tbuckley/cabot-search huggingface dataset:
Frequent overexpression of NECTIN-4 in CNS metastases from urothelial carcinoma.
Authors: Richard Weiten, Constantin Rieger, Melanie von Brandenstein, Enno Storz, Yuri Tolkach, Thomas Stehle, Teresa Schmidt, Martin Glas, Tobias Blau, Kathy Keyvani, Viktor Grünwald, Michael Hölzel, Axel Heidenreich, Markus Eckstein, Niklas Klümper
Journal: Journal of Clinical Oncology (2025)

804 Background: The combination of enfortumab vedotin plus pembrolizumab (EV/P) has become the new standard of care for advanced or metastatic urothelial carcinoma (mUC) due to its high efficacy. However, patients with active central nervous system (CNS) metastases were excluded from the EV-302 trial. More recently, NECTIN-4 amplifications have been identified as genomic predictors of EV response and long-term survival in patients with mUC. Additionally, early evidence suggests that EV may cross the blood-brain barrier and be effective in patients with CNS metastases. Therefore, we aimed to evaluate NECTIN-4 expression and amplification in patients with mUC involving CNS metastases. Methods: Immunohistochemical staining for NECTIN-4, with H-score evaluation, was performed in both non-CNS mUC (n=152) and CNS mUC patient cohorts (n=17). In addition, we developed a NECTIN-4-specific fluorescence in situ hybridization (FISH) assay to correlate NECTIN-4 copy number variations (CNVs) with membranous NECTIN-4 protein expression in CNS mUC. Results: Membranous NECTIN-4 protein expression was more abundant in CNS mUC (n=12/17; with H-score ≥ 100; median H-score 160; interquartile range [IQR] 250-85) than in non-CNS mUC samples (n=58/152; median H-score 40; IQR 0-140, p&lt;0.001). Amplification data are currently being generated and will be presented at the conference. Conclusions: The substantial expression of NECTIN-4 in CNS metastases from UC, along with the results of the EV-302 trial and the identification of NECTIN-4 amplifications as genomic predictors of EV response and long-term survival in patients with mUC, supports the potential use of EV/P in treating patients with CNS mUC.
PSMA-based PET imaging in newly diagnosed, high-risk localized prostate cancer, a National Cancer Institute (NCI) Cancer Moonshot trial.
Authors: Nikhil Pramod, Baris Turkbey, Peter Choyke, Liza Lindenberg, Esther Mena, Ravi Amrit Madan, Michele Reed, Philip Eclarinal, Maria Merino, Adam G. Sowalsky, Krishnan R. Patel, Deborah E. Citrin, James L Gulley, William Douglas Figg, William L. Dahut, Peter A. Pinto, Fatima Karzai
Journal: Journal of Clinical Oncology (2025)

327 Background: Prospective randomized trials have suggested that prostate specific membrane antigen (PSMA)-based PET/CT may improve the detection of metastatic disease in patients with high-risk prostate cancer (HR-PCa) diagnosed by conventional imaging. Of patients with HR-PCa who undergo radical prostatectomy (RP), the majority will experience PSA recurrence within 5 years. PSMA-based PET/CT may improve patient selection for local therapy, suggesting that this imaging advancement may be integral to improving patient outcomes. Here, we present results from the NCI cohort of NCT03976843, which evaluated the use of 18F-DCFPyL PSMA- PET/CT in newly diagnosed HR-PCa prior to RP. Methods: Enrolled patients (pts) had HR-PCa (biopsy Gleason score [GS] ≥8, PSA &gt;20, or ≥T3) with negative conventional imaging (CT &amp; bone scan). Pts underwent 18F-DCFPyL PSMA PET/CT and prostate MRI prior to RP. The primary hypothesis was that the subgroup of patients with a negative pre-operative PET/CT would have improved progression-free survival (PFS) over historical controls. Progression was defined as a confirmed PSA ≥ 0.2 ng/mL and PET/CT at progression. Correlatives included IHC of RP specimens and expert NCI radiologic imaging review. Results: Forty patients enrolled, and 38 patients underwent RP. Of the 38, the median age was 68 years old (61-71 years old), median PSA was 8.15 ng/mL (5.75-16.25), median biopsy GS was 8 (8-9), and median RP GS was 7 (7-8). Pre-operative PET/CT demonstrated regional lymphadenopathy in 2 patients (5.3%), and the median SUVmax of the index lesion was 12.6 (6.6-17.1). At a median follow-up of 2.2 years, the 2- and 4-year PFS was 76% (63%-91%) and 45% (22%-95%), respectively. The median PFS was 3.2 years. Of the 11 pts who underwent progression restaging, 2 had recurrent pelvic nodal disease, and 9 had no visible disease. No AEs were observed. Conclusions: These results support 18F-DCFPyL PET/CT as a safe and effective pre-operative staging strategy with the potential to improve patient selection for local definitive therapy. Expert NCI radiologic review for this multisite study, with correlative molecular and genomic work, is ongoing. Clinical trial information: NCT03976843 .
Clinical and Translational Results from PORTER, a Multi-cohort Phase 1 Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer
Authors: Matthew D. Galsky, Karen A. Autio, Christopher R. Cabanski, Kristopher Wentzel, Julie N. Graff, Terence W. Friedlander, Timothy R. Howes, Kristin M. Shotts, Julie Densmore, Marko Spasic, Diane M. Da Silva, Richard O. Chen, Jennifer Lata, Jeffrey Skolnik, Tibor Keler, Michael J. Yellin, Theresa M. LaVallee, Justin Fairchild, Silvia Boffo, Jill O'Donnell-Tormey, Ute Dugan, Nina Bhardwaj, Sumit K. Subudhi, Lawrence Fong
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer (mCRPC). Novel combinations may enhance immunotherapy efficacy. Patients and Methods: We conducted an open-label, non-comparative platform trial (NCT03835533) in mCRPC to assess nivolumab-based combinations. The cohorts were: A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg intravenously Q3W, B) stereotactic body radiation therapy 30-50 Gray, CDX-301 75 μg/kg subcutaneously for 5 days, poly-ICLC 1 mg intramuscularly twice weekly for 3 weeks, and nivolumab 480 mg Q4W, and C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on Lead-in Day 8, Day 1 of Cycles 1-3, then Q12W, and nivolumab 480 mg Q4W. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control. Results: 43 patients enrolled (N = 14, 15, 14 in Cohorts A, B, C). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one Grade 5 TRAE in Cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with pre-existing memory/regulatory T cells, TNFα, and other inflammatory pathways. Conclusions: Cohort B, which combined radiation therapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Pre-existing rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.
Whole-slide multiplexed tissue imaging of prostate adenocarcinoma to investigate immune niches in high- versus low-grade tumors.
Authors: Ali Amiryousefi, Jeremiah Wala, Brian William Labadie, Aishwarya Atmakuri, Kiranj Chaudagar, Eamon Toye, Andréanne Gagné, Jia-Ren Lin, Eliezer Mendel Van Allen, Akash Patnaik, Peter Sorger
Journal: Journal of Clinical Oncology (2025)

224 Background: The tumor-immune microenvironment (TME) is crucial in the progression of prostate cancer (PCa), yet little is known about its spatial organization and immune composition in treatment-naïve, localized PCa. While immunotherapy has had limited success in metastatic PCa, its efficacy in localized disease remains largely unknown. This study aims to dissect tumor-immune interactions in primary PCa and explore differences in immune landscape between low- and high-Gleason PCa, thus providing biologic insights for immunotherapy actionability. Methods: We performed spatial profiling of radical prostatectomy (RP) specimens from 28 treatment-naïve prostate cancer patients. These included 14 patients with low-grade disease (Gleason Grade Group 1–2) and 14 patients with high-grade disease (Gleason Grade Group 4–5). Using multiplex cyclic immunofluorescence (CyCIF) and a 27-marker panel, we obtained single-cell resolution across whole-slide images. Tumor and stromal compartments were manually annotated, and immune cell densities and neighborhood were analyzed and compared between low- and high-grade tumors. Spatial analysis focused on identifying immune clusters (IC -suggestive of tertiary lymphoid structures -TLS) and quantified the degree of immune infiltration along with characterization of T cell exhaustion markers such as CD8+PD1+TCF1+ cells. Results: High-grade tumors exhibited significantly higher infiltration of CD8+ T cells and CD20+ B cells compared to low-grade tumors. Spatial profiling revealed organized ICs, especially in high-grade tumors, which exhibited characteristics consistent with TLS. These ICs were enriched with precursor-exhausted CD8+PD1+TCF1+ T cells (TPEX), suggesting a state of immune exhaustion that may be therapeutically reactivatable. The presence of TLS and immune exhaustion markers in high-grade tumors highlights a more active immune microenvironment than previously appreciated in primary prostate cancer. Conclusions: Our findings reveal that a subset of high-grade prostate cancers harbor an organized, immune-infiltrated tumor microenvironment, including adaptive immune features such as TLS and CD8+ T cell exhaustion. These immune landscapes, marked by significant CD8+ and CD20+ cell infiltration and spatial clustering, suggest that high-grade prostate tumors may be amenable to immune-based therapies, despite the failure of immune checkpoint blockade in metastatic PCa. These results raise the hypothesis that immunotherapy might be effective in treatment-naïve high-grade prostate cancer. Future efforts should explore whether these immune profiles can be leveraged for risk stratification or as biomarkers for response to immunotherapy in advanced disease.
A phase 1b, open-label, multicenter study of xaluritamig in patients with newly diagnosed localized intermediate- or high-risk prostate cancer in the neoadjuvant setting.
Authors: David Yoonsuk Oh, Deepak Kilari, Christopher Darr, Kevin Kayvan Zarrabi, Jessica E. Hawley, Russell Kent Pachynski, Scott T. Tagawa, Yuanquan Yang, Simon Buetikofer, Qing Xia, Gunhild Von Amsberg
Journal: Journal of Clinical Oncology (2025)

TPS434 Background: There are currently no standard neoadjuvant treatments for patients with localized prostate cancer despite improved outcomes with neoadjuvant therapy in multiple other solid tumors. Xaluritamig is a bispecific T-cell engager (TCE) that simultaneously engages the six-transmembrane epithelial antigen of the prostate 1 (STEAP1) expressed on prostate cancer cells and the CD3 complex on T cells, thereby leading to T-cell mediated lysis of the STEAP1 expressing prostate cancer cells. In an ongoing trial (NCT04221542), xaluritamig has demonstrated deep, early, and durable responses in patients with metastatic castration-resistant prostate cancer. Notably, TCEs as a class of therapy have demonstrated the potential to have even greater efficacy and safety when used in earlier stages of disease where the overall disease burden is less and immune fitness is generally better. These data suggest that xaluritamig may be safely administered in the neoadjuvant setting and lead to pathologic responses with subsequent improvement in disease control and long-term clinical outcomes. In the current study, safety and feasibility as well as preliminary efficacy of neoadjuvant xaluritamig are being evaluated in patients with newly diagnosed localized intermediate or high-risk prostate cancer. Methods: This Phase 1b, open-label, multicenter study plans to enroll approximately 30 patients diagnosed with localized intermediate or high-risk prostate cancer and are planned for radical prostatectomy. Eligibility criteria includes histologically or cytologically confirmed prostate adenocarcinoma with Gleason Score ≥4+3 and an initial prostate specific antigen (PSA) of ≥10 ng/ml, no evidence of metastasis outside of the surgical resection field (PSMA-PET positive locoregional lymph nodes or less or equal 5 local lymph nodes on MRI can be enrolled), or use of any prior therapy for prostate cancer. The study includes a 28-day screening period, a two-cycle neoadjuvant treatment period (each cycle lasting 28 days), a safety follow-up visit (up to 42 days) after surgery, and a long-term follow-up period (up to 42 months). The last dose of xaluritamig will be administered about 14 to 28 days prior to undergoing radical prostatectomy. Primary outcomes will evaluate xaluritamig through treatment-emergent and treatment-related adverse events, and feasibility of radical prostatectomy. Secondary outcomes will assess PSA response, imaging-based response on multiparametric magnetic resonance imaging (mpMRI) prior to prostatectomy, pathologic response and the pharmacokinetics of xaluritamig. The study is open for enrollment as of October 2024. Clinical trial information: NCT06613100 .
Clinical features and prognostic value of CDK12 mutation in prostate cancer patients.
Authors: Hanyang Tao, Baijun Dong
Journal: Journal of Clinical Oncology (2025)

103 Background: Studies have reported that biallelic loss of CDK12 in prostate cancer patients leads to genomic instability and an increase in tandem duplications. However, the prognostic relevance of CDK12 mutations has not been fully validated. Therefore, we assessed the clinical characteristics and outcomes of prostate cancer patients with CDK12 mutations, comparing this genomic subtype with prostate cancer lacking any genetic alterations. Methods: A total of 141 prostate cancer patients diagnosed between November 2010 and March 2024 were included. Genomic characteristics of biopsy tissues or plasma ctDNA were analyzed using next-generation sequencing to identify patients with CDK12 mutations and those without any genetic mutations. Due to the low incidence of biallelic CDK12 loss in this patient cohort, we integrated data from metastatic tumor biopsies and liquid biopsies. Notably, cfDNA and prostate cancer tumor biopsies from the same individuals have shown strong concordance in identifying somatic alterations. Results: We evaluated the clinical characteristics of the two groups of prostate cancer patients, and patients with CDK12 mutations were more aggressive and had a higher proportion of initial metastasis [77.05% (47/61) vs. 56.67% (51/80), P=0.013]. The median PSA at diagnosis was higher (60.63ng/ml vs. 38.02ng/ml), and the proportion of pathological Gleason score ≥8 was higher (85.25% (52/61) vs. 60.00% (48/80), P &lt; 0.01). Patients with localized CDK12 mutations had shorter time to metastasis (median 34.10 months vs. 56.22 months, p &lt; 0.001) and shorter survival than those without deleterious genetic alterations. Patients with CDK12 mutations had shorter median progression-free survival with conventional androgen-deprivation therapy, abiraterone, and docetaxel than those without deleterious mutations. However, the use of novel anti-male therapy, PARPi, immunotherapy or focal ablation can still prolong the survival of patients. Conclusions: CDK12 mutations are associated with metastasis and higher pathological malignancy, and they also serve as a predictive factor for poor clinical outcomes in patients receiving standard androgen deprivation therapy, abiraterone, or docetaxel treatment. Therefore, prostate cancer patients with CDK12 mutations may need to consider novel anti-androgen therapies, or combined interventions such as PARP inhibitors, immunotherapy, or focal treatments. This study underscores the importance of molecular diagnostics and the necessity of employing appropriate therapeutic strategies for CDK12-mutated prostate cancer. Overall, given the significant heterogeneity in clinical behavior, our research highlights the importance of this molecular subtype in prostate cancer and serves as a foundation for future prospective studies to further characterize the CDK12 subtype in prostate cancer.
Efficacy of systemic treatments for advanced non-clear cell renal cell carcinoma: A single-arm systematic review and meta-analysis.
Authors: Xinyuan Wei, Yu Shen, Jiayu Liang, Jinge Zhao, Xingming Zhang, Junru Chen, Guangxi Sun, Xu Hu, Pengfei Shen, Hao Zeng, Zhenhua Liu
Journal: Journal of Clinical Oncology (2025)

550 Background: Non-clear cell renal cell carcinoma (nccRCC) represents a genetically and histologically diverse subset of renal cancers, accounting for 15–30% of all renal malignancies. Patients with nccRCC generally face poorer prognoses compared to those with clear cell renal cell carcinoma (ccRCC). While many therapies, such as tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors (ICI), have broadened treatment options for nccRCC, high-quality randomized controlled trials (RCTs) assessing these treatments remain scarce. Consequently, RCT-based reviews provide an incomplete understanding of systemic therapy in nccRCC. In contrast, single-arm trials (SATs), more commonly conducted in nccRCC patients, offer additional insights into therapeutic efficacy. This study aims to synthesize evidence from both RCTs and SATs to comprehensively evaluate the efficacy of systemic treatments for nccRCC. Methods: We conducted a systematic review and meta-analysis of SATs and arms of RCTs, retrieving studies from PubMed, MEDLINE, EMBASE, and the Cochrane Library up to October 1, 2024. Primary outcome was objective response rate (ORR), and secondary outcomes were progression-free survival (PFS), and overall survival (OS). A random-effects meta-analysis was employed to pool data, and subgroup analyses were conducted based on treatment regimens. Results: Thirty-two studies encompassing 1,958 patients were included in the meta-analysis. The pooled ORR across all treatments and therapy lines for nccRCC was 20% (95% CI 15%–26%). The median PFS and OS were 5.56 months (95% CI 4.03–7.09 months) and 17.25 months (95% CI 12.48–22.01 months), respectively. Among them, the pooled ORR for TKI and ICI monotherapy was 19% (95% CI 10%–30%) and 19% (95% CI 13%–26%), respectively, while the pooled ORR for TKI and ICI combination therapy was 39% (95% CI 28%–51%). For first-line therapy, the ORR was 20% (95% CI 12%–28%). Combination therapies (e.g., TKI+ICI, TKI+mTOR and ICI+ICI) demonstrated a higher pooled ORR of 32% (95% CI 19%–46%), while monotherapies (TKI, mTOR or ICI) had an ORR of 14% (95% CI 8%–21%). In papillary RCC (pRCC), the ORR for first-line therapy was 17% (95% CI 9%–26%). Combination therapies showed an ORR of 31% (95% CI 14%–51%), and single-agent therapies had an ORR of 12% (95% CI 6%–21%). Conclusions: This meta-analysis provides evidence supporting the efficacy of existing systemic therapies, particularly combination therapies, in advanced nccRCC. However, the inherent limitations of single-arm analysis necessitate further large-scale, multicenter trials to validate these findings and guide future clinical practice.
Evaluating clinical tools to monitor cardiovascular (CV) risk in men with localized high-risk or locally advanced prostate cancer (LHRPC) treated with hormone therapy (HT).
Authors: Neha Venkatesh, Pankaj Kumar Chauhan, Kabir Grewal, Ana Aparicio, Patrick Glen Pilié, Sumit Kumar Subudhi, Paul Gettys Corn, Bilal Ahmed Siddiqui, Amado J. Zurita, Daniel Frigo, Christopher Logothetis, Pavlos Msaouel, Efstratios Koutroumpakis, Andrew Warren Hahn
Journal: Journal of Clinical Oncology (2025)

116 Background: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSIs) indirectly increase CV risk. There are no risk estimation tools specific to men with prostate cancer undergoing HT. Current practice utilizes tools designed for the general population, such as the AHA/ACC ASCVD risk score. Herein, we investigate the applicability of such general population risk tools in men receiving pre-operative HT for LHRPC. Methods: We conducted a retrospective analysis of men with LHRPCa who received 6 months of pre-operative ADT + apalutamide +/- abiraterone on NCT. Cardiometabolic factors of interest were extracted from the electronic medical record, and ASCVD risk scores were calculated alongside metabolic syndrome (MetS) Z scores (calculated using ASCVD calculator https://tools.acc.org/ldl/ascvd_risk_estimator/#!/calulate/estimator/ and metabolic syndrome severity calculator https://metscalc.org/metscalc/ ). Results: Sixty-four patients had data available to calculate baseline and end-of-treatment (EOT) ASCVD risk and MetS Z scores. Prior to initiation of HT, 46.8% of patients were on antihypertensive treatment, 11.3% had diabetes mellitus, and 45.2% were on lipid-lowering therapy. After 6 months of ADT + ARSI, the median change in ASCVD risk score was 0.95, and 21% of patients exhibited a clinically significant increase in ASCVD risk score of ≥ 2.5%. The median change in the metabolic syndrome Z score was -0.36, indicating a decrease in metabolic syndrome risk. 28% of all patients demonstrated an increase in metabolic syndrome risk after 6 months of HT. Conclusions: Despite the known association between HT and increased CV risk, most patients in this study did not experience a clinically meaningful increase in either ASCVD risk or MetS Z score. These findings suggest that general population risk estimation tools may not reflect temporal evolution of CV risk in patients undergoing HT. This study also highlights an unmet need for novel risk assessment tools specifically tailored to identify at-risk men among those treated with HT.