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Background: Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells., Materials and Methods: INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety., Results: Eighty-five patients were included and randomized to arm A (n = 42) and arm B (n = 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (P = 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, P = 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, P = 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found., Conclusions: The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.

Background: Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214., Patients and Methods: Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients., Results: With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time., Conclusions: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Current treatments of anxiety and depressive disorders are plagued by considerable side effects and limited efficacies, underscoring the need for additional molecular targets that can be leveraged to improve medications. Here, we have identified a molecular cascade triggered by chronic stress that exacerbates anxiety- and depressive-like behaviors. Specifically, chronic stress enhances Src kinase activity and tyrosine phosphorylation of calmodulin, which diminishes MyosinVa (MyoVa) interaction with Neuroligin2 (NL2), resulting in decreased inhibitory transmission and heightened anxiety-like behaviors. Importantly, pharmacological inhibition of Src reinstates inhibitory synaptic deficits and effectively reverses heightened anxiety-like behaviors in chronically stressed mice, a process requiring the MyoVa-NL2 interaction. These data demonstrate the reversibility of anxiety- and depressive-like phenotypes at both molecular and behavioral levels and uncover a therapeutic target for anxiety and depressive disorders., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Vessel perforation during thrombectomy is a severe complication and is hypothesized to be more frequent during medium vessel occlusion (MeVO) thrombectomy. The aim of this study was to compare the incidence and outcome of patients with perforation during MeVO and large vessel occlusion (LVO) thrombectomy and to report on the procedural steps that led to perforation., Methods: In this multicenter retrospective cohort study, data of consecutive patients with vessel perforation during thrombectomy between January 1, 2015 and September 30, 2022 were collected. The primary outcomes were independent functional outcome (ie, modified Rankin Scale 0-2) and all-cause mortality at 90 days. Binomial test, chi-squared test and t -test for unpaired samples were used for statistical analysis., Results: During 25 769 thrombectomies (5124 MeVO, 20 645 LVO) in 25 stroke centers, perforation occurred in 335 patients (1.3%; mean age 72 years, 62% female). Perforation occurred more often in MeVO thrombectomy (2.4%) than in LVO thrombectomy (1.0%, p <0.001). More MeVO than LVO patients with perforation achieved functional independence at 3 months (25.7% vs 10.9%, p =0.001). All-cause mortality did not differ between groups (overall 51.6%). Navigation beyond the occlusion and retraction of stent retriever/aspiration catheter were the two most common procedural steps that led to perforation., Conclusions: In our cohort, perforation was approximately twice as frequent in MeVO than in LVO thrombectomy. Efforts to optimize the procedure may focus on navigation beyond the occlusion site and retraction of stent retriever/aspiration catheter. Further research is necessary in order to identify thrombectomy candidates at high risk of intraprocedural perforation and to provide data on the effectiveness of endovascular countermeasures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) varies, being influenced by blood-related factors such as transcriptional profiling and immune cell ratios. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. This study analyzed pre-treatment blood samples from 152 chemotherapy-naive mCRPC patients participating in a phase 2 clinical trial (NCT02288936) and a validation cohort. We used CIBERSORT-X to quantify 22 immune cell types and assessed their prognostic significance using Kaplan-Meier and Cox regression analyses. Reduced CD8 T-cell proportions and elevated monocyte levels were substantially connected with a worse survival. High monocyte counts correlated with a median survival of 32.2 months versus 40.3 months for lower counts (HR: 1.96, 95% CI 1.11-3.45). Low CD8 T-cell levels were associated with a median survival of 31.8 months compared to 40.3 months for higher levels (HR: 1.97, 95% CI 1.11-3.5). These findings were consistent in both the trial and validation cohorts. Multivariate analysis further confirmed the independent prognostic value of CD8 T-cell counts. This study highlights the prognostic implications of specific blood immune cells, suggesting they could serve as biomarkers in mCRPC patient management and should be further explored in clinical trials.

The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.

Background and Objective: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data., Methods: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS)., Key Findings and Limitations: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest., Conclusions and Clinical Implications: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities., Patient Summary: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%., Results: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib., Conclusions: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC)., Methods: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay)., Results: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff., Conclusions: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels., (© 2023. The Author(s).)

Background and Objective: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL)., Methods: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration., Key Findings and Limitations: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy., Conclusions and Clinical Implications: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301., Patient Summary: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Patients with advanced penile squamous cell carcinoma (PSCC) have poor outcomes and very limited therapeutic options are available. Most PSCC cases have high PD-L1 expression, which is associated with worse prognosis. Immunotherapy targeting PD-L1 could benefit patients with PSCC. Our aim was to evaluate the efficacy and safety of the anti-PD-1 antibody retifanlimab in patients with advanced/metastatic PSCC., Methods: ORPHEUS was a single-arm, multicenter, phase 2 trial in 18 patients with advanced/metastatic PSCC, previously untreated with anti-PD-1/anti-PD-L1 agents. Patients received retifanlimab 500 mg intravenously every 4 wk for up to 2 yr. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included the clinical benefit rate (CBR), disease control rate, duration of response (DoR), time to response, progression-free survival (PFS), overall survival (OS), maximum tumor shrinkage, and safety. The Wilson method was used for the primary endpoint, and the Clopper-Pearson and Kaplan-Meier methods for secondary endpoints., Key Findings and Limitations: Median follow-up was 7.2 mo. The ORR was 16.7% (95% confidence interval [CI] 5.8-39.2); three patients had a partial response. Median DoR was 3.3 mo (range 1.8-8.5). The CBR was 22.2% (95% CI 6.4-47.6%). Median PFS was 2.0 mo (95% CI 1.6-3.3) and median OS was 7.2 mo (95% CI 3.0-9.8). One patient (5.6%) experienced grade 3 treatment-related adverse events (AEs). There were no grade >= 4 treatment-related AEs. The small sample size is the main limitation., Conclusions and Clinical Implications: Single-agent retifanlimab exhibited signals of clinical activity in advanced/metastatic PSCC, with no new safety signals. Further investigation of retifanlimab in this setting is warranted., Patient Summary: Advanced penile cancer of the squamous cell type is a rare tumor with poor prognosis. The aggressiveness of this cancer is usually associated with high levels of a protein called PD-L1. We investigated whether retifanlimab, an immunotherapy drug against PD-1, has activity against this type of penile cancer. Tumor regression or stabilization occurred in one-third of the patients and the side effects were manageable., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma., Methods: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival., Results: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group., Conclusions: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti-PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC)., Objective: To report updated OS and safety by ctDNA status., Design, Setting, and Participants: This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples., Intervention: Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr., Outcome Measurements and Statistical Analysis: OS, relapse rates, and safety by ctDNA status were assessed., Results and Limitations: Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73-1.13]; median follow-up 46.8 mo [interquartile range, 36.1-53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3-9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42-0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5-not estimable]; 50-99% reduction, 34.3 mo [95% CI 15.2-not estimable]; <50% reduction, 19.9 mo [95% CI 16.4-32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design., Conclusions: Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings., Patient Summary: Among patients with urothelial cancer after surgery, survival was poorer if tumor-derived DNA was detected in their bloodstream; these patients' survival was longer with atezolizumab versus observation. Bloodstream tumor-derived DNA may identify patients who benefit from atezolizumab., (Copyright © 2023. Published by Elsevier B.V.)

Background: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations., Methods: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity., Results: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related)., Conclusions: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib., Clinical Trial Registration: NCT02780687., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients., Competing Interests: Conflict of interest: J.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, Esteve, Hutchmed, Ipsen, Merck, Novartis, Roche, Sanofi, Lilly, Eisai, Bayer, and ITM, and has received research support from Pfizer, Novartis, Astrazeneca, Eisai, AAA, Amgen, Bayer, Roche, Gilead, and ITM. M.B. reports Advisory from Novartis, Ipsen, and Pfizer. P.J.-F. has received speaker honoraria or consultant honoraria from Adacap, Astellas, BMS, Lilly, and MSD. D.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from Janssen Oncology, Roche/Genetech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, BMS, MSD, Bayer, Lilly, Sanofi, Pierre Fabre, and Boerhinger. F.S. has received honoraria for medical education and research activity from Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, MSD/Merck, and Hutchmed. A.T. has provided scientific advice and/or received honoraria from ADACAP, Ipsen, Novartis, and Pfizer. R.G.-C. has provided scientific advice and/or received honoraria or funding for continuous medical education from ADACAP, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier, and Sanofi, and has received research support from Pfizer, BMS, and MSD. The remaining authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors., Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons., Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher., Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Predictors of radiological complications attributable to reperfusion injury remain unknown when baseline setting is optimal for endovascular treatment and procedural setting is the best in stroke patients with large vessel occlusion (LVO)., Aims: To identify clinical and radiological/procedural predictors for hemorrhagic transformation (HT) and cerebral edema (CED) at 24 hr in patients obtaining complete recanalization in one pass of thrombectomy for ischemic stroke ⩽ 6 h from symptom onset with intra-cranial anterior circulation LVO and ASPECTS ⩾ 6., Methods: We conducted a cohort study on prospectively collected data from 1400 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke., Results: HT was reported in 248 (18%) patients and early CED was reported in 260 (19.2%) patients. In the logistic regression model including predictors from a first model with clinical variables and from a second model with radiological/procedural variables, diabetes mellitus (odds ratio (OR) = 1.832, 95% confidence interval (CI) = 1.201-2.795), higher National Institutes of Health Stroke Scale (NIHSS) (OR = 1.076, 95% CI = 1.044-1.110), lower Alberta Stroke Program Early CT (ASPECTS) (OR = 0.815, 95% CI = 0.694-0.957), and longer onset-to-groin time (OR = 1.005, 95% CI = 1.002-1.007) were predictors of HT, whereas general anesthesia was inversely associated with HT (OR = 0.540, 95% CI = 0.355-0.820). Higher NIHSS (OR = 1.049, 95% CI = 1.021-1.077), lower ASPECTS (OR = 0.700, 95% CI = 0.613-0.801), intravenous thrombolysis (OR = 1.464, 95% CI = 1.061-2.020), longer onset-to-groin time (OR = 1.002, 95% CI = 1.001-1.005), and longer procedure time (OR = 1.009, 95% CI = 1.004-1.015) were predictors of early CED. After repeating a fourth logistic regression model including also good collaterals, the same variables remained predictors for HT and/or early CED, except diabetes mellitus and thrombolysis, while good collaterals were inversely associated with early CED (OR = 0.385, 95% CI = 0.248-0.599)., Conclusions: Higher NIHSS, lower ASPECTS, and longer onset-to-groin time were predictors for both HT and early CED. General anesthesia and good collaterals were inversely associated with HT and early CED, respectively. Longer procedure time was predictor of early CED., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Manuel Cappellari received consultancy or advisory board fees or speaker’s honoraria from Boehringer Ingelheim, Pfizer/Bristol Meyer Squibb, and Daiichi Sankyo. Andrea Zini received consulting fees from Boehringer-Ingelheim consulting fees from Boehringer-Ingelheim, Alexion and CLS Behring. All other authors report no conflicts of interest. The other authors report no conflicts.

Background: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated., Methods: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2., Results: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC., Conclusions: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours., Trial Registration: ClinicalTrials.gov, NCT02599324., (© 2023. The Author(s).)

Purpose: The MORPHEUS platform was designed to identify early efficacy signals and evaluate the safety of novel immunotherapy combinations across cancer types. The phase Ib/II MORPHEUS-UC trial (NCT03869190) is evaluating atezolizumab plus magrolimab, niraparib, or tocilizumab in platinum-refractory locally advanced or metastatic urothelial carcinoma (mUC). Additional treatment combinations were evaluated and will be reported separately., Patients and Methods: Patients had locally advanced or mUC that progressed during or following treatment with a platinum-containing regimen. The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoints included investigator-assessed progression-free survival (PFS) and overall survival (OS). Safety and exploratory biomarker analyses were also conducted., Results: Seventy-six patients were randomized to receive either atezolizumab plus magrolimab (n = 16), atezolizumab plus niraparib (n = 15), atezolizumab plus tocilizumab (n = 15), or atezolizumab monotherapy (control; n = 30). No additive benefit in ORR, PFS, or OS was seen in the treatment arms versus the control. The best confirmed ORR was 26.7% with atezolizumab plus magrolimab, 6.7% with atezolizumab plus niraparib, 20.0% with atezolizumab plus tocilizumab, and 27.6% with atezolizumab monotherapy. Overall, the treatment combinations were tolerable, and adverse events were consistent with each agent's known safety profile. Trends were observed for shrinkage of programmed death-ligand 1-positive tumors (atezolizumab, atezolizumab plus magrolimab, atezolizumab plus tocilizumab), inflamed tumors, or tumors with high mutational burden (atezolizumab), and immune excluded tumors (atezolizumab plus magrolimab)., Conclusions: The evaluated regimens in MORPHEUS-UC were tolerable. However, response rates for the combinations did not meet the criteria for further development in platinum-experienced locally advanced or mUC., (©2023 American Association for Cancer Research.)

Introduction: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301., Materials and Methods: Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety., Results: In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%., Conclusions: After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed., (Copyright © 2023. Published by Elsevier Ltd.)

AbstractRecent experimental evidence demonstrates that shifts in mutational biases-for example, increases in transversion frequency-can change the distribution of fitness effects of mutations (DFE). In particular, reducing or reversing a prevailing bias can increase the probability that a de novo mutation is beneficial. It has also been shown that mutator bacteria are more likely to emerge if the beneficial mutations they generate have a larger effect size than observed in the wild type. Here, we connect these two results, demonstrating that mutator strains that reduce or reverse a prevailing bias have a positively shifted DFE, which in turn can dramatically increase their emergence probability. Since changes in mutation rate and bias are often coupled through the gain and loss of DNA repair enzymes, our results predict that the invasion of mutator strains will be facilitated by shifts in mutation bias that offer improved access to previously undersampled beneficial mutations.

Background: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC., Materials and Methods: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR)., Results: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks 1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown)., Conclusions: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/m 2 1-h intravenous infusion every 3 weeks in a cohort of 73 patients with pretreated endometrial cancer. The primary endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and an exploratory translational study. Confirmed complete (CR) and partial response (PR) was reported in two and six patients, respectively (ORR = 11.3%; 95%CI, 5.0-21.0%). Median DoR was 9.2 months (95%CI, 3.4-18.0 months), median PFS was 2.6 months (95%CI, 1.4-4.0 months) and median OS was 9.3 months (95%CI, 6.1-12.8 months). Molecular subtypes showed differences in PFS rate at 6 months (p53abn 23.7% vs. "No Specific Molecular Profile" [NSMP] 42.9%) and median OS (p53abn 6.6 months vs. NSMP 16.1 months). The most common treatment-related adverse events (mostly grade 1/2) were fatigue (54.8% of patients), nausea (50.7%), vomiting (26.0%) decreased appetite (17.8%). and constipation, (19.2%). The most common grade 3/4 toxicity was neutropenia (43.8%; grade 4, 19.2%; febrile neutropenia, 4.1%). In conclusion, considering the exploratory aim of this trial and the hints of antitumor activity observed together with a predictable and manageable safety profile, further biomarker-based development of lurbinectedin is recommended in this indication in combination with other agents. Clinicaltrials.gov identifier: NCT02454972., (© 2023. The Author(s).)

Efficacy and safety of mechanical thrombectomy (MT) for stroke with posterior circulation large vessel occlusion (LVO) is still under debate. We aimed to compare the outcomes of stroke patients with posterior circulation LVO treated with intravenous thrombolysis (IVT) (< 4.5 h after symptom onset) plus MT < 6 h after symptom onset with those treated with IVT alone (< 4.5 h after symptom onset). Patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS) and in the Italian centers included in the SITS-ISTR were analysed. We identified 409 IRETAS patients treated with IVT plus MT and 384 SITS-ISTR patients treated with IVT alone. IVT plus MT was significantly associated with higher rate of sICH (ECASS II) compared with IVT alone (3.1 vs 1.9%; OR 3.984, 95% CI 1.014-15.815), while the two treatments did not differ significantly in 3-month mRS score ≤ 3 (64.3 vs 74.1%; OR 0.829, 95% CI 0.524-1.311). In 389 patients with isolated basilar artery (BA) occlusion, IVT plus MT was significantly associated with higher rate of any ICH compared with IVT alone (9.4 vs 7.4%; OR 4.131, 95% CI 1.215-14.040), while two treatments did not differ significantly in 3-month mRS score ≤ 3 and sICH per ECASS II definition. IVT plus MT was significantly associated with higher rate mRS score ≤ 2 (69.1 vs 52.1%; OR 2.692, 95% CI 1.064-6.811) and lower rate of death (13.8 vs 27.1%; OR 0.299, 95% CI 0.095-0.942) in patients with distal-segment BA occlusion, while two treatments did not differ significantly in 3-month mRS score ≤ 3 and sICH per ECASS II definition. IVT plus MT was significantly associated with lower rate of mRS score ≤ 3 (37.1 vs 53.3%; OR 0.137, 0.009-0.987), mRS score ≤ 1 (22.9 vs 53.3%; OR 0.066, 95% CI 0.006-0.764), mRS score ≤ 2 (34.3 vs 53.3%; OR 0.102, 95% CI 0.011-0.935), and higher rate of death (51.4 vs 40%; OR 16.244, 1.395-89.209) in patients with proximal-segment BA occlusion. Compared with IVT alone, IVT plus MT was significantly associated with higher rate of sICH per ECASS II definition in patients with stroke and posterior circulation LVO, while two treatment groups did not differ significantly in 3-month mRS score ≤ 3. IVT plus MT was associated with lower rate of mRS score ≤ 3 compared with IVT alone in patients with proximal-segment BA occlusion, whereas no significant difference was found between the two treatments in primary endpoints in patients isolated BA occlusion and in the other subgroups based on site occlusion., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Pulmonary embolism (PE) represents one of the leading causes of death worldwide and mainly treated with medical management, although the utility of more invasive approaches has emerged more recently. This meta-analysis aims to evaluate the 30-day mortality of intermediate-to-high risk PE across different treatment strategies., Methods: A systematic literature review and meta-analysis was conducted using PubMed and Cochrane databases. All studies reporting 30-day mortality rates in intermediate-to-high-risk PE were included. Meta-regression analysis and sensitivity analysis were performed on the primary endpoint, 30-day mortality, and secondary endpoints (RV/LV ratio, mPAP, and long-term mortality, any bleeding events)., Results: Of the 2390 studies published between 2000 and 2022, 76 studies (74 observational and 2 RCTs for a total of 1,194,285 patients in the medical cohort and 3007 in the interventional cohort) were included. The median age was 71.4 (IQR 62.8-77.3) years, 53.6% were women. 30-day mortality in the patients treated with medical management was 9.1% (6.6-12.6). In the interventional cohort, 30-day mortality was 2.1% (1.5-3.1) while the pre- vs post-procedure change in mean difference was -6.1 mmHg (-11.2 to -1.1) for mPAP and - 0.41 (-0.51 to - 0.31) for RV/LV ratio. The overall bleeding rate in the interventional cohort was 4.9% (CI 2.6-8.9), without differences between the two strategies (RR 1.26 CI 0.89-1.78)., Conclusion: Intermediate-high-risk mortality in pulmonary embolisms treated with medical management remains high in the modern era. Despite the absence of comparative studies, an interventional approach may have a lower 30-day mortality rate and a good safety profile., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear., Methods: A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted., Results: The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients)., Conclusion: Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit., Competing Interests: Declaration of Competing Interest This research did not receive additional support from an organization beyond the authors’ academic institutions. Guillermo de Velasco: GDV is supported by ISCIII-AES-2021 PI21/01922 Consulting and advisory services from Pfizer, Novartis, Bayer, Roche, Ipsen, Astellas Pharma, Bristol-Myers Squibb, MSD and Merck; research funding from Ipsen; and Honoraria, travel and accommodation expenses from Pfizer, Ipsen, Bristol-Myers-Squibb, Astellas Pharma and Roche; Daniel Castellano: Consulting or Advisory Role—Astellas Pharma; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Ipsen; Janssen Oncology; Lilly; MSD Oncology; Novartis; Pfizer; Pierre Fabre; Roche/Genentech; Sanofi; Roberto Iacovelli: Advisory Board member—Astellas, BMS, EISAI, IPSEN, Janssen, MSD, Novartis, Pfizer, Sanofi. Consultant for Astellas, EISAI, MSD, Pfizer; Laurence Albiges: Consulting/advisory role—BMS, Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb, Bayer, and Cerulean; research funding—Pfizer and Novartis. Rest of authors including corresponding author confirm no other conflict of interest to disclose. The authors declare there are no patents to disclose. The authors declare there are not addition relationships or activities to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration., Objective: To present the final data from TRITON2., Design, Setting, and Participants: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy., Outcome Measurements and Statistical Analysis: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint., Results and Limitations: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively., Conclusions: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene., Patient Summary: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression., Material and Methods: From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method., Results: LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02)., Conclusions: We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing., 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 Font, Domenech, Ramirez, Marqués, Benítez, Ruiz de Porras, Gago, Carrato, Sant, Lopez, Castellano, Malats, Calle and Real.)

The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Purpose: There is an increasing interest in the role of sex and gender in cancer patients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET., Methods: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment., Results: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female patients., Conclusions: Sex-related differences in toxicity with the MKI treatment require targeted information and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jorge Hernando: Speakers Bureau: Angelini, Leo, Eisai, Adacap, Novartis, Pfizer, Advanz, Ipsen. Alejandro García-Alvarez: Speakers Bureau: Angelini. Travel/Accommodation, Expenses: Pfizer, Ipsen, EISAI, Advanz, AAA. Toni Ibrahim: Advisory board (Amgen, Galxosmithkline and Pharmamar). Cover Participation at scientific meeting (Istituto gentili and Pharmamar). Enrique Grande: EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, AstraZeneca, 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. EG has received research grants from Pfizer, AstraZeneca, Astellas, and Lexicon Pharmaceuticals. Eric Raymond: Consulting and Share holder for Genoscience Pharma, StromaCare, SCOR life science. Share Holder at Neuronax. Scientific and steering committee at Onward Therapeutics and BeiGen. Received travel grant for data presentation from BeiGen. Rocio Garcia-Carbonero: RGC has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD. Ramon Salazar: Invited speaker: Advanced Accelerator Applications, Amgen, Astellas, Bayer, BMS, Eisai, GSK, Janssen Oncology, Lilly, Pierre Fabre, Roche, Sanofi Genzyme. Expert testimony: AstraZeneca, Celgene, Merck, MSD, Novartis, Pfizer. Advisory Board: Agendia, Amgen, Ferrer, Guardant Health, Ipsen, Lilly, Merck, MSD, Novartis, Pfizer, Roche Diagnostic, Roche Farma, Tayhoo, VCN-BCN. Alex Teule: Speakers Bureau: AAA, Pfizer, Ipsen, Novartis, AstraZeneca. Travel, Accommodation, Expenses: AAA, Pfizer, Ipsen, Novartis, AstraZeneca. Salvatore Tafuto: S.Tafuto has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Boerhinger, Ipsen, Merck, PharmaMar and has received research support from NOVARTIS, IPSEN. Vicente Alonso: VA has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Amgen, Ipsen, Merck, Pierre Fabre, Roche, Servier and Sanofi. Daniel Castellano: Advisory role Lilly, Pierre Fabre, Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Ipsen, Bayer, Sanofi, Janssen Oncology, Pfizer, Bristol Myers Squibb, Astellas Pharma, Novartis, MSD Oncology, Sanofi. The rest of the authors declare no conflict of interest for this publication., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)-positive breast cancer. We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors. In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are key antiangiogenic drugs for renal cancer treatment. While Von Hippel-Lindau dysfunction constitutes the base for VEGFR-TKIs sensitivity, the role for individual and concurrent mutations in the genes encoding for the chromatin remodelers Polybromo-1 ( PBRM1 ) and Lysine Demethylase 5C ( KDM5C ) is poorly understood. Here, we analyzed the tumor mutational and expression profiles of 155 unselected clear cell RCC (ccRCC) cases treated with first-line VEGFR-TKIs and the ccRCC cases of IMmotion151 trial were used for validation. We found that concurrent PBRM1 and KDM5C ( PBRM1 & KDM5C ) mutations occurred in 4-9% of cases and were enriched in Memorial Sloan Kettering Cancer Center favorable-risk patients. In our cohort, tumors only mutated in PBRM1 or concurrently mutated in PBRM1 and KDM5C had increased angiogenesis (P=0.0068 and 0.039; respectively), and tumors only mutated in KDM5C showed a similar trend. Best response to VEGFR-TKIs corresponded to PBRM1 & KDM5C mutated cases, followed by those mutated only in KDM5C or only in PBRM1 (P=0.050, 0.040 and 0.027 versus non-mutated cases, respectively), with a trend for longer progression free survival (PFS) in the group with only PBRM1 mutated (HR=0.64; P=0.059). Validation in the IMmotion151 trial revealed a similar correlation with increased angiogenesis and the PFS of patients in the VEGFR-TKI-arm was the longest in PBRM1 & KDM5C mutated cases, intermediate for only PBRM1 or only KDM5C mutated patients and the shortest in non-mutated cases (P=0.009 and 0.025, for PBRM1 & KDM5C and PBRM1 versus non-mutated cases). In conclusion, somatic PBRM1 and KDM5C mutations are common in patients with metastatic ccRCC and likely cooperate increasing tumor angiogenesis and VEGFR-TKI-based antiangiogenic therapy benefit., Competing Interests: None., (AJCR Copyright © 2023.)

Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence., Objective: To present the voting results of the APCCC 2022., Design, Setting, and Participants: The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions., Outcome Measurements and Statistical Analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions., Results and Limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer., Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer., Twitter Summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer., Take-Home Message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aurelis Omlin: Advisory role (compensated, institutional): Astra Zeneca, Astellas, Bayer, Janssen, Molecular Partners, MSD, Pfizer, Roche, Sanofi Aventis. Research support (institutional): TEVA, Janssen. Travel support: Astellas, Bayer, Janssen, Sanofi Aventis. Speakers Bureau (compensated, institutional): Bayer, Astellas, Janssen. Fizazi Karim: Participation to advisory boards or talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Janssen, MSD, Novartis, Pfizer, Sanofi. Honoraria are provided to Gustave Roussy, my institution. Participation to advisory boards with personal honorarium for: CureVac, Orion. Bossi Alberto: Honoraria: Astellas, Ipsen, Janssen, Myovant. Consulting or advisory role: Astellas, Ipsen, Janssen, Myovant. Speakers’ bureau: Astellas, Ipsen, Elketa. Research funding: Astellas, Ipsen, Myovant. Travel, accommodations, expenses: Janssen. Tombal Bertrand: Advisor for Astellas, Amgen, Bayer, Curium, Ferring, Myovant, Janssens, MSD, Novartis (AAA), Pfizer, Sanofi. Gillessen Silke: SG received personal honoraria for participation in advisory boards for Sanofi, Orion, Roche, Amgen, MSD; other honoraria from RSI (Televisione Svizzera Italiana); invited speaker for ESMO, Swiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary oncology (SAMO), Orikata academy research group, China Anti-Cancer Association Genitourinary Oncology Committee (CACA-GU); Speaker’s bureau for Janssen Cilag; travel grant from ProteoMEdiX; institutional honoraria for advisory boards for Bayer, Janssen Cilag, Roche, AAA International including Indipendent Data Monitoring Committee and IDMC and Steering Committee member for Amgen, Menarini Silicon Biosystems, Astellas Pharma, Tolero Pharmaceutcials, MSD, Pfizer, Telixpharma, BMS and Orion; patent royalties and other intellectual property for a research method for biomarker WO2009138392. Ian Davis: Research Funding: Company: Astellas Pharma, Recipient: Your Institution; Company: Pfizer, Recipient: Your Institution; Company: Roche/Genentech, Recipient: Your Institution; Company: MSD Oncology, Recipient: Your Institution; Company: AstraZeneca, Recipient: Your Institution; Company: Janssen Oncology, Recipient: Your Institution; Company: Eisai, Recipient: Your Institution; Company: Bayer, Recipient: Your Institution; Company: Amgen, Recipient: Your Institution; Company: Bristol-Myers Squibb, Recipient: Your Institution; Company: Movember Foundation, Recipient: Your Institution; Company: Exelixis, Recipient: Your Institution; Company: Ipsen, Recipient: Your Institution; Company: Medivation, Recipient: Your Institution; Company: Seagen, Recipient: Your Institution. Patents, Royalties, Other Intellectual Property: Please describe: International Patent Application No: PCT /US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research; Recipient: You. Christopher Sweeney: Receipt of grants/research supports: Astellas, Bayer, Janssen, Pfizer, Sanofi, Dendreon; Receipt of honoraria or consultation fees: Astellas, Bayer, Janssen, Pfizer, Sanofi, Lilly, Genentech. Eric J. Small: Receipt of honoraria or consultation fees: Jannsen, Johnson & Johnson; Participation in a company sponsored speaker’s bureau: Jannsen, Fortis, Teon, Ulgragenyx, Fortis, Harpoon Johann de Bono: Receipt of grants/research supports: Professor De Bono is an employee of The Institute of Cancer Research, which has received funding or other support for his research work from Astellas, Astra Zeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income); Receipt of honoraria or consultation fees: Professor De Bono has served on advisory boards and received fees from Amgen, Astellas, Astra Zeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon. Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Participation in a company sponsored speaker’s bureau: AstraZeneca, MSD. Matthew Smith: Receipt of grants/research supports: Clinical trial funding to my institution from: Amgen, Bayer, ESSA, Janssen, ORIC, Pfizer; Receipt of honoraria or consultation fees: Amgen, Astellas, Astrazeneca, Bayer, Janssen, ORIC, Pfizer. Neal Shore: Receipt of honoraria or consultation fees: Abbvie, Amgen, Astellas, Astrazeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care, Invitae, Janssen, MDxhealth, Merck, Myvovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Propella, Sanofi, Genzyme, Sesen Bio, Tolmar, Urogen; Partecipation in a company sponsored speaker's bureau: Astellas, Astrazeneca, Bayer, Clovis Oncology, Foundation Medicina, Janssen, Merck, Pfizer, Guardant Health. Nicholas James: Receipt of grants/research supports: • Funding for STAMPEDE trial – Coordinating PI – financial interest, Institutional. Name of commercial company: Astellas. • Funding for RADIO trial bladder cancer – Coordinating. PI – financial interest, Institutional. Name of commercial company: AstraZeneca. • Funding for STAMPEDE trial – Coordinating PI – No. financial interest, Institutional. Name of commercial company: Janssen; Receipt of honoraria or consultation fees: • Advisory Board – Advice around PARP inhibitors, Personal,<€5000. Name of commercial company: AstraZeneca dvisory Board – Prostate cancer therapies, Personal,<€5000. Name of commercial company: Clovis. Expert Testimony – Assisted with submissions. regarding licensing for abiraterone, Institutional>€100,001. Name of commercial company: Janssen. Advisory Board – Prostate cancer therapies, Personal, €5001–€10,000. Name of commercial company: Janssen. Advisory Board – Bladder cancer therapy, Personal,<€5000. Name of commercial company: Merck. Advisory Board – Prostate cancer therapies, Personal,<€5000. Name of commercial company: Novartis Expert Testimony – Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel, Institutional,>€100,001. Name of commercial company: Sanofi. Advisory Board - Docetaxel, Personal,<€5000. Name of commercial company: Sanofi. Participation in a company sponsored speaker’s bureau: Bayer, Novartis. Nicolas MOTTET: Receipt of grants/research supports: Astellas, Sanofi Pasteur, Pierre Fabre; Receipt of honoraria or consultation fees: Astellas, Jansen, BMS, Bayer, IPSEN, Ferring, Sanofi, Steba, Astra Zeneca, Carrik, Arquer. diagnostics, GE, Takeda. Thomas ZILLI. AFFILIATION: Geneva University Hospital, Geneva, Switzerland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Varian Medical Systems International AG; Debiopharm. Receipt of honoraria or consultation fees: Janssen, Astellas, Debiopharm, Ferring, Varian Medical Systems International AG. Participation in a company sponsored speaker’s bureau: Janssen, Astellas, Debiopharm. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Geneva 07.02.2022. Christopher Logothetis. AFFILIATION: MD Anderson Cancer Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, ORIC Pharmaceuticals, Novartis, Aragon Pharmaceuticals. Receipt of honoraria or consultation fees: Merck, Sharp & Dohme, Bayer, Amgen. Participation in a company sponsored speakers bureau: None. Stock shareholder: None. Spouse/partner: None. Other support (please specify): None. Signature: Date: February 7, 2022. William Oh. AFFILIATION: Chief Medical Officer at Sema4 and Clinical Professor of Medicine, Div. of Hematology/Medical Oncology at Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Receipt of honoraria or consultation fees: GSK, Janssen, Merck, Pfizer. Participation in a company sponsored speakers bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 7, 2022. Himisha Beltran. AFFILIATION: Dana Farber Cancer Institute. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, AbbVie/Stemcentrx, Eli Lilly, Millennium Pharmaceuticals, Bristol Myers Squibb. Receipt of honoraria or consultation fees: Janssen, Astellas, Astra Zeneca, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Amgen, Oncorus, LOXO. Participation in a company sponsored speaker’s bureau: NONE. Stock shareholder: NONE. Spouse/partner: NONE. Other support (please specify): Signature: Date: Feb 7, 2022. Pirkko-Liisa Kellokumpu-Lehtinen. AFFILIATION: Tampere University and Tampere University Hospital, Tampere, Finland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Only directly to my hospital; Lilly, Merck and Finnish Cancer Society. Receipt of honoraria or consultation fees: BMS, Merck. Participation in a company sponsored speaker’s bureau: NONE. Stock shareholder: NONE. Spouse/partner: NONE. Other support (please specify):reimbursement of expenses to attend conference; Sanofi. Signature: Date: Feb 7, 2022. Prof. Mark A. Rubin, MD. AFFILIATION: University of Bern, Department for BioMedical Research (DBMR). Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, Roche, Novartis. Receipt of honoraria or consultation fees: NeoGenomics Labs. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Feb 8, 2022. Prof. Dr. Thomas Steuber. AFFILIATION: Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: NONE. Receipt of honoraria or consultation fees: Astellas, Amgen, Bayer, Janssen, ProteoMedix, Sanofi, Merck, Astra Zeneca. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Feb 8, 2022. Prof. Rob Bristow. AFFILIATION: University of Manchester. I have no potential conflict of interest to report. IGNACIO DURAN. AFFILIATION: HOSPITAL UNIVERSITARIO MARQUES DE VALDECILLA. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Roche and Astra-Zeneca. Receipt of honoraria or consultation fees: Bristol Myers Squibb, MSD, Ipsen, Roche- Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 8th 2022. FERNANDO MALUF. AFFILIATION: ONCOLOGIST. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Hiroyoshi Suzuki. AFFILIATION: Department of Urology, Toho University Sakura Medical Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Takeda, AsahiKasei, Taiho, Ono, Chugai, Sanofi, Daiichi-Sankyo, Nihon, Nippon Shinyaku. Receipt of honoraria or consultation fees: Bayer, Janssen, AstraZeneca, Astellas, Chuga-Roche, MSD. Participation in a company sponsored speaker’s bureau:Takeda, Bayer, Janssen, AstraZeneca, Astellas, Sanofi. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 8th 2022. Danny M. Rabah. AFFILIATION: King Saud University and king Faisal specialist hospital and research centre. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. LEVENT TÜRKERİ. AFFILIATION: ACIBADEM M.A. AYDINLAR UNIVERSITY, ISTANBUL, TURKEY. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Mark Frydenberg. AFFILIATION: ACIBADEM M.A. AYDINLAR UNIVERSITY, ISTANBUL, TURKEY. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Anders Bjartell. AFFILIATION: Dept. Of Urology, Skane University Hospital Malmö, Sweden. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Ferring, Bayer, Astellas. Receipt of honoraria or consultation fees: Astellas, AstraZeneca, Bayer, Janssen, Merck, Recordati, Sandoz. Participation in a company sponsored speaker’s bureau:Astellas, Bayer, IPSEN, Janssen, Recordati, Sandoz. Stock shareholder: LIDDS Pharma, Glactone Pharma, WntResearch. Spouse/partner: NONE. Other support (please specify): Signature: Date: February 9th 2022. Dingwei Ye. AFFILIATION: Fudan University Shanghai Cancer Center. I have no potential conflict of interest to report. Signature: Date: February 9th 2022. Ros Eeles. AFFILIATION: ………………………………………. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: GU-ASCO, The Royal Marsden NHS Foundation Trust, University of Chicago, ESMO, AstraZeneca UK Limited. Receipt of honoraria or consultation fees: Honorarium as speaker. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): January 2016. Signature: Date: February 15th 2022. Inge van Oort. AFFILIATION: Urology, Radboudumc, Nijmegen, The Netherlands. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Astellas, Bayer, Janssen. Receipt of honoraria or consultation fees: Astellas, Bayer, MSD-Astra Zeneca, Janssen. Participation in a company sponsored speaker’s bureau: Bayer, Astellas. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 22nd 2022. Ravindran Kanesvaran. AFFILIATION: Urology, Radboudumc, Nijmegen, The Netherlands. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Sanofi, Eisai. Receipt of honoraria or consultation fees: MSD, BMS, AstraZeneca, Amgen, Astellas, Johnson&Johnson, Novartis, Merck, Pfizer. Participation in a company sponsored speaker’s bureau:MSD, BMS, AstraZeneca, Amgen, Astellas, Johnson&Johnson, Novartis, Merck, Pfizer. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 22nd 2022. Signature: Date: February 9th 2022. Nicola Fossati. AFFILIATION: Urology, Ente Ospedaliero Cantonale (EOC), Lugano, CH. I have no potential conflict of interest to report. Signature: Date: February 1st March 2022. Hiroji Uemura. AFFILIATION: Department of Urology and Renal Transplantation, Yokohama City University Medical Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: none. Receipt of honoraria or consultation fees: Bayer, Janssen, Sanofi, Takeda, Astellas, AstraZeneca, Amgen, Dai-ichi Sankyo, Pfizer, MSD, Chugai. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: none. Spouse/partner: none. Other support (please specify): none. Signature: Date: March 7th 2022. Lisa Horvath. AFFILIATION: Chris O′Brien Lifehouse. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Astellas. Receipt of honoraria or consultation fees: Astellas, Janssen, Bayer, Imagion Biosystems. Participation in a company sponsored speaker’s bureau:Astellas, Janssen, Bayer. Stock shareholder: Imagion Biosystems. Spouse/partner: Connected Medicine Solutions (Employee, stocks). Other support (please specify): none. Signature: Date: March 9th 2022. Robert Reiter. AFFILIATION: UCLA Urology. X I have no potential conflict of interest to report. Signature: Date: March 11th 2022. Daniel Castellano. AFFILIATION: MEDICAL ONCOLOGIST HEAD GU UNIT HOSPITAL UNIVERSITARIO 12 DE OCTUBRE. MADRID-UNIVERSIDAD COMPLUTENSE. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: JANSSEN. Receipt of honoraria or consultation fees:ASTELLAS, ROCHE, MERCK, PFIZER, NOVARTIS, MSD, BMS, IPSEN, GILEAD, JANSSEN, BAYER. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: none. Spouse/partner: none. Other support (please specify): none. Signature: 28th March 2022. Sandy Srinivas. AFFILIATION: Stanford University, CA. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:BAYER, JANSSEN, MERCK, NOVARTIS. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31ST March 2022. Matthew Sydes. AFFILIATION: MRC Clinical Trials Unit at UCL. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:ASTELLAS, CLOVIS ONCOLOGY, JANSSEN, NOVARTIS, PFIZER, SANOFI AVENTIS. Receipt of honoraria or consultation fees:ELI LILLY, JANSSEN. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Ekeke, Onyanunam Ngozi. AFFILIATION: DEPARTMENT OF SURGERY, UNIVERSITY OF PORT HARCOURT TEACHING HOSPITAL, PORT HARCOUT, NIGERIA. X I have no potential conflict of interest to report. Signature: Date: March 30 h 2022. Susan Halabi, PhD. AFFILIATION: Duke University. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:ASCO TAPUR, Astellas. Receipt of honoraria or consultation fees:Sanofi, Aveo Oncology. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Cora N. Sternberg, MD, FACP. AFFILIATION: Eeill Cornell Medicine, New York Presbyterian. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas Pharma, Astrazeneca, Bayer, Genzyme, Gilead, Incyte, Medscape, Janssen, Bristol Myers Squibb, Merck, Msd, Pfizer, Roche, Impact Pharma, Sanofi-Genzyme, Urotoday, Cco Clinical, Nci. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Hirotsugu Uemura. AFFILIATION:. Kindai University Faculty of Medicine. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:AstraZeneca, Janssen, Takeda, Astellas, Sanofi, Taiho, Ono pharm, Kissei. Receipt of honoraria or consultation fees:Bayer, Sanofi, Janssen, MSD, Ono, BMS, Pfizer. Participation in a company sponsored speaker’s bureau:Bayer, Sanofi, Janssen, MSD, Ono, BMS, Pfizer. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Orazio Caffo. AFFILIATION: Santa Chiara Hospital – Trento (Italy). Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:AAA, Astella, Bayer, Janssen, MSD, Pfizer. Participation in a company sponsored speaker’s bureau:Astellas, Bayer, Janssen, Ipsen, MSD. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Valérie Fonteyne. AFFILIATION:Ghent University Hospital. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Ipsen. Receipt of honoraria or consultation fees:Ipsen, Astellas, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Muhammad Bulbul. AFFILIATION: American University of Beirut. X I have no potential conflict of interest to report. Signature: Date: March 31st 2022. Claire Vale. AFFILIATION: MRC Clinical Trials Unit at UCL. X I have no potential conflict of interest to report. Signature: Date: March 31st 2022. MRABTI Hind. AFFILIATION: Institut National d′oncologie, Mohamed V University. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas, Sanofi, Janssen, AstraZeneca, Ipsen, MSD, Pfizer, Amgen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Deborah Mukherji. AFFILIATION: American University of Beirut. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas. Receipt of honoraria or consultation fees:Astellas, Janssen, MSD, Ipsen, BMS. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Sloan Kettering Cancer Center. AIQ Pharma. Epic Sciences. Janssen. Menarini Silicon Biosystems. ThermoFisher. Howard I. Scher, MD, FASCO. AFFILIATION: Memorial Sloan Kettering Cancer Center. Howard I. Scher, MD, FASCO - Disclosure Form. March 31, 2022. Honoraria. Sidney Kimmel Cancer Center, Jefferson Health. Elsevier, LTD. Arsenal Capital. Consultancy/Advisory Board. Ambry Genetics Corporation, Konica Minolta,Inc. Amgen. Bayer. Janssen Research & Development, LLC. Pfizer Inc. Sun Pharmaceuticals Industries, Inc. WCG Oncology. Research Funding to Memorial Sloan Kettering Cancer Center. AIQ Pharma. Epic Sciences. Janssen. Menarini Silicon Biosystems. ThermoFisher. Evan Y. Yu, M.D. AFFILIATION: Fred Hutchinson Cancer Center and University of Washington. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Lantheus, Merck, Seagen. Receipt of honoraria or consultation fees:Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Exelixis, Janssen, Merck, Sanofi. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Gedske Daugaard. AFFILIATION: Rigshospitalet, Copenhagen. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Bayer, Sanofi, Astellas, MSD, Bristol Myers. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 30th March 2022. Celestia S. Higano, MD, FACP. AFFILIATION: University of Columbia. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:None last 24 months. Receipt of honoraria or consultation fees:AstraZeneca, Astellas, Genentech, Merck Sharp & Dohme, Myovant, Tolmar, Vaccitech, Verity. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: CTI Biopharma. Spouse/partner: none. Other support (please specify): Expert testimony, Ferring. Signature: 31st March 2022. Dr. Vedang Murthy. AFFILIATION: Radiotion Oncology. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Varian Medical Systems. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau: Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Gero Kramer. AFFILIATION: Department of Urology, Medical University of Vienna. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:None. Receipt of honoraria or consultation fees:Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Novartis, Sanofi Genzyme, Takeda, Ferring. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Niven Mehra. AFFILIATION: Radboudumc. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas, Astrazeneca, BMS. Receipt of honoraria or consultation fees:Astellas, Astrazeneca, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Juan Pablo Sade. AFFILIATION: Instituto Alexnder Fleming, Buenos Aires, Argentina. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Janssen, Astellas, AtraZeneca, MSD, BMS. Receipt of honoraria or consultation fees:Janssen, Bayer, Pfizer, Astellas. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3rd April 2022. Dr Maria De Santis. AFFILIATION: Charité Universitätsmedizin Berlin, Department of Urology. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, EISAI, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Iwona Skoneczna. AFFILIATION: Maria Sklodowska-Curie National Research Institute of Oncology, Szpital Grochowski, Warsaw, Poland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas, Bayer, BMS, Janssen, Roche. Receipt of honoraria or consultation fees:Astellas, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Laurence Klotz. AFFILIATION: University of Toronto. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:miR Scientific, Exact Imaging. Receipt of honoraria or consultation fees:miR Scientific, Antev. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 30th March 2022. Yüksel Ürün. AFFILIATION: Ankara University School of Medicine. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas, AtraZeneca, BMS, Janssen Oncology, MSD, Pfizer, Roche. Participation in a company sponsored speaker’s bureau:Astellas, Amgen, AtraZeneca, BMS, Janssen Oncology, Pfizer, Roche. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 01st April 2022. Howard R. Soule. AFFILIATION: Prostate Cancer Foundation. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Compugen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 4th April 2022. Simon Chowdhury. AFFILIATION:. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Janssen Oncology, Beigene, Clovis Oncology, Pfizer,. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:Janssen Oncology, AstraZeneca, Bayer, Pfizer, Sandoz. Stock shareholder:. Spouse/partner:. Other support (please specify): Janssen Oncology (Advisory board). Novartis (advisory board, consultancy). Bayer (Advisory board). Astellas (advisory board, consultancy). Athenex (advisory board). Beigene (advisory board). Clovis Oncology (Advisory board). Telix (advisory board, consultancy). Curve.Life (founder and stock). Huma (consulting fees and Stock). Remedy Bio: consulting fees, Stock. Signature: 4th April 2022. Daniel Heinrich. AFFILIATION: Innlandet Hospital, Department of Oncology and Radiotherapy, Gjøvik, Norway. X I have no potential conflict of interest to report. Signature: Date: 28th February 2022. Raya Leibowitz. AFFILIATION: Shamir Medical Center, Zerifin, Be’er Yaakov, Israel. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:MSD, BMS, Isotopia, Bayer, AstraZeneca, Astellas, Janssen, Pfizer. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 05th April 2022. Raja Khauli. AFFILIATION: American University of Beirut Medical Ctr Clinical. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify): honoraria: Astellas, Janssen, Algorithm SAL. Signature: 06th April 2022. Axel Merseburger. AFFILIATION: Campus Lübeck, University Hospital Schleswig-Holstein. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Lectures/Speaker/Honoraria:. Astra Zeneca, Bristol-Myers Squibb, Eisai, Ferring, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Astellas, Novartis, Pfizer, Recordati and Roche. Consultant:. AstraZeneca, Astellas, Bristol-Myers Squibb, Ferring, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer, Recordati and Roche. Research and clinical trials:. AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer und Roche. Signature: 06th April 2022. Carmel Pezaro. AFFILIATION: Sheffield Teaching Hospitals NHS Foundation Trust. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify): Bayer, Ipsen (travel support). Signature: 06th April 2022. All remaining authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The management of tandem extracranial internal carotid artery and intracranial large vessel occlusion during endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) has been under-investigated. We sought to investigate outcomes of AIS patients with tandem occlusion (TO) treated with carotid artery stenting (CAS) compared to those not treated with CAS (no-CAS) during EVT., Methods: We performed a cohort study using data from AIS patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. Outcomes were 3 months' mortality, functional outcome, complete and successful recanalization, any intracranial hemorrhage, parenchymal hematoma and symptomatic intracerebral hemorrhage., Results: Among 466 AIS patients with TO, CAS patients were 122 and no-CAS patients were 226 (118 excluded). After adjustment for unbalanced variables, CAS was associated with a lower rate of 3 months' mortality (OR 0.407, 95% CI 0.171-0.969, p = 0.042). After adjustment for pre-defined variables, CAS was associated with a lower rate of 3 months' mortality (aOR 0.430, 95% CI 0.187-0.989, p = 0.047) and a higher rate of complete recanalization (aOR 1.986, 95% CI 1.121-3.518, p = 0.019), successful recanalization (aOR 2.433, 95% CI 1.263-4.686, p = 0.008) and parenchymal hematoma (aOR 2.876, 95% CI 1.173-7.050, p = 0.021). CAS was associated with lower 3 months mortality (OR 0.373, 95% CI 0.141-0.982, p = 0.046) and higher rates of successful recanalization (OR 2.082, 95% CI 1.099-3.942, p = 0.024) after adjustment for variables associated with 3 months' mortality and successful recanalization, respectively., Conclusions: Among AIS patients with TO, CAS during EVT was associated with a higher rate of successful reperfusion and a lower rate of 3 months' mortality., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC)., Methods: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort., Results: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort., Conclusions: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers., (© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.)

Background: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management., Objective: To present consensus voting results for select questions from APCCC 2022., Design, Setting, and Participants: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3., Outcome Measurements and Statistical Analysis: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement., Results and Limitations: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis., Conclusions: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown., Objective: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib., Design, Setting, and Participants: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS)., Outcome Measurements and Statistical Analysis: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib., Results and Limitations: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively)., Conclusions: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance., Patient Summary: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The X chromosome in non-African humans shows less diversity and less Neanderthal introgression than expected from neutral evolution. Analyzing 162 human male X chromosomes worldwide, we identified fourteen chromosomal regions where nearly identical haplotypes spanning several hundred kilobases are found at high frequencies in non-Africans. Genetic drift alone cannot explain the existence of these haplotypes, which must have been associated with strong positive selection in partial selective sweeps. Moreover, the swept haplotypes are entirely devoid of archaic ancestry as opposed to the non-swept haplotypes in the same genomic regions. The ancient Ust'-Ishim male dated at 45,000 before the present (BP) also carries the swept haplotypes, implying that selection on the haplotypes must have occurred between 45,000 and 55,000 years ago. Finally, we find that the chromosomal positions of sweeps overlap previously reported hotspots of selective sweeps in great ape evolution, suggesting a mechanism of selection unique to X chromosomes., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560)., Patients and Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method., Results: Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales., Conclusions: Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: Homologous recombination repair gene mutations (HRRm) are common in urothelial carcinoma (UC), rendering tumor cells sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. We assessed efficacy and safety of durvalumab (anti-programmed cell death ligand-1) plus olaparib (PARP inhibitor) in patients with metastatic UC (mUC)., Methods: This randomized, multicenter, double-blind, phase II trial enrolled untreated, platinum-ineligible patients with mUC. Patients (N = 154) were randomly assigned 1:1 to receive durvalumab (1,500 mg intravenously once every 4 weeks) plus olaparib (300 mg orally, twice daily) or durvalumab plus placebo. The primary end point was progression-free survival (PFS) assessed by investigators per RECIST version 1.1. Secondary end points included overall survival in all patients and PFS in patients with HRRm., Results: Overall, median PFS was 4.2 months (95% CI, 3.6 to 5.6) for durvalumab plus olaparib and 3.5 months (95% CI, 1.9 to 5.1) for durvalumab plus placebo (hazard ratio [HR], 0.94; 95% CI, 0.64 to 1.39; log-rank P value, .789). Median overall survival was 10.2 months (95% CI, 7.0 to 13.9) and 10.7 months (95% CI, 7.2 to 17.3), respectively (HR, 1.07; 95% CI, 0.72 to 1.61). In the 20% of patients with HRRm, median PFS was 5.6 months (95% CI, 1.9 to 8.1) and 1.8 months (95% CI, 1.7 to 2.2), respectively (HR, 0.18; 95% CI, 0.06 to 0.47). Treatment-related grade 3 or 4 adverse events occurred in 18% and 9% of patients, respectively., Conclusion: Adding olaparib to durvalumab did not improve survival outcomes in an unselected mUC population. Efficacy outcomes with durvalumab were similar to those reported for other anti-programmed cell death-1/programmed cell death ligand-1 agents. However, the results of secondary analyses suggest a potential role for PARP inhibition in patients with UC harboring HRRm.

Background: Bellmunt Risk Score, based on Eastern Cooperative Oncology Group (ECOG) performance status (PS), hemoglobin levels and presence of liver metastases, is the most established prognostic algorithm for patients with advanced urothelial cancer (aUC) progressing after platinum-based chemotherapy. Nevertheless, existing algorithms may not be sufficient following the introduction of immunotherapy. Our aim was to develop an improved prognostic model in patients receiving second-line atezolizumab for aUC., Methods: Patients with aUC progressing after cisplatin/carboplatin-based chemotherapy and enrolled in the prospective, single-arm, phase IIIb SAUL study were included in this analysis. Patients were treated with 3-weekly atezolizumab 1200 mg intravenously. The development and internal validation of a prognostic model for overall survival (OS) was performed using Cox regression analyses, bootstrapping methods and calibration., Results: In 936 patients, ECOG PS, alkaline phosphatase, hemoglobin, neutrophil-to-lymphocyte ratio, liver metastases, bone metastases and time from last chemotherapy were identified as independent prognostic factors. In a 4-tier model, median OS for patients with 0-1, 2, 3-4 and 5-7 risk factors was 18.6, 10.4, 4.8 and 2.1 months, respectively. Compared with Bellmunt Risk Score, this model provided enhanced prognostic separation, with a c-index of 0.725 vs 0.685 and increment in c-statistic of 0.04 (p<0.001). Inclusion of PD-L1 expression did not improve the model., Conclusions: We developed and internally validated a prognostic model for patients with aUC receiving postplatinum immunotherapy. This model represents an improvement over the Bellmunt algorithm and could aid selection of patients with aUC for second-line immunotherapy., Trial Registration Number: NCT02928406., Competing Interests: Competing interests: AB: Honoraria, advisory and research funding from Roche, BMS, MSD, Ipsen, Debiopharm, Basilea, Pierre Fabre and Janssen; and steering committee member for Roche. AM: Lectures/speaker honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Astellas, Novartis, Pfizer and Roche; consultant for AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSA Pharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer and Roche; research and clinical trials support from AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSA Pharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer and Roche. YL: Personal fees from Roche, Janssen, Astellas, MSD, Pfizer, BMS, Immunomedics, AstraZeneca, Sanofi and Seattle Genetics; grants from Janssen, MSD and Sanofi; non-financial support from Janssen, Roche, AstraZeneca and Sanofi. NJ: Consultancy from Merck, Roche and AstraZeneca; trial funding (to institution) from Merck, Roche and AstraZeneca. EC: Research grants from Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB; consultancy from Abbvie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm and Sanofi; and speakers fees from Abbvie, Amgen, Bristol Myers Squibb, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB. DC: Personal fees for advisory boards/speaker engagements from Roche, Janssen, Astellas, MSD, Ipsen, Pfizer, Bristol-Myers Squibb, Bayer, AstraZeneca, Novartis, Lilly, Sanofi, Pierre Fabre and Boehringer Ingelheim. FL-R: Honoraria from AstraZeneca, Bayer, BMS, Lilly, MSD, Pfizer, Roche and Thermo Fisher; and research funding from Lilly, Roche and Thermo Fisher. FC: Advisory role for BMS, MSD, Pfizer and AstraZeneca. MK: Honoraria/consultation for Bayer, BMS, Eusai, Novartis, Merck, MSD, Pfizer and Roche; travel grants from Ipsen, Janssen, Merck and Novartis. GdV: Support for clinical trials and scientific projects for Pfizer, Roche and Ipsen; and speaker fees and consulting for Pfizer, Novartis, Roche, MSD, Astellas, Bayer, Ipsen, Janssen, Merck, EUSA Pharma and BMS. RZ: None. KT: None. CNS: Consultant for Pfizer, Merck, MSD, AstraZeneca, Astellas, Sanofi Genzyme, Roche-Genentech, Incyte, BMS, Foundation Medicine, Immunomedics (now Gilead), Medscape, UroToday, CCO Clinical, Janssen and NCI., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sapanisertib, a dual mTORC1/2 inhibitor, may offer more complete inhibition of the PI3K/AKT/mTOR pathway than mTORC1 inhibitors, such as everolimus. This phase II study evaluated the efficacy and safety of single-agent sapanisertib and sapanisertib plus the PI3Kα inhibitor TAK-117, vs. everolimus in patients with advanced clear cell renal cell carcinoma (ccRCC) that had progressed on or after VEGF-targeted therapy., Materials and Methods: Patients with histologically confirmed, advanced ccRCC were randomized 1:1:1 to receive single-agent everolimus 10 mg once daily, single-agent sapanisertib 30 mg once weekly, or sapanisertib 4 mg plus TAK-117 200 mg, both once daily for 3 days/week, in 28-day cycles. The primary endpoint was progression-free survival (PFS)., Results: Ninety-five patients were treated with everolimus or sapanisertib (n = 32 each), or sapanisertib plus TAK-117 (n = 31). There were no significant differences in PFS among the 3 groups or across any subgroups. Median PFS was 3.8 months with everolimus vs. 3.6 months with sapanisertib (HR, 1.33; 95% CI, 0.75-2.36), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75-2.52). No significant differences in overall survival were seen among groups. Overall response rate was 16.7%, 0%, and 7.1%, respectively. Discontinuations due to treatment-emergent adverse events were 15.6%, 28.1%, and 29.0%., Conclusion: Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns., Patients and Methods: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary end point was objective response rate (ORR) per RECIST v1.1 by BICR., Results: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. Median follow-up was 62.9 months (range, 58.6-70.9; data cutoff October 1, 2020). At 48 months, OS rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; PFS rates were 9.5% and 2.7%, respectively. Median duration of response (DOR) was 29.7 months (range, 1.6+ to 60.5+) for pembrolizumab and 4.4 months (range, 1.4+ to 63.1+) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. Median follow-up was 56.3 months (range, 51.2-65.3; data cutoff September 26, 2020). Confirmed ORR was 28.9% (95% CI, 24.3-33.8), and median DOR was 33.4 months (range, 1.4+ to 60.7+); 36-month DOR rate was 44.8%. Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports., Conclusion: With approximately 5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients. Clinical trial registry and ID: ClinicalTrials.gov, NCT02256436 (KEYNOTE-045) and NCT02335424 (KEYNOTE-052)., (Copyright © 2022. Published by Elsevier Ltd.)