assess whether statin exposure affects the survival of patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab., Patients and Methods: Medical records of patients with documented mRCC treated with second- or third-line nivolumab were reviewed at ten institutions from Italy, Spain and the USA. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit. Univariate and multivariate analyses were used to explore the association of variables of interest with survival., Results: A total of 219 patients with mRCC receiving nivolumab between January 2016 and September 2021 were eligible for inclusion in this study; 59 (27%) were statin users. The median OS (34.4 versus 18.6 months, p = 0.017) and PFS (11.7 versus 4.6 months, p = 0.013) resulted apparently longer in statin users. Stratified by age, longer median OS and PFS were associated with statin exposure in both patients aged ≥70 y (median OS: 21.4 versus 10.1 months, p = 0.047; median PFS: 16.4 versus 4.6 months, p = 0.022) and &lt;70 y (median OS: 34.4 versus 21.4 months, p = 0.043; median PFS: 10.3 versus 4.6 months, p = 0.042). Overall clinical benefit resulted higher in statin users than non-users (71% versus 54%, p = 0.030)., Conclusions: Our study suggests a prognostic impact of statin use in patients receiving nivolumab for mRCC., Competing Interests: Conflict of interest statement The authors declare to have no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Immunotherapy with nivolumab (a monoclonal antibody that targets the programmed cell death protein 1, PD1) has become the standard treatment for patients with metastatic renal cell carcinoma (mRCC) after progression to single-agent tyrosine kinase inhibitors. However, the optimal duration of immunotherapy in this setting has not yet been established., Patients and Methods: We retrospectively reviewed all patients treated with nivolumab at our institution from January 2014 to December 2021 and identified those who discontinued treatment for reasons other than disease progression (PD). We then associated progression-free survival (PFS) and overall survival following treatment cessation with baseline clinical data., Results: Fourteen patients were found to have discontinued treatment. Four patients (28.6%) ceased treatment due to G3/G4 toxicities, whereas the remaining ten (71.4%) opted to discontinue treatment in agreement with their referring clinicians. The median duration of the initial treatment with nivolumab was 21.7 months (7.5-37.3); during treatment, two patients (14.3%) achieved stable disease as the best response, and the remaining twelve (85.7%) a partial response. At a median follow-up time of 24.2 months after treatment discontinuation, 7 patients (50%) were still progression-free. The median PFS from the date of discontinuation was 19.8 months (15.2 - not reached); a radiological objective response according to RECIST and treatment duration of more than 12 months were associated with a longer PFS. Three patients were re-treated with Nivolumab after disease progression, all of whom achieved subsequent radiological stability., Conclusion: In our experience, the majority of patients who discontinued treatment in the absence of PD were still progression-free more than 18 months after discontinuation. Patients whose initial treatment duration was less than 12 months or who did not achieve a radiological objective response had a greater risk of progression. Immunotherapy rechallenge is safe and seems capable of achieving disease control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bimbatti, Dionese, Lai, Cavasin, Basso, Mattana, Pierantoni, Zagonel and Maruzzo.)

Background: Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC., Methods: In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression-free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated., Results: After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4-NR) in actively treated patients and 3 months (95% CI: 2-4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1-6 vs. 2-5; p = 0.6) and OS (12 and 4 months, 95% CI: 3-NR vs. 2-NR; p = 0.2)., Conclusion: After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy., Methods and Materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse., Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression., Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)