tbuckley/cabot-search huggingface dataset:
Vasculo-immune modulatory effects of anti-VEGF therapy in metastatic clear cell renal cell carcinoma: The A-PREDICT trial.
Authors: Lewis Au, Zayd Tippu, Husayn Pallikonda, Anne-Laure Cattin, Georgia Whitton, Andrew Rowan, Annika Fendler, Jahangeer Malik, Ekaterini Boleti, Naveen Vasudev, Martin Highley, Agnieszka Michael, Tim Eisen, Steven Penegar, Rebecca Lewis, Lucy Kilburn, Judith Bliss, Charles Swanton, James Larkin, Samra Turajlic
Journal: Journal of Clinical Oncology (2025)

572 Background: Anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors and checkpoint inhibitors (CPI) a standard-of-care treatment for clear cell renal cell carcinoma (ccRCC). We investigated the biology underpinning benefit of anti-VEGFR TKI in the phase II A-PREDICT trial (NCT01693822), evaluating pre- and post-treatment, fresh multiregion tumour biopsies in patients with metastatic ccRCC treated with first-line axitinib. Methods: We analysed 123 tumour samples from 52 patients, 28 with paired pre/post-treatment samples. Post-treatment samples included week-9, nephrectomy, and on-progression timepoints. ‘Responders’ had progression-free survival (PFS) ≥6 months (n=35), ‘non-responders’ with PFS &lt;6 months (n=17). We applied a custom Nanostring panel for gene expression analysis and multiplex immunofluorescence (mIF) for orthogonal validation. Wilcoxin test was used to analyze paired observations. Results: At baseline, angiogenesis scores were similar between responders and non-responders (p=0.22). Post-treatment, the angiogenesis, vascular sprouting, and endothelial cell proliferation signature scores were significantly decreased (p=0.023, 0.0034, &amp; 0.0082, respectively) in all patients, suggesting suppression of angiogenesis and neovascularisation irrespective of clinical outcomes. mIF in 3 patients (with PFS of 3, 5.6, &amp; 100 months) confirms widespread intratumoral vessel depletion. Immune deconvolution analysis shows total levels of T cells and CD8 + T cells were similar pre- and post-treatment, suggesting axitinib did not enhance immune cell trafficking. Rather, axitinib promoted increased levels of exhausted CD8 + T cells post-treatment (p=0.01). M2 tumour-associated macrophages increased post-treatment in responders (p=0.033) but not in non-responders (p=0.44). A minority of patients had durable (&gt;2 years) responses to axitinib (n=7/65, 6 with tissue for analysis). In these patients, we found higher levels of pre-treatment intratumoral cytotoxic immune cells (p=0.041) and NK cells (p=0.015) compared to patients with primary resistant disease. Conclusions: Axitinib suppressed angiogenesis and neovascularisation leading to intratumoral vessel depletion, and therapy response associates with features of an immunosuppressive TME. Baseline endogenous immune priming appears critical for durable response to anti-VEGF therapy. These data are relevant to understanding the clinical efficacy of combined anti-VEGF and CPI regimens. Clinical trial information: NCT01693822 .
Late onset of apalutamide-related skin toxicity in Black men with advanced prostate cancer: A diverse real-world analysis.
Authors: Chen H Yong, Alaa Ahmed Genidy Aly, Debra Hannah Josephs, Deborah Enting, Kate Smith, Danielle Crawley, Nabil Mahmoud Abdelfattah, Elias Pintus
Journal: Journal of Clinical Oncology (2025)

23 Background: Apalutamide (APA)- related skin toxicity is a common adverse reaction of varying incidence by ethnicity 1 . We have limited data on APA-related skin toxicity in Black men due to under-representation in clinical trials 2 . This real-world analysis evaluates APA-related skin toxicity and its differential impact across Black and White men in an ethnically diverse population at two high-volume cancer centers in London, United Kingdom. Methods: We investigated 120 prostate cancer patients treated with APA between 2021 and 2023. Skin toxicity incidence and grading, time to onset and drug discontinuation rates were examined. Adverse event causality was attributed by treating physicians and graded by the Common Terminology Criteria for Adverse Events v5.0 based on body surface area involvement. The cumulative incidence of APA-related skin toxicity and APA discontinuation rates were estimated by Gray’s method. Results: 111 patients were included in our analysis, represented by 35 (31.5%) Black and 76 White men (68.4%). 18 men (16.2%) had pre-existing autoimmune or skin disease. 108 men (97%) commenced APA at 240 mg. At 24-month follow up, APA-related skin toxicity of any grade and Grade 3, were seen in 23 (23%) and 12 men (12%) respectively. There was no significant difference in skin toxicity incidence or severity between Black and White men (Table). The median time to skin toxicity was 179 and 84 days in Black and White men respectively, with late onset (&gt;6 months) events more commonly seen in Black men. APA discontinuation rate due to skin or other Grade 3 toxicity was similar (24-month, 11.4% in Black vs 9.2% in White men). Based on multivariable competing risk analysis, skin or autoimmune disease, or eosinophil count at baseline had no significant impact on incidence or severity of skin toxicity. Conclusions: Late onset of APA-related skin toxicity is seen more commonly in Black men, thus requires clinical vigilance and monitoring. There is no significant ethnicity disparity in incidence or severity for APA-related skin toxicity. No significant risk factors for incidence and severe skin toxicity were identified. Cumulative incidence of APA-related skin toxicity at 6 and 24 months. Skin Toxicity Ethnicity 6-months 24-months p-value Any grade 0.851 White 14% 21% Black 11% 25% Grade 3 0.954 White 9.2% 11% Black 2.9% 13%
Hypofractionated radiotherapy for prostate cancer (HYDRA): An individual patient data meta-analysis of randomized trials in the MARCAP consortium.
Authors: Amar Upadhyaya Kishan, Yilun Sun, David P. Dearnaley, Emma Hall, Alison Tree, Charles Catton, Himanshu Lukka, William Robert Lee, Howard M. Sandler, Luca Incrocci, Wilma Heemsbergen, Jessica Karen Wong, Eric M. Horwitz, Karen E. Hoffman, Comron Hassanzadeh, Deborah A. Kuban, Giuseppe Sanguineti, Stefano Arcangeli, John Nikitas, Daniel Eidelberg Spratt
Journal: Journal of Clinical Oncology (2025)

385 Background: Trials comparing moderately hypofractionated radiotherapy (MHFRT) against conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs. superiority) and MHFRT dose. Herein, we compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT. Methods: Individual patient data were obtained from 7 phase III trials comparing MHFRT vs. CFRT: three (n=3454) with isodose and four (n=2426) with dose-escalated MHFRT. Meta-analyses were designed to compare progression-free survival (PFS), late grade ≥2 genitourinary (GU) and late grade ≥2 gastrointestinal (GI) physician-scored toxicity, and clinically-significant decrements in patient-reported urinary or bowel quality of life (QOL). Results: After a median follow-up of 5.4 years (interquartile range [IQR], 4.6-7.2) and 7.1 years (IQR 5.7-8.4) following isodose and dose-escalated MHFRT, there were no differences in PFS (hazard ratio [HR] 0.92, 95%CI 0.81-1.05 and HR 0.94, 95%CI 0.82-1.09, respectively). Neither isodose nor dose-escalated MHFRT were associated with increased odds of grade ≥2 GU toxicity (odds ratio [OR] 1.16 95CI% 0.86-1.57 and OR 1.20, 95%CI 0.95-1.51). The odds of grade ≥2 GI toxicity were higher with dose-escalated (OR 1.48, 95%CI 1.14-1.92) but not isodose MHFRT (OR 1.30, 95% 0.59-2.87). Isodose MHFRT did not show different odds of urinary (OR 1.03, 95%CI 0.51-2.09) and bowel (OR 0.76, 95%CI 0.40-1.43) QOL decrements, while dose-escalated MHFRT was associated with greater odds of bowel (OR 1.68, 95%CI 1.07-2.61), but not urinary (OR 1.57, 95%CI 0.87-2.85), QOL decrement. Conclusions: Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel and urinary toxicity. Isodose regimens, e.g. 60 Gy in 20 fractions, should be the standard MHFRT regimen for localized prostate cancer.
Serum biomarkers in metastatic castration-resistant prostate cancer (mCRPC) patients receiving [ <sup>177</sup> Lu]Lu-PSMA-617 therapy: Post hoc analysis of a phase II clinical trial.
Authors: Emilio Francesco Giunta, Irene Marini, Anna Sarnelli, Nicole Brighi, Flavia Foca, Giuseppe Schepisi, Cristian Lolli, Manuela Monti, Silvia Nicolini, Maria Concetta Cursano, Giovanni Rosti, Ilaria Grassi, Giovanni Paganelli, Stefano Severi, Federica Matteucci, Maddalena Sansovini, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2025)

190 Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) has been recently approved for metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have assessed the efficacy of 177 Lu-PSMA-617, but only half of the eligible patients seem to obtain a clear benefit from it. Currently, there is a lack of validated biomarkers that could help find the best candidates for this radioligand therapy. Methods: In the IRST185.03, a single-arm monocentric phase II clinical trial, 142 mCRPC patients received 177 Lu-PSMA-617 at a dose of 3.7-5.5 Gbq every 8-12 weeks for a maximum of 4 cycles. Baseline blood samples were collected within 7 days from the first dose of 177 Lu-PSMA-617. Hemoglobin (Hb), alkaline phosphatase (ALP), prostate-specific antigen (PSA), carcinoembryonic Antigen (CEA), chromogranin A (CgA), and neuron-specific Enolase (NSE), as well as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were analyzed at both uni- and multivariate levels to evaluate their correlation to progression-free survival (PFS). Results: At the time of data cut-off, after a median follow-up time of 44.0 months, the median PFS in the global cohort was 7.0 months. At univariate analysis, among serum biomarkers, lower PLR (cut-off: 210, HR: 0.66, 95% CI: 0.44-0.99, p=0.04), lower ALP (cut-off: upper limit of normal, HR: 0.51, 95% CI: 0.34-0.75, p&lt;0.01), lower PSA (cut-off: median value, HR: 0.51, 95% CI: 0.35-0.74, p&lt;0.01), and lower CEA (cut-off: upper limit of normal, HR: 0.55, 95% CI: 0.32-0.95, p=0.03) were associated with longer PFS. Among clinical characteristics, the previous use of docetaxel (HR: 1.48, 95% CI: 1.04-2.10, p=0.03) was associated with shorter PFS. At multivariate analysis, only PSA and CEA remained prognostic for PFS (p=0.01 and 0.02. respectively). Conclusions: High PSA and CEA levels appeared the only serum predictors of poor clinical outcome to 177 Lu-PSMA-617 therapy in mCRPC. The role of CEA as potential biomarker associated with 177 Lu-PSMA-617 needs to be confirmed since it could be linked to aggressive prostate cancer variant. Clinical trial information: 2016-002732-32 .
Real world effectiveness of systemic treatment in patients (pts) with advanced upper tract urothelial carcinoma (UTUC) with histological variants.
Authors: Fabien Moinard-Butot, Karim Amrane, Luca Campedel, Damien Pouessel, Mostefa Bennamoun, Aude Flechon, Matthieu Roulleaux Dugage, None Pierre-Etienne Jr., Constance Thibault, Baptiste Abbar, Jean-Baptiste Barbe-Richaud, Clement Dumont, Philippe Barthelemy
Journal: Journal of Clinical Oncology (2025)

722 Background: Upper tract urothelial carcinoma is a rare and heterogeneous disease that accounts for up to 5% of all urothelial neoplasms. Variant histology is an important prognostic factor in patients affected by bladder cancer and its presence is associated with adverse pathological features and worse survival outcomes. However, few data exists regarding the impact of histological variants in patients affected by UTUC treated with systemic therapy. Methods: PEMBROBLAD is a retrospective multicenter RW study conducted in 24 French GETUG centers. Eligible patients had advanced UC with mixed variants (UC-V) or pure non-UC (NUC). All patients received ICI as a second line treatment. We identified all patients with UTUC within the whole study cohort. The primary endpoint was overall response rate (ORR) in first-line setting; secondary endpoints included disease control rate (DCR) in first-line setting, overall response rate (ORR) in second-line setting, DCR in second-line setting and overall survival (OS). Results: Out of 139 patients (pts) in the PEMBROBLAD cohort, 32 had UTUC. Median age was 72 years (range 49-88), 69.6 % were male with ECOG PS 0/1 in 64.5% of cases. Mixed UC represented 75% (n=24) of UTUC with histological variants. The most common were squamous cell carcinoma (n=9, 37.5%), micropapillary (n=7, 29.2%), sarcomatoïd (n=3, 12.5%), neuroendocrine (n=1, 4.2%), nested (n=4, 16.7%) and adenocarcinoma (n=3, 37.5%). Non UC concerned 25% (n=8) of UTUC with histological variants, including 4 patients with squamous cell carcinoma (n=4, 50%). Fifteen pts (46.9%) was treated with Carboplatin based combination in first-line and 14 pts (43.75%) with Cisplatin based treatment. The ORR was 33.3% and DCR was 50.0%. All patients received immunotherapy in second-line setting. The ORR was 18.7% and DCR was 28.1%. Median overall survival from first-line treatment is 8.9 months (CI95%, 3.6-18.5). Serious TRAE occurred in 5 pts (16.1%). Discontinuation due to TRAEs occurred in 9.6% of pts. Thirteen pts (41.9%) had a third-line of treatment. Conclusions: Our results suggest efficacy of chemotherapy in first-line setting and ICI in pretreated advanced UC-V and NUC. No new safety concerns were identified. Survival data will be updated for the meeting.
Safety and efficacy of FGFR inhibitors in urothelial carcinoma: A systematic review and meta-analysis.
Authors: Oguz Kagan Sahin, Ayesha Ayesha, Paweł Łajczak, Sriharsha Koduru, Rafae Ali Khan, Giulia Almirón, Hussam Akram
Journal: Journal of Clinical Oncology (2025)

782 Background: Urothelial carcinoma is the most frequently occurring bladder cancer and originates from urothelial cells lining the bladder and the urinary tract. Fibroblast growth factor receptor (FGFR) inhibitors are the emerging treatment option, due to their ability to alter FGFR signaling which plays a role in tumor proliferation, survival, and angiogenesis. This study aims to assess the efficacy of FGFR inhibitors for urothelial carcinoma. Methods: We conducted a systematic review and single-arm meta-analysis by systematically searching PubMed, Cochrane, and Embase for studies evaluating the efficacy and/or safety of FGFR inhibitors for urothelial carcinoma. The primary measures of effect were hazard ratios (HRs) and the proportion of events per 100 observations, both with 95% confidence intervals (CIs), pooled using a random-effects model with a generalized linear mixed model (GLMM). Heterogeneity was assessed using the I² statistic and Cochran’s Q test. Statistical analyses were performed using RStudio v4.3.3. Results: We included 19 studies, comprising two cohort studies and 17 clinical trials, five of which were randomized controlled trials (RCTs), with a combined total of 1,187 patients. The pooled median overall survival (mOS) was 8.77 months (95% CI, 7.28; 10.56), the pooled median progression-free survival (mPFS) was 3.46 months (95% CI, 2.73; 4.40), and the median duration of response (mDOR) was 5.38 months (95% CI, 4.72; 6.14). The grade ≥ 3 adverse effects rate was 49.43% (95% CI, 35.44; 63.51%). The overall objective response rate (ORR) was 24.16% (95% CI, 17.65; 32.14%), in the subgroup analysis of 218 patients using Erdafitinib ORR was 42.25%. The progressive disease and stable disease rates were 48.64% (95% CI, 38.88; 58.50%) and 26.07% (95% CI, 20.01; 33.21%), respectively. Conclusions: Our meta-analysis suggests that FGFR-targeted treatment regimens show promising clinical activity in urothelial carcinoma with a comparable safety profile to conventional treatment modalities.
AVENANCE real-world study of avelumab first-line (1L) maintenance treatment for advanced urothelial carcinoma (UC): Analyses in low tumor burden subgroups.
Authors: Philippe Barthelemy, Yohann Loriot, Constance Thibault, Aude Flechon, Eric Voog, Jean Christophe Eymard, Camille Simon, Damien Pouessel, Matthieu Chasseray, Veronique Lorgis, Constant Josse, Prisca Lambert, Laurent Paret, Marine Gross-Goupil
Journal: Journal of Clinical Oncology (2025)

718 Background: The effectiveness and safety of avelumab 1L maintenance was confirmed in the large real-world AVENANCE study in France. In patients with advanced UC, low tumor burden is associated with a better prognosis, which may inform treatment decisions. Here, we report post hoc analyses from AVENANCE in subgroups with disease characteristics associated with low tumor burden. Methods: AVENANCE (NCT04822350) is a noninterventional ambispective study that enrolled patients with locally advanced or metastatic UC who were progression free after 1L platinum-based chemotherapy (PBC) and who had previous, ongoing, or planned avelumab 1L maintenance treatment. The primary endpoint is overall survival (OS) from the start of avelumab treatment. In post hoc analyses, OS and progression-free survival (PFS) were analyzed in subgroups who had locally advanced disease, nonvisceral metastases (excluding bone), or lymph node (LN)–only disease at the start of PBC. Results: Of patients with available data in the overall effectiveness population (N=595), 49 (8.3%) had locally advanced disease, 80 (14.7%) had nonvisceral metastases, and 61 (10.3%) had LN-only disease. At data cutoff (July 15, 2024) in the overall effectiveness population, median follow-up from start of avelumab was 33.2 months (95% CI, 31.7-34.2), median OS was 21.2 months (95% CI, 17.3-23.3), and median PFS was 5.7 months (95% CI, 5.2-6.6). In subgroups with locally advanced disease, nonvisceral metastases, or LN-only disease, median OS (95% CI) was not reached (17.4 months-not estimable [NE]), 27.2 months (16.8-NE), and not reached (19.9 months-NE), and median PFS (95% CI) was 19.8 months (9.6-NE), 9.0 months (5.8-16.1), and 13.4 months (6.9-26.5), respectively. Subsequent treatment was received by 17 patients (34.7%) with locally advanced disease (enfortumab vedotin [EV] in 3 [6.1%]), 45 patients (56.3%) with nonvisceral metastases (EV in 12 [15.0%]), and 33 patients (54.1%) with LN-only disease (EV in 8 [13.1%]). Conclusions: Subgroup analyses from AVENANCE show pronounced clinical benefits with avelumab 1L maintenance in subgroups with low tumor burden characteristics. Results are consistent with previous analyses from JAVELIN Bladder 100 and other real-world studies (eg, READY, an Italian compassionate use program) and further support the use of avelumab 1L maintenance as a standard of care in patients with advanced UC without progression after 1L PBC, including those with low tumor burden. Clinical trial information: NCT04822350 .
Assessment of the proficiency of ChatGPT-4o in an image-based robot-assisted radical prostatectomy scenario.
Authors: Jiakun Li, Jing Zhao, Zeqi Wang, Le Tong, Bairong Shen, Qiang Wei
Journal: Journal of Clinical Oncology (2025)

423 Background: Surgery is a process that heavily relies on complex visual information. Many AI-based surgical teaching and assistance applications have emerged. However, the application of the newly released ChatGPT-4o in surgical contexts remains unexplored. This study aims to investigate the ability of ChatGPT-4o in analyzing and recognizing anatomical structures, surgical procedures, and operational precautions based on image information in a surgical context. Utilizing screenshots from robot-assisted radical prostatectomy videos sourced from the internet. Methods: We developed a test comprising 77 images and 65 questions, with a total score of 100 points. The test includes sections on anatomical structures, surgical procedures, and operational precautions. We sequentially input the questions into the ChatGPT-4o model and employed strategies to enhance its performance during the test. A passing score was set at 60 points or above, and an excellent score at 80 points or above. Results: ChatGPT-4o achieved a score of 68, surpassing the passing threshold. The accuracy for non-image questions was higher than for image-based questions (85.71% vs. 58.46%, χ² = 7.78, p = 0.005), and questions with fewer images had a higher accuracy than those with multiple images (71.11% vs. 30.00%, p &lt; 0.001). Furthermore, we found ChatGPT-4o performed differently in recognizing different structures, with the highest accuracy for questions involving muscle and fascia (100%) and the lowest for those involving nerve and vessel structures (33.33%). Conclusions: ChatGPT demonstrated commendable abilities in image recognition and problem analysis in surgical contexts. We hope that the results of this study will contribute to future applications of ChatGPT in AI-assisted surgical teaching and assistance.
CHAPTER-Platform-201: Phase 2 trial of pimitespib plus enzalutamide for patients with metastatic castration-resistant prostate cancer.
Authors: Nobuaki Matsubara, Masaki Shiota, Hiroji Uemura
Journal: Journal of Clinical Oncology (2025)

TPS296 Background: Metastatic castration-resistant prostate cancer (mCRPC) patients (pts), especially those who experience disease progression while on androgen receptor signaling inhibitor (ARSI) therapy, have a poor prognosis and limited treatment options. Although taxanes are an available options, a second ARSI is more frequently used in this setting because of the toxicity of taxanes, pts’ preference, and comorbidities. However, the efficacy of a second ARSI is limited because of cross-resistance. The main mechanisms of cross-resistance are androgen receptor (AR) genomic alterations (AR amplification and mutation), AR splice variants, and upregulation of the glucocorticoid receptor (GR) and components of the PI3K/AKT pathway. Therefore, new treatment options for mCRPC after ARSI therapy are urgently needed. Pimitespib (PIMI) is a novel heat shock protein 90 (HSP90) inhibitor approved for treating Gastrointestinal Stromal Tumor. HSP90 is a molecular chaperone and forms the structure of client proteins. Many of HSP90's client proteins, such as AR and GR, which represent components of the PI3K/AKT pathway, have been identified as prostate cancer-related proteins required for tumor development; their activation depends on HSP90. PIMI suppresses the expression of AR and GR, which are client proteins related to bypass pathways, such as the PI3K/AKT pathway, by inhibiting HSP90 expression; this may help overcome acquired resistance to ARSI. This phase 2 study investigated the efficacy of PIMI in combination with enzalutamide (ENZ) in pts with mCRPC refractory to ARSI. Methods: This phase 2 study was conducted in pts with mCRPC who showed disease progression on one ARSI. The study includes two parts: feasibility part (FP) and expansion part (ExP). The FP is evaluated with six pts to determine the maximum tolerated dose of PIMI (160 mg/day or 120 mg/day, orally; 5 days on/2 days off) in combination with a standard dose of ENZ (160 mg/day, orally; once daily). The ExP is an open-label, randomized trial evaluating the efficacy and safety of a determined dose of PIMI in combination with ENZ versus ENZ monotherapy. Forty pts are randomized 1:1 to each arm. The primary endpoint of FP is dose-limiting toxicity, and ExP is blinded independent central review of radiographic progression-free survival (rPFS). The secondary endpoints include investigator-assessed rPFS, overall survival, objective response rate, pharmacokinetics, and safety. Among pts for whom mCRPC was diagnosed, those with histologically or cytologically confirmed prostate adenocarcinoma and prior refractory status to one ARSI are eligible for enrollment. Pts who had received taxanes for mCRPC are excluded. Enrollment began in July 2023 and is currently ongoing. Clinical trial information: 2031230263 .