Browse Articles

Genome-wide association to identify SNPs associated with severe adverse events and clinical outcomes in advanced renal cell carcinoma treated with nivolumab.

520 Background: Immune checkpoint inhibitors (ICIs) have markedly changed the management of advanced renal cell carcinoma (RCC). However, ICIs frequently induce immune-related adverse events (irAEs), which vary widely among patients and may affect treatment outcomes. We conducted a genome-wide association study (GWAS) to explore genetic markers associated with severe treatment-related adverse events (trAEs) and to examine their potential impact on prognosis. Methods: Between August 2019 and September 2020, patients with advanced clear cell RCC (ccRCC) receiving nivolumab were enrolled at 23 institutions in Japan (protocol ID: UMIN000037739). Follow-up was completed in March 2021. A total of 223 patients were included: 113 in a development set and 110 in a validation set. GWAS was performed in the development cohort to identify single nucleotide polymorphisms (SNPs) associated with severe trAEs. Candidate SNPs were then assessed in the validation cohort, and their relationship with clinical outcomes was further explored. Results: Sixteen SNPs were associated with severe trAEs in the development set, of which thirteen were successfully genotyped in the validation set. Eight SNPs demonstrated consistent trends, although statistical significance was not reached. Notably, rs2545737 located in CHD1 was associated with prolonged progression-free survival (PFS). Additional analyses revealed that higher CHD1 expression correlated with improved overall survival in nivolumab-treated patients, but not in those receiving everolimus. Conclusions: Although findings from the development set were not fully replicated in the validation cohort, this study provides insights into the genetic predisposition to trAEs and highlights CHD1 as a potential biomarker linking treatment safety and efficacy. Further large-scale validation is warranted to confirm these observations.

Optimizing neoadjuvant ADT duration prior to radiotherapy in high-risk prostate cancer: Rationale and clinical need.

259 Background: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for high-risk prostate cancer (HRPC). However, the optimal duration of neoadjuvant ADT (nADT) prior to definitive treatment remains unclear, as shorter durations may be insufficient for tumor control while prolonged therapy risks immune suppression and increased toxicity. Determining the ideal nADT duration should help maximize efficacy and improve outcomes. Methods: Patients with prostate cancer who underwent radical prostatectomy at Roswell Park (1995–2019; Protocol BDR 125520) were included. Data on age, race, PSA levels, Gleason score, stage, treatment details, and nADT duration were collected. The study included 43 men treated with nADT for up to one year before surgery, excluding those with prior radiotherapy or chemotherapy. A matched control cohort of 43 cases who did not receive ADT was selected based on age, stage, Gleason grade, and year of diagnosis. Tissue from FFPE blocks was analyzed using H&E staining, immunohistochemistry (IHC), RNA sequencing (RNA-seq), and quantitative multiplex immunofluorescence (qmIF) with the Vectra Polaris to evaluate the expression and spatial distribution of key markers, including CD8, CD4, CD68, FOXP3, NKX3.1, and HLADR. Spatial relationships between tumor and immune cells were quantified using PhenoptReports, providing insights into cell proximities and interactions within the tumor microenvironment. Subsequent statistical analyses were conducted using OriginPro. Results: The duration of nADT plays a critical role in shaping immune dynamics and tumor control, with its efficacy confirmed by decreased TMPRSS2 expression across all treatment durations prior to prostatectomy. Short-term nADT (≤2 months) results in limited CD8+ T-cell infiltration and spatial alignment with tumor cells, indicating weak immune engagement. Intermediate-duration nADT (3–5 months) drives robust immune activation, marked by enhanced CTLs-tumor interactions as CD8+ and CD4+ T-cells cluster near tumor cells while effectively suppressing M2 macrophage density and proximity. In contrast, prolonged nADT (≥6 months) shifts the immune microenvironment toward suppression, characterized by M2 macrophage enrichment near tumor cells, leading to immune exhaustion and reduced tumor control. Conclusions: These findings underscore the critical role of spatial dynamics and the importance of optimizing nADT duration, with 3–5 months emerging as the most effective window for maximizing survival outcome while minimizing adverse immune effects. Moreover, understanding the shift toward immune suppression over time opens avenues for strategies to counteract this effect, potentially improving long-term outcomes in the management of HRPC patients.

Profiling BCRAness phenotype in public prostate cancer datasets without homologous repair gene mutations.

223 Background: Co-inhibition of PARP and androgen receptor activity may enhance antitumor efficacy irrespective of HRR alterations, as suggested by TALAPRO and PROPEL. This may result from pathway crosstalk or alternative mechanisms generating a BRCAness phenotype not captured by standard genomic panels. Identifying these mechanisms is critical to optimize patient selection. We aimed to determine the prevalence of transcriptomic BRCAness in prostate cancer patients without HRR mutations across publicly available datasets, including primary tumors and metastases. Methods: RNA sequencing data were analyzed to identify oncogenic DNA repair mutations using RNAmut , a tool that detects expressed somatic variants from RNA-seq data. Variants identified as oncogenic were subsequently filtered, retaining those with a variant allele frequency (VAF) $≥0.4. The BRCAness phenotype was evaluated with expHRD , a transcriptome-based algorithm deriving a homologous recombination deficiency (HRD) score. Tumors with expHRD ≥42 were classified as HRD-high (BRCAness), consistent with the Myriad MyChoice CDx cutoff. Datasets included treatment-naïve localized tumors ( TCGA-PRAD , n=497; GSE216490 , n=95; GSE54460 , n=98) and metastatic samples from castration-resistant prostate cancer (mCRPC; GSE147250 , n=138). Results: In primary prostate cancer patients from the TCGA-PRAD dataset, a high BRCAness score was associated with faster disease progression, validating the tool's ability to identify this profile. Within the TCGA dataset, 1.3% of patients without mutations in homologous recombination repair (HRR) genes exhibited a BRCAness profile. Similar findings were observed in the GSE216490 dataset, where 4.2% of patients showed BRCAness, and in the GSE54460 dataset, where 2.0% of patients were classified as such. A higher prevalence of the BRCAness phenotype was observed in metastatic compared with localized disease: among patients without HRR mutations, 20.1% of metastatic tumors displayed high BRCAness scores. Conclusions: A high prevalence of BRCAness was observed in HRR-negative mCRPC, which may partly explain the clinical benefit of PARP inhibitor and ARPI combinations in all-comer populations. Validation of this strategy in pivotal trials is essential to refine patient selection and optimize therapeutic strategies.

Genomic profiling in circulating tumor DNA from a multicenter prospective study of radium-223 in bone-metastatic castration-resistant prostate cancer: The KYUCOG-1901 study.

211 Background: Circulating tumor DNA (ctDNA) testing has emerged as a novel approach in cancer precision medicine. We investigated the genomic landscape and clinical utility of ctDNA in patients receiving radium-223 (Ra-223) for bone-metastatic castration-resistant prostate cancer (mCRPC). Methods: This prospective observational multicenter study enrolled patients treated with Ra-223 for bone-mCRPC. Targeted sequencing of cell-free DNA from plasma at baseline (BL) and end of treatment (EOT), along with paired leukocyte DNA, was performed using an 88-gene panel. Associations between ctDNA profiles and clinical outcomes including biomarker response, radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed. Results: Of 93 patients analyzed, ctDNA was successfully profiled in 84 BL and 74 EOT samples, with matched data available for 68 patients. A ctDNA fraction ≥5% (rPFS; hazard ratio [HR], 95% confidence interval [CI]; 2.44, 1.47-4.08), as well as TP53 alteration (rPFS; HR, 95% CI; 2.65, 1.30-5.42), alterations in TP53 , RB1 or PTEN (rPFS; HR, 95% CI; 3.57, 2.04-6.25), and cell cycle pathway alterations (rPFS; HR, 95% CI; 3.47, 2.00-6.25) at BL, were significantly associated with shorter rPFS and OS. Dynamic changes in ctDNA between BL and EOT correlated with distinct PSA-PFS, ALP-PFS, rPFS, and OS although PSA and ALP declines were not associated. Conclusions: ctDNA profiling outperformed PSA and ALP in monitoring disease trajectory and predicting outcomes. These findings highlight ctDNA as a promising biomarker to guide and optimize Ra-223 therapy in mCRPC. Clinical trial information: UMIN000040358 . Association between ctDNA profile at baseline and radiographic progression-free survival. 　 Median, 8.8 months Univariate analysis Adjusted with ctDNA fraction 　 n=84 HR 95% CI P–values 　 HR 95% CI P–values DNA amount  cfDNA amount, ≥20 ng/ml 18 3.4 1.56 0.89–2.75 0.12  ctDNA fraction, ≥5% 32 5.6 2.44 1.47–4.08 0.0006* Altered gene  AR 13 5.7 2.18 1.18–4.03 0.013* 1.80 0.92–3.52 0.087  TP53 9 3.4 2.65 1.30–5.42 0.0077* 2.46 1.19–5.09 0.016*  RB1 9 3.3 2.94 1.42–6.10 0.0037* 2.04 0.73–5.69 0.17  BRCA2 12 4.5 1.71 0.89–3.29 0.11 1.28 0.62–2.66 0.51  MSH6 9 6.2 1.06 0.48–2.33 0.88 1.07 0.48–2.34 0.87  CHD1 9 3.5 2.10 1.03–4.25 0.040* 1.47 0.64–3.37 0.37  APC 13 6.2 1.49 0.79–2.79 0.21 1.22 0.62–2.38 0.56  SPOP 9 5.5 2.45 1.19–5.08 0.015* 1.76 0.75–4.16 0.20  ZFHX3 10 5.6 2.07 1.01–4.26 0.047* 1.17 0.43–3.20 0.76  TP53/RB1/PTEN 20 3.4 3.57 2.04–6.25 <0.0001* 3.60 1.80–7.21 0.0003* Altered pathway  AR–associated 9 3.1 2.70 1.32–5.55 0.0067* 1.94 0.82–4.63 0.13  Cell cycle 22 3.5 3.47 2.00–6.03 <0.0001* 3.50 1.79–6.85 0.0003*  PI3K 16 3.5 2.26 1.26–4.06 0.0063* 1.86 0.96–3.61 0.066  DNA repair 23 5.7 1.53 0.89–2.62 0.12 1.21 0.65–2.25 0.54  Chromatin modifier 18 6.0 1.73 0.99–3.02 0.055 1.46 0.80–2.68 0.22  WNT 15 6.2 1.50 0.83–2.72 0.18 1.28 0.69–2.40 0.44

Navigating Ternary Doping in Li‐ion Cathodes With Closed‐Loop Multi‐Objective Bayesian Optimization

ABSTRACT To further improve secondary battery materials, we are increasingly exploring highly complex composition spaces in attempts to optimize multiple properties simultaneously. While our past work has done this in systematic manners using high‐throughput experimentation, the exponential increase in the search space with triple doping makes grid search prohibitively expensive. Here, we demonstrate a closed‐loop, multi‐objective machine learning approach to guide the high‐throughput workflow to efficiently navigate a space with approximately 14 million unique combinations. The test system is LiCoPO 4 , which we have previously explored using systematic codoping that was effective in optimizing one property only: energy density. To learn multiple electrochemical metrics, we first pretrain a set transformer on the public Materials Project database as a feature extractor, then attach a multi‐task Gaussian process head and finetune the entire model on our high‐throughput data. Through 3 rounds of active learning, we demonstrate that with a very small number of samples (as few as 125 random compositions and 63 predicted), we are able to simultaneously optimize four key electrochemical properties. Relative to the undoped system, the best composition raises our composite figure of merit up to five times. This establishes an end‐to‐end workflow for accelerated battery materials design to be used in the rapidly growing field of autonomous materials discovery.

Giant Specific Power Generation Capacity of Micro‐Thermoelectric Generators Enabled by High‐Entropy Cocktail Strategy

ABSTRACT Specific power generation capacity Γ P is a critical performance metric for micro‐thermoelectric generators ( μ ‐TEGs), yet the best reported values are constrained to a few hundred µW cm −2 K −2 . Here, we report a giant Γ P of ∼5000 µW cm −2 K −2 in μ ‐TEGs based on the anomalous Nernst effect (ANE) in medium‐entropy (FeCoNi) 100‐ x Pt x films. Leveraging the high‐entropy cocktail strategy, we have simultaneously achieved a large anomalous Nernst thermopower S xy (>1.4 µV K −1 ) and low resistivity ρ xx (<85 µΩ cm), and suppressed the classical and quantum size effects on both S xy and ρ xx at the optimal composition of x ≈ 50 and film thickness of a few nanometers, enabling the record‐high Γ P . The underlying mechanism arises from cocktail‐driven modulation of energy‐band smearing, density of states, and Berry curvature at the Fermi surface, resulting in an ultrashort carrier mean‐free‐path of ∼3 nm, an ultrahigh carrier density of ∼10 23 cm −3 , and a large anomalous Nernst conductivity above 1.7 A m −1 K −1 . This claim is further supported by first‐principles calculations, which collectively highlight the experimental and theoretical potential of utilizing such materials for high‐performance μ ‐TEG applications.

Mannose metabolic pathway senses glucose supply and regulates cell fate decisions

Fruquintinib plus serplulimab as first-line therapy in metastatic or unresectable non-clear cell renal cell carcinoma (nccRCC): Updated efficacy and safety data from a multicenter, single-arm, phase II trial.

422 Background: Despite recent advancements, non-clear cell renal cell carcinoma (nccRCC) remains a significant therapeutic challenge with poor prognosis. Innovative therapeutic strategies are urgently needed. We previously reported promising anti-tumor activity of the combination of fruquintinib (small-molecule VEGFR inhibitor) and serplulimab (anti–PD-1 antibody) as first-line therapy in metastatic or unresectable nccRCC patients (pts). Here, we present the updated efficacy and safety data. Methods: This study was designed to enroll 39 treatment-naïve pts (aged 18–80 years, ECOG performance status 0–1) with metastatic or unresectable nccRCC. All pts received fruquintinib (5 mg QD, orally, 2 weeks on/1 week off) plus serplulimab (4.5 mg/kg, IV, Q3W). The primary endpoint was progression-free survival (PFS) per RECIST 1.1, while secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: As of September 30th, 2025, 38 pts were enrolled across 3 centers. The median age was 53.5 years (range 19–78), with 68.4% being male; 44.7% had an ECOG performance status of 1. Histological subtypes included papillary (50.0%), unclassified (18.4%), fumarate hydratase-deficient (13.2%), TFE3-rearranged (7.9%), chromophobe (5.3%) and rare variants (5.2%). Sarcomatoid features were observed in 5 pts. The most frequent metastatic sites were lymph nodes (52.6%), lungs (34.2%), peritoneum (34.2%). With a median follow-up of 10 months (95% CI: 9.2–15.9) for PFS, the median PFS was not reached, and the 9-month PFS rate was 87.3%. Among the 36 efficacy evaluable pts, 1 achieved complete response, 18 achieved partial response and 16 had stable disease, yielding an ORR of 52.8% (95% CI: 36.5–69.1) and a DCR of 97.2% (95% CI: 85.5–99.9). Three pts experienced rapid progression (progressing within 4 months in this study), all with sarcomatoid differentiation. 94.7% pts experienced at least one treatment-related adverse event (TRAE) of any grade, with the most common (≥15%) TRAEs were rash (28.9%), proteinuria (26.3%), hypertension (26.3%), hypothyroidism (21.1%), increased ALT or AST (21.1% each), fever (18.4%) and increased blood creatinine (15.8%). The majority of these events were grade 1 or 2, except for one pt who experienced a grade 3 increased AST. No serious adverse events (SAEs) or adverse events leading to permanent discontinuation of medication were observed during the study period, and no TRAEs resulting in death were reported. Conclusions: The combination of fruquintinib and serplulimab showed promising anti-tumor activity with acceptable tolerability as first-line treatment for metastatic or unresectable nccRCC. This novel combination therapy has the potential to become a valuable therapeutic option for this challenging disease. Clinical trial information: NCT05831891 .

Circulating tumor DNA performance in primary retroperitoneal lymph node dissection: A stage-based analysis.

590 Background: Novel biomarkers appear to have use in the surveillance and treatment monitoring of testicular germ cell tumors (GCT). Recently, ctDNA has been demonstrated to detect GCT/teratoma in both primary and post-chemotherapy retroperitoneal lymph node dissection (RPLND), however the association of ctDNA levels by stage has not yet been determined. In this study, we sought to determine the utility of ctDNA for predicting active GCT on P-RPLND by comparing patients’ RPLND histology with their pre-operative ctDNA status in those with clinical stage I and II disease. Furthermore, we determined the association between ctDNA levels and clinical stage at RPLND. Methods: Patients undergoing primary (P-RPLND) from March 2023 to October 2025 had prospectively collected plasma ctDNA assay. Patients were stratified by clinical stage (CS) based on pre-operative cross-sectional imaging. The association between ctDNA positivity and P-RPLND histology was assessed. Test statistics were calculated for ctDNA to detect active cancer on RPLND. Additionally, the association between ctDNA levels and CS as a surrogate for disease volume was determined. Results: Sixty-four patients undergoing P-RPLND had pre-operative ctDNA collection with a median age of 37 (IQR:29-42). Plasma was collected on average, 8 days pre-operatively. Ten (16%) patients underwent P-RPLND for CS I and 54 (84%) for CS II disease. ctDNA was positive in 47 (73%) patients in the entire cohort. In the CS I cohort, 7 patients had a (-) ctDNA all of which had no disease on P-RPLND. Of the 54 patients in the CS II cohort, 44 (81%) had a (+) ctDNA. No false positives were found in this cohort. The SN, SP, PPV, and NPV in the CS I cohort were 100%, 78%, 33%, and 100% and in the CS II cohort were 88%, 100%, 100%, and 40%, respectively. Additionally, ctDNA level does not appear to correlate to disease volume at this juncture (r 2 =0, p=0.948). Conclusions: Circulating tumor DNA may have use in predicting retroperitoneal histology on P-RPLND. In CS I disease a negative test appears to be correlated with an absence of disease. In CS II disease, no false positives were found. ctDNA appears to be a binary test for detecting active disease in the retroperitoneum. Test statistics for circulating tumor DNA in detecting GCT for patients undergoing P-RPLND stratified by patients with CS I and CS II disease. CS 1 (N=10) Disease positive (n=1) Disease negative (n=9)  + ctDNA (n=3) 1 2 PPV=33%  - ctDNA (n=7) 0 7 NPV=100% SN=100% SP=78% CS 2 (N=54) n=50 n=4  + ctDNA (n=44) 44 0 PPV=100%  - ctDNA (n=10) 6 4 NPV=40% SN=88% SP=100%

A multicenter, open-label, phase II study of adaptive combination immunotherapy with VEGFR-TKI for advanced renal cell carcinoma.

TPS575 Background: The KEYNOTE-426 trial found superior progression-free survival (PFS) and overall survival (OS) with pembrolizumab plus axitinib versus sunitinib in advanced renal cell carcinoma (RCC). However, current treatment paradigms involve continuous therapy administration for two years or until disease progression, potentially exposing patients to unnecessary treatment burden and quality of life toxicities. Adaptive dosing strategies, which allow for periods of treatment interruption following documented response, may preserve therapeutic efficacy while reducing cumulative toxicity and healthcare costs. NCT06860386 aims to evaluate feasibility and PFS with adaptive pembrolizumab plus axitinib in advanced RCC. Methods: NCT06860386 is a multicenter, open-label, phase II trial evaluating adaptive combination immunotherapy in advanced RCC. The study will enroll 75 patients aged ≥18 years with treatment-naïve, unresectable advanced or metastatic clear cell RCC. Patients will receive pembrolizumab (200 mg every 21 days) plus axitinib (5 mg twice daily) in 9-week treatment cycles. Radiographic assessment using RECIST 1.1 criteria will be performed at baseline and at 9-week intervals. Patients achieving target lesion reduction > 20% from baseline at the first post-treatment assessment will be eligible for adaptive treatment. Upon initiating adaptive treatment, study therapy administration is paused and may be re-initiated when radiographic assessment demonstrates target lesion growth to baseline size or greater. Study therapy may again be paused when target lesion reduction > 20% is achieved per RECIST. Treatment-free intervals and re-initiation cycles are continued until disease progression occurs during active treatment or other discontinuation criteria are met. Primary endpoints include progression-free survival and enrollment feasibility rate, defined as the proportion of patients eligible to proceed to adaptive treatment who consent to participate. Key secondary endpoints include safety, patient-reported outcomes, and cost effectiveness. Clinical trial information: NCT06860386 .

Impact of age, number of cycles of chemotherapy and presence of visceral metastases on PSA response in patients on triplet therapy (ADT + darolutamide + docetaxel) for mHSPC: UK real world data from the RECOMMEND study.

67 Background: Darolutamide has authorisation for treatment of metastatic hormone sensitive prostate cancer (mHSPC) in combination with docetaxel chemotherapy and androgen deprivation therapy (ADT), known as triplet therapy, based on ARASENS trial results. The RECOMMEND Study is a prospective real-world evaluation of clinical outcomes in patients with mHSPC treated with this regimen in the UK. Methods: 315 patients were enrolled from 21 UK centres over 20 months from November 2022. Data cut-off was 22 September 2025. Disease characteristics were evaluated. Descriptive statistics have been used for patient demographics and PSA changes with treatment were analysed. Results: Median patient age was 67 (range 38-84) years. Performance status was 0 (62.7%) or 1 (37.3%). 70.2% had a Gleason score ≥8. 78 patients (24.6%) had next generation imaging (NGI) at diagnosis. Most patients were de novo metastatic (92.1%) with metastases (mets) in bone (87.6%), nodes (62.5%), lung (13%) and liver (2.9%). Median time from start of ADT to start of darolutamide was 8 weeks (IQR 4.9-10.6), within the 12 weeks specified by NICE guidelines. At data cut off, 252 patients had reached 12 months (m) from darolutamide start (12mFU) with 26 stopping treatment. Median PSA (ng/mL) at diagnosis was 136 (range 1-6670). At the end of docetaxel median PSA was 0.4 (<0.1–162) which decreased further at 6m FU to 0.18 (0-523). PSA response at 6m FU was PSA 50 93.8% (273/291) and PSA 90 71.8% (209/291) and at 12m FU it was PSA 50 91.9% (226/246) and PSA 90 78.5% (193/246). There was no significant difference in the proportion of patients achieving PSA ≤0.2 ng/mL at 6m or 12m FU with age (<75 vs ≥75), in patients who received ≤4 vs >4 cycles of docetaxel or in those with or without visceral mets (lung/liver) see table. Conclusions: In the RECOMMEND Study, PSA response rates at 6m and 12m after starting darolutamide were similar irrespective of age (<75 vs ≥75), number of cycles of docetaxel (≤4 vs >4) or the presence or absence of visceral mets (lung/liver). This provides important and meaningful real-world evidence in this setting, enabling patients and clinical teams to make informed choices. ADT+darolutamide+docetaxel in mHSPC in the RECOMMEND study shows similar and sustained efficacy as reported in the ARASENS trial. Diagnosis Docetaxel Start 6m FU 12m FU Number 315 312 298 252 Median PSA ng/mL (range) 136 (1-6670) 6.2 (0-2883) 0.18 (0-523) 0.07 (0-86) % PSA ≤0.2 0 3.5 55 64.3 Visceral mets PSA ≤0.2 %(number) No Yes 0 (0/266) 0 (0/49) 3 (8/263) 6.1 (3/49) 55.4 (139/251) 53.2 (25/47) 65 (139/214) 60.5 (23/38) Docetaxel cycles PSA ≤0.2 %(number) ≤4 >4 0 (0/37) 0 (0/277) 2.7 (1/37) 3.6 (10/275) 55.2 (16/29) 55 (148/269) 61.5 (16/26) 64.6 (146/226) Age PSA ≤0.2 %(number) <75 ≥75 0 (0/269) 0 (0/46) 4.1 (11/266) 0 (0/46) 55.3 (141/187) 53.5 (23/43) 63.1 (135/214) 71.1 (27/38)

Harnessing Dynamic Metal‐Oxide Interfaces for Durably Active Fuel Cell Electrocatalysis

ABSTRACT While metal‐oxide interfaces can profoundly modulate the performance of (electro)catalysts, their dynamic nature under operational conditions remains poorly understood, and a compromise between activity and stability persists as a central challenge. Herein, we reveal a dynamic, “breathing” interface behavior in MO x /Pt (M = In, Sn, Sb) systems during the cathodic oxygen reduction reaction (ORR) in proton‐exchange membrane fuel cells. By constructing well‐defined Pt octahedra decorated with ultrathin p‐block metal oxide overlayers, we demonstrate that an oxygen‐deficient M–Pt interface forms at reducing potentials and improves the ORR activity following a trend of In–Pt > Sn–Pt ∼ Sb–Pt via interfacial charge transfer, while oxidizing potentials generate an oxygen‐enriched M–O–Pt structure that effectively suppresses Pt dissolution and improves catalytic durability, particularly with SnO x overlayers. We further validate that harnessing the dynamic metal‐oxide interfaces represents a new and generalizable strategy to break the activity and stability trade‐off for a wide range of shaped or non‐shaped Pt and Pt‐bimetallic catalysts, most notably in InSnO x ‐decorated PtCo catalysts.

Breaking the Intermediate Solvation Shell on Single‐Atom Catalysts With a Proximal Group Perturber for Enhanced Oxygen Reduction

ABSTRACT The electrocatalytic performance is governed by the immediate microenvironment surrounding the active site, particularly the hydrogen‐bond network that stabilizes reaction intermediates. While cation effects in aqueous electrolytes allow tuning of this network, this powerful leveraging is absent in proton‐exchange membrane fuel cells (PEMFCs), where proton is the sole cation. Here, we demonstrate a general strategy of “immobilized molecular perturbation” for single‐atom catalysts, which moves the tuning function from the electrolyte to the catalyst's second coordination sphere. Using the oxygen reduction reaction (ORR) on Fe─N─C as a model, we demonstrate that proximal P─O groups act as steric and hydrogen‐bonding perturbers. This engineered microenvironment selectively weakens the solvation shell of key * OH intermediates, as confirmed by spectroscopy and computations, thereby facilitating the rate‐determining step of * OH desorption. This regulation endows the catalyst with exceptional performance, achieving a half‐wave potential of 0.861 V in 0.5 m H 2 SO 4 and a peak power density of 1024 mW cm −2 in a H 2 /O 2 PEMFC. Furthermore, it exhibits outstanding stability with 72 % current retention after 253 h at 0.65 V, positioning it among the best‐reported non‐precious metal catalysts. This work shifts the paradigm from exclusive active‐center optimization to deliberate local microenvironment engineering, enabling accelerated electrocatalysis in device‐relevant environments.

KRAS4a and KRAS4b show distinct lipid-dependent regulation of RAS-RAF membrane dynamics

Rescuing cancer immunotherapy with plasma exchange in bladder cancer 1 (ReCIPE-B1).

TPS898 Background: Enfortumab vedotin with pembrolizumab (EV/Pembro) is now first-line therapy for locally advanced or metastatic urothelial carcinoma (la/mUC) following the EV-302/KEYNOTE-A39 trial, which demonstrated a 67.7% response rate and prolonged survival. However, ~35% of cancers exhibited primary resistance and most responders relapse within one year, with post-EV/Pembro therapies achieving < 15% response and median survival < 3 years. We previously showed that therapeutic plasma exchange (TPE) removed soluble PD-L1 and other immune checkpoint inhibitor (ICI) blocking soluble factors from the blood and that this overcame ICI resistance. Combining TPE with EV/Pembro rechallenge may overcome acquired resistance and restore antitumor immunity. Methods: RECIPE-B1 [NCT07087860] is an open-label, randomized phase II trial enrolling 50 patients (1:1) with EV/Pembro-refractory la/mUC and ECOG 0–2. Arm A receives TPE on days 1–3 followed by EV 1.25 mg/kg IV plus pembrolizumab 200 mg IV on day 3 of each 21-day cycle for the first three cycles, then continues EV/Pembro alone from cycle 4. Arm B receives investigator’s-choice next-line standard of care (SOC) per NCCN guidelines. Tumor assessments occur at the end of cycle 4 (±28 days) and every 12 weeks thereafter; safety is monitored each cycle (CTCAE v5.0). The primary endpoint is objective response rate (ORR) by RECIST 1.1, comparing TPE + EV/pembro versus SOC. Secondary endpoints include progression-free survival, overall survival, duration of response, quality of life (EORTC QLQ-CIPN20), and safety. Correlative studies evaluate circulating and urinary tumor DNA and exosomal biomarkers (including exosomal Nectin-4) as predictors of response and resistance. The trial is open at Mayo Clinic; as of September 2025, 2 of 50 patients have been enrolled, with planned accrual of ~2 patients/month and central coordination at Mayo Clinic and affiliates. Clinical trial information: NCT07087860 .

Characterization of patients (pts) responding to enfortumab vedotin plus pembrolizumab (EV+P): Exploratory analysis from the phase 3 EV-302 trial of EV+P vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).

746 Background: EV-302/KEYNOTE-A39 (NCT04223856) showed sustained efficacy benefits after long-term follow-up for pts with previously untreated la/mUC treated with EV+P vs chemo, establishing EV+P as the standard of care (SOC) in this setting. We previously reported an exploratory analysis of responders from EV-302 (Gupta S, et al. ASCO 2025, Abs 4502). After approximately 2.5 years of median follow-up, confirmed objective response rate (complete response [CR] + partial response [PR]) was 67.5% with EV+P and 44.2% with chemo; CR was 30.4% and 14.5%, respectively. For pts with CR, median PFS by blinded independent central review (BICR), median OS, and median duration of CR were not estimable (NE) with EV+P. Among pts with CR in the EV+P arm, median treatment (tx) duration was longer than in the overall population, but no worsening of safety was seen. Building on this exploratory analysis, we report additional data to further characterize responders in EV-302. Methods: Pts were randomized 1:1 to receive EV (1.25 mg/kg; D1 and D8, IV) + P (200 mg; D1, IV) or chemo (gemcitabine + cisplatin (cis)/carboplatin). Primary endpoints were PFS by BICR and OS. Secondary endpoints included ORR, duration of response (DOR), and safety. An exploratory subgroup analysis evaluated outcomes in responders. Results: Median follow-up (cutoff: Aug 8, 2024) was 29.1 mo (95% CI, 28.5-29.9). 886 pts were randomized to EV+P (n = 442) vs chemo (n = 444). Median time to objective response was 2.1 mo with both EV+P and chemo. In the EV+P and chemo arms, respectively, median DOR was 23.3 (17.8-NE) mo and 7.0 (6.2-9.0) mo in responders, 24.4 (17.8-NE) mo and 8.3 (5.9-10.8) mo in cis-eligible pts, and 21.9 (15.7-NE) mo and 6.6 (5.5-9.3) mo in cis-ineligible pts. Median time to CR was 4.3 mo with EV+P and 4.2 mo with chemo. In the EV+P arm, 88/437 (20.1% of the response evaluable set) achieved PR then converted to CR; 38/441 (8.6%) did in the chemo arm. With most pts achieving CR initially experiencing PR (88/133 with EV+P and 38/64 with chemo), median time from first PR to CR was 4.5 mo with EV+P and 6.1 mo with chemo. Among responders in the EV+P arm, the median number (range) of cycles was 12 (1-54) for EV and 17 (1-35) for P. Conclusions: Among pts achieving objective response, PFS and OS were longer in the EV+P arm than in the chemo arm. Durable responses were seen regardless of cis eligibility. Most pts in CR achieved PR before CR, with pts in the EV+P arm converting to CR more rapidly than those in the chemo arm. The safety profile of EV+P in responders was consistent with that of the overall population, and no new safety signals were identified. These data, together with long-term outcomes for pts with CR and PR, reinforce EV+P as the SOC for 1L tx of pts with la/mUC. Clinical trial information: NCT04223856 .

Racial disparities and trends in the in-hospital mortality for malignant prostate cancer.

39 Background: Prostate cancer is a leading cause of cancer-related death among men in the United States (U.S). Despite therapeutic advances, racial disparities persist, with African American men experiencing higher incidence and poorer survival. Data on racial differences in inpatient outcomes, particularly in-hospital mortality, remain limited. This study evaluated racial and ethnic variations in in-hospital mortality among patients hospitalized with malignant prostate cancer (MPC) in the U.S. Methods: The U.S National Inpatient Sample (NIS) from 2016 to 2020 was queried for patients diagnosed with MPC. We used International Classification of Diseases, 10th Revision, Procedure Coding System (ICD-10-PCS) code “C61” to identify patients who were hospitalized for MPC. The study was exempt from institutional review board approval as the NIS database contains deidentified patient information. Multivariable regression analysis was performed to determine the odds of in-hospital mortality among patients with MPC. Multivariable logistic regression followed by marginal effects was used to plot yearly trends in in-hospital mortality. All the outcomes were adjusted for age, gender, Charlson comorbidity index (CCI) and hospital characteristics. All Statistical analyses were conducted using STATA 19 software. Results: The current retrospective study analyzed 98,000 patients hospitalized for MPC between 2016 to 2020. The racial distribution among study patients included: Whites (68,000; 69.4%), African Americans (17,738; 18.1%), Hispanics (7,154; 7.3%), and other minorities (5,098; 5.2%). African Americans were more likely to be hospitalized at a relatively younger age, and with a higher co-morbidity burden (mean age: 69.4 years; mean CCI: 5.5; p<0.01) when compared to Whites (mean age: 73 years; mean CCI: 4.8), Hispanics (mean age: 71.1 years; mean CCI: 5.1) and other minorities (mean age: 71.5 years; mean CCI: 5.0). A total of 3,626 (3.7%) patients died during the study period. On multivariable analysis, a higher absolute in-hospital mortality was observed in African Americans (OR: 1.14, 95% CI: 1.07 – 1.22, p <0.01) and other minorities (OR: 1.19, 95% CI: 1.06 – 1.34, p <0.01), when compared to Whites (OR: reference). Similarly, an increasing trend of in-hospital mortality was observed in African Americans (from 1.6% mortality per annum in 2016 to 2.0% in 2020; trend p <0.01) and Hispanics (from 1.1% mortality per annum in 2016 to 1.6% in 2020; trend p = 0.02). No change in mortality was observed among Whites (trend p = 0.171) and other minorities (trend p = 0.479) during the study period. Conclusions: Racial disparities persist in in-hospital outcomes among patients with MPC in the U.S. African American and Hispanic patients experienced increasing in-hospital mortality over time, highlighting the need for targeted interventions to address inequities in access, comorbidity management, and inpatient care.

IDeate-Prostate02: A phase 1/2, open-label umbrella substudy of ifinatamab deruxtecan-based treatment combinations or as monotherapy in participants with previously treated metastatic castration-resistant prostate cancer.

TPS297 Background: There is a high unmet need for effective therapies to improve outcomes from metastatic castration-resistant prostate cancer (mCRPC). Ifinatamab deruxtecan (I-DXd; MK-2400/DS-7300a), a B7-H3-directed antibody-drug-conjugate with a plasma-stable tetrapeptide-based cleavable linker and the potent topoisomerase I inhibitor payload DXd, has antitumor activity in in-vitro and in-vivo models. A first-in-human phase 1/2 study of I-DXd demonstrated promising antitumor activity and encouraging duration of response in heavily pretreated participants with mCRPC, with a manageable safety profile. These results merit further clinical investigation of I-DXd-based investigational treatment combinations to identify benefit in patients with mCRPC. Methods: IDeate-Prostate02 is a phase 1/2, multicenter, open-label, umbrella substudy of I-DXd-based treatments. Participants with mCRPC, evaluable B7-H3, and previously treated with 1 or 2 androgen receptor pathway inhibitors (ARPIs) but no prior docetaxel for mCRPC, will be included. Two monotherapy arms, each with ~80 to ~120 participants, will enroll participants into the Efficacy Phase; Arm 1: docetaxel and Arm 2: I-DXd. Two I-DXd combination arms will enroll participants into the Safety Lead-in (n~10), followed by Efficacy (n~50) phases: Arm 3: I-DXd+MK-5684, and Arm 4: I-DXd+ARPI. Administered treatments and stratification factors are in the Table. Primary end points are safety, tolerability, and prostate-specific antigen response rate (≥50% reduction) for the Efficacy Phase, and safety and phase 2 dose recommendations for the Safety Lead-in. Key secondary end points include objective response and survival evaluations. Recruitment is ongoing. Previously presented at 26th Annual Meeting of the Society of Urologic Oncology; December 2–5, 2025; Phoenix, AZ. Clinical trial information: NCT06863272 . Arm Administered Treatments Arm 1 Docetaxel at 75 mg/m 2 IV q3w with prednisone/prednisolone at 10 mg/day po or per label Arm 2 I-DXd at 12 mg/kg IV q3w Arm 3 I-DXd at 8, 10, or 12 mg/kg IV q3w + opevesostat at 5 mg po bid with fludrocortisone at 0.1 mg po qd, dexamethasone (adjusted as required) at 1.5 mg po qd, and hydrocortisone at 100 mg intramuscularly or po Arm 4 I-DXd at 8, 10, or 12 mg/kg IV q3w + ARPI as either abiraterone acetate at 1000 mg po qd with prednisone/prednisolone at 10 mg/day po or per label, or enzalutamide at 160 mg po qd (prior treatment dependent) Stratification for randomization Subgroups  B7-H3 expression High vs. low  Metastasis location Liver vs. bone only vs. other bid, twice daily; IV, intravenously; po, orally; q3w, every 3 weeks; qd, once daily.

Close and Enhance the Cancer‐Immunity Cycle by Engineered Dual‐Targeted Nano‐Adaptors

ABSTRACT The cancer‐immunity cycle (CIC) provides a conceptual framework for eliciting effective anti‐tumor immune responses by targeting key events in systemic immunity. However, the successful completion of the CIC often requires the coordinated action of multiple therapeutic modalities, necessitating their integration into a unified system to overcome the limitations of conventional combination therapies. Here, we present a multimodal and programmable platform that integrates diverse therapeutic biomolecules into single agents, enabling the construction of versatile nanomedicines and bispecific antibodies through dual‐targeted nano‐adaptor (TNA) nanotechnology to potentiate the CIC. Specifically, TNA nanomedicines target five critical steps within the CIC, including antigen release, dendritic cell (DC) maturation, T‐cell activation, mitigation of T‐cell exhaustion, and tumor cell killing. Meanwhile, TNA bispecific antibodies enhance DC‐T cell interactions to strengthen adaptive immunity and reinforce NK‐tumor cell interactions to promote cytotoxicity. We demonstrate that TNAs elicit robust anti‐tumor immunity, eradicating established tumors and suppressing metastatic dissemination. Owing to their modular and programmable architecture, TNAs hold broad potential for applications in immunotherapy and beyond.

A Mn ²⁺ ‐Based Pyrochlore Magnet With Fragile Magnetic Order and Strong Spin Fluctuations

ABSTRACT Pyrochlore magnets, built from corner‐sharing tetrahedra, serve as magnetic frameworks that attract extensive attention due to their exotic quantum spin states. Here we present K 3 Mn(MoO 4 ) 2 Cl, a chemically tailored pyrochlore magnet derived from Na 3 Mn(CO 3 ) 2 Cl, where Mn 2+ ions form an ideal 3D frustrated network. Millimeter‐sized single crystals of K 3 Mn(MoO 4 ) 2 Cl were successfully achieved via a simple high‐temperature self‐flux method. Thermodynamic measurements reveal a sharp transition at 258 mK, yet only ∼15% of the expected Rln6 entropy is recovered, indicating pronounced spin fluctuations in this long‐range ordered state. Remarkably, the ordered state is highly sensitive to perturbations, disappearing under a magnetic field of about 0.2 T, while magnetization along [111] shows a feature consistent with a near half‐saturated state. Our results establish the newly discovered pyrochlore magnets as a chemically engineered pyrochlore platform, in which geometrical frustration and fragile magnetic order interplay, thereby offering new opportunities to explore emergent magnetic phenomena in three dimensions.