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TulmiSTAR-02: A phase I/II open-label study of dose escalation and expansion of tulmimetostat in combination with darolutamide versus darolutamide, and tulmimetostat with abiraterone in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
TPS302 Background: Patients (pts) with mHSPC, especially those with high-volume disease, have a poor prognosis due to progression to castration-resistance, highlighting a substantial unmet need for more effective therapies. Androgen receptor pathway inhibitors (ARPIs) including darolutamide and abiraterone, have demonstrated clinical activity in pts with mHSPC. Inhibition of enhancer of zeste homolog 2 (EZH2) improves the effects of ARPIs by increasing sensitivity to AR inhibition through upregulation of AR signaling, further corroborating the rationale that EZH2 inhibition could deepen the response elicited by ARPIs and delay resistance. Tulmimetostat is an investigational, novel, oral, next-generation dual inhibitor of EZH2/EZH1. This phase I/II study evaluates the safety, tolerability and preliminary efficacy of tulmimetostat in combination with darolutamide or abiraterone in pts with de novo or recurrent mHSPC (NCT07190300). Methods: This two-part, open-label, global, multicenter, phase I/II, dose escalation and expansion study includes male pts (≥18 years) who may have received one prior taxane-based therapy without progression and/or prior ARPI (≤6 months in mHSPC). The phase I study will enroll ~30 pts in each part and phase II, a randomized part of the study (5:5:3), will enroll ~143 pts with ECOG performance status 0-2, and life expectancy >6 months. In the phase II study, randomization will be stratified by combining disease volume and prior use of taxane. Study details are described in the table below. Dose escalation will be guided by Bayesian logistic regression model with overdose control. The prostate-specific antigen <0.2 ng/mL rate will be assessed by stratified Miettinen and Nurminen method. The time-to-event efficacy endpoints will be estimated by Kaplan–Meier method. Clinical trial information: NCT07190300 . Phase Parts Treatment Objectives I 1 Tulmimetostat PO QD escalating doses + darolutamide 600 mg PO BID Primary: RDE, safety, tolerability Secondary: PK 2 Tulmimetostat PO QD escalating doses + abiraterone 1000 mg PO QD II Tulmimetostat dose 1 PO QD + darolutamide 600 mg PO BID Primary: BCR (defined as PSA decline <0.2 ng/mL at 6 months) Secondary: rPFS, OS, OR, BOR, DOR, PSA50 response, BCR of <0.1 ng/mL, time to CRPC, safety, tolerability, PK, TTSSE Tulmimetostat dose 2 (optional) + darolutamide 600 mg PO BID Control arm (darolutamide 600 mg PO BID) BCR, biochemical response rate; BID, Twice a day; BOR, best overall response; CRPC, castration–resistant prostate cancer; DOR, duration of response; QD, once a daily; OR, objective response; OS, overall survival; PK, pharmacokinetics, PSA, prostate-specific antigen; PO, oral; RDE, recommended dose for expansion; rPFS, radiographic progression-free survival; TTSSE, time to first symptomatic skeletal event.
The EMPOWER trial: Evaluating a home-based physical activity program (PAP) with the ExerciseRx digital platform vs. health education (HE) in people with non-muscle invasive bladder cancer (NMIBC).
TPS881 Background: The NMIBC population is emblematic of older patients with cancer, with a high burden of frailty, sarcopenia, mobility impairment, and multimorbidity. “Exercise as Medicine” has emerged as a critical component of comprehensive cancer care with reported benefits across physical, mental, emotional, and social domains as well as oncologic outcomes. However, most adults with cancer do not meet recommended physical activity guidelines. We are conducting a randomized controlled trial comparing the efficacy of a home-based physical activity program (PAP) delivered via the ExerciseRx digital health tool to guideline-based Health Education (HE) with respect to 1) improvement of physical function and 2) impact on health-related quality of life, frailty, treatment-associated toxicity, and oncologic outcomes. Methods: We will recruit and randomize 100 patients in a 1:1 ratio to PAP or HE arms. The PAP arm will be provided with a 12-week personalized, home-based exercise program (~20-30 minutes, 4x weekly) via the ExerciseRx app as well as a weekly graded progression in personalized step count goals. The HE arm will receive printed education on guideline-based exercise recommendations in line with National Comprehensive Cancer Network (NCCN) Survivorship for Healthy Living Guidelines. The ExerciseRx platform is comprised of 1) a provider dashboard embedded in the electronic health record, for recommending exercises and monitoring progress, and 2) a patient app, that delivers exercise plans and tracks exercise repetitions using native sensors in smart devices. Step count in both study groups will be tracked with Fitbit (Inspire 3). Eligibility criteria: English-speaking adults ( > 18 years) with a history of NMIBC who are willing and able to participate in walking and home exercise safely. The primary outcome of interest is the change in average daily Fitbit-assessed step count between baseline and 12 weeks, and 4-weeks after intervention completion (16 weeks). Secondary outcomes include change in Short Physical Performance Battery performance, patient-reported quality of life (EORTC-QLQ-C30, -NMIBC24), and frailty (Cancer and Aging Resilience Evaluation), Treatment burden and PRO-CTCAE v.6.0 assessed side effects, exercise-related AEs, and Resilience. Feasibility, usability, and app utilization metrics will be assessed. Enrollment will commence 2/2026. NCT pending.
SPECTRA study: A phase II trial of supraphysiological androgen to enhance treatment activity with DNA-damaging agents in men with metastatic castration resistant prostate cancer (mCPRC).
TPS279 Background: Prostate cancer models exhibit paradoxical growth suppression following exposure to supraphysiological androgen levels. Translated clinically, this therapeutic approach is termed bipolar androgen therapy (BAT), which induces fluctuations of testosterone (T) levels between supraphysiological and castrate ranges, via cyclical parenteral T administration. Prior studies of BAT show PSA50 response (i.e. >50% decline in PSA from baseline) rate of 25% and median progression-free survival (PFS) of ~6 months in patients with mCRPC. Induction of dsDNA damage may mediate anti-tumor effects of BAT, with prior studies showing that PARP inhibitors and ionizing radiation have the potential to augment such effects - likely as a consequence of BAT suppressing genes involved in homologous recombination repair (HRR) and non-homologous end joining. To develop more active BAT regimens, we are conducting a trial testing the hypothesis that BAT combined with other DNA-damaging agents including cytotoxic chemotherapy or 177Lutetium-PSMA-617 (LuPSMA) will be more effective than historically observed with BAT alone. Methods: This open-label, single center phase II trial is investigating the effects of BAT plus carboplatin AUC 5 IV (Cohort 1), etoposide 100 mg PO daily (Cohort 2), or LuPSMA 7.4 GBq IV (Cohort 3). Men with asymptomatic mCRPC treated with ≥1 prior androgen receptor pathway inhibitor are eligible for any cohort based on their preference and in consultation with the treating provider. All patients continue ADT and receive T cypionate 400 mg IM on Day 1 of an every 28 day cycle (Cohorts 1; 2) or Day 1 of an every 6 week cycle (Cohort 3). Each cohort is divided into subcohorts where cycle 1 consists of either BAT monotherapy, carboplatin/etoposide/LuPSMA monotherapy, or combination therapy. Metastatic tissue biopsies are obtained on Cycle 1, Day 8 to assess differences in DNA damage (e.g. γH2ax IHC) between subcohorts. After Cycle 1, all patients receive combination therapy until radiographic progression. The primary endpoint is to determine PSA50 response following 12 weeks combination therapy. Enrollment of 21 patients per cohort (n=63 total) provides 86% power to detect PSA50 of ≥50% for each cohort vs a null hypothesis of PSA50 of 25% at a 1-sided α=0.1. Secondary endpoints: radiographic response rate, radiographic PFS, PSA PFS, overall survival. Correlative work will assess differences in outcomes based on HRR mutation status and evaluate other genomic and transcriptomic features associated with treatment response/resistance. Cohorts 1 and 2 are open to accrual with 23/63 patients enrolled as of October 2025 (NCT06039371). Clinical trial information: NCT06039371 .
Individual Single‐Crystalline Irregular In <sub>2</sub> O <sub>3</sub> Microcavity for Ultrasensitive Semiconductor‐Based SERS Biosensor
ABSTRACT Surface‐enhanced Raman spectroscopy (SERS) achieves ultrahigh sensitivity at the molecular level and enables water‐interference‐free detection. However, the development of single‐particle semiconductor substrates that do not rely on gap‐enhanced electromagnetic fields remains challenging. Herein, capitalizing on the dual merits of morphology‐induced prolonged light accumulation and structure‐improved interfacial charge transfer, we developed an ultrasensitive semiconductor‐based individually SERS system based on a highly crystalline irregular hexagonal prism In 2 O 3 (I‐In 2 O 3 ) microcavity. Finite‐difference time‐domain simulations and photoluminescence spectra confirmed the successful establishment of a whispering‐gallery‐mode microcavity on the I‐In 2 O 3 platform. This microcavity enables the long‐term confinement and oscillation of resonant photons, thereby significantly enhancing light–matter interactions. Aberration‐corrected electron microscopy demonstrated that although I‐In 2 O 3 single crystals were isostructural to regular hexagonal prisms, they exhibit contracted lattice parameters. Density functional theory calculations further revealed that atomic‐scale compressive lattice strain induces electronic band restructuring, enhancing the interfacial interactions between individual particle substrates and adsorbed molecules at the atomic level. In addition, the I‐In 2 O 3 SERS system demonstrates quantitative and multiplexing capabilities for rapid antibiotic detection. This work presents new perspectives for constructing supersensitive semiconductor SERS sensors using a micron‐scale single‐particle platform.
Modular Assembly of Lipid Nanoparticles for Targeted mRNA Therapeutics and Vaccines
Abstract Targeted mRNA delivery remains a key challenge for lipid nanoparticles (LNPs), as existing surface functionalization strategies often suffer from uncontrolled cross‐linking, aggregation, and immunogenicity. Conventional tetrameric streptavidin‐biotin coupling, while biochemically robust, has limited translational potential due to its multivalency and poor structural control. Here, a monomeric streptavidin (mSA)‐based modular assembly platform is presented that enables rapid, stable, and customizable functionalization of LNPs. The monovalent design of mSA prevents aggregation and significantly reduces immunogenicity compared with conventional streptavidin. By fusing mSA to Fc‐binding domains (Z and C), universal linkers are created that can directly bind unmodified commercial antibodies, allowing plug‐and‐play construction of targeted LNPs without chemical modification. This approach supports interchangeable antigen or antibody labeling, yielding monodisperse and reproducible nanoparticles. Demonstrated across diverse therapeutic contexts—including virus‐like nanoparticle vaccines, tumor‐targeted mRNA therapy, and efficient transfection of primary mouse T cells (up to 98%)—the platform offers a generalizable and clinically adaptable strategy for precise mRNA delivery and vaccine development.
Long-term clinical outcomes with <i>Clostridium butyricum</i> MIYAIRI 588 (CBM588) and TOPOSCORE assessment in patients receiving immune checkpoint inhibitor (ICI)-based combinations for metastatic renal cell carcinoma (mRCC).
507 Background: Two randomized phase I trials demonstrated that CBM588, a live biotherapeutic, may enhance the antitumor efficacy of frontline ICI-based regimens in mRCC (Dizman et al Nat Med 2022; Ebrahimi et al Nat Med 2024). For the first time, we present an updated, pooled analysis of long-term clinical outcomes from a combined cohort of these two studies. Methods: Data from two open-label, randomized phase I clinical trials were analyzed. Eligible patients were adults with advanced or metastatic RCC, Karnofsky performance status ≥70%, no prior systemic therapy, and measurable disease per RECIST 1.1. Participants were randomized to receive nivolumab/ipilimumab or nivolumab/cabozantinib alone (standard of care [SOC]) or with CBM588 (SOC + CBM588). The pooled clinical outcomes including objective response rate (ORR; complete response [CR] or partial response [PR]), disease control rate (DCR; CR, PR, or stable disease [SD] ≥ 6 months), progression-free survival (PFS), and overall survival (OS), were compared between treatment groups, using Fisher’s Exact test and Kaplan Meier log rank test, respectively. The TOPOSCORE, a measure of microbial dysbiosis associated with poor prognosis with ICIs, was derived for all stool samples collected across both studies, using previously published bioinformatic methods (Derosa et al Cell 2024). Results: Fifty-nine patients were included: 20 received SOC and 39 received SOC + CBM588. The median age was 65 years (range 36-90); 69.5% were male, 88.1% had clear-cell mRCC, and 67.8% had intermediate/poor IMDC risk. Baseline characteristics were similar in both arms. Pooled ORR and DCR were 66.7% and 82% with SOC + CBM588 versus 20% and 55% with SOC alone (p = 0.001 and p = 0.019, respectively). Median follow-up was 43.9 months (95% CI 42.5-73) for SOC+CBM and 44.1 months (95% CI 35.4-NE) for SOC. Median PFS was 32.0 months (95% CI 16.6-NE) with SOC + CBM588 and 3.7 months (95% CI 2.6-17.0) with SOC, with a hazard ratio (HR) of 0.36 (95% CI 0.19-0.67; p = 0.001). Median OS was 52.7 months (95% CI 37.3-NE) with SOC+CBM588 and 45.7 months (95% CI 29.2-NE) with SOC (HR 0.69, 95% CI 0.32-1.47, p = 0.33). Exploratory analysis using the TOPOSCORE microbiome metric showed that baseline microbiota profiles were similar between SOC and SOC + CBM588 in both trials. Notably, however, baseline gut microbiota composition was associated with treatment response in the dual ICI subgroup, but not in the ICI + VEGFR-TKI subgroup. Conclusions: In this pooled analysis of two randomized phase I trials, the addition of CBM588 to frontline ICI-based therapy was associated with higher ORR and prolonged PFS compared with SOC alone, supporting the design of the upcoming phase III SWOG BIOFRONT study. We also identify baseline TOPOSCORE as a potential predictor of benefit with dual ICI regimens. Clinical trial information: NCT05122546 , NCT03829111 .
Impact of social environment on prostate cancer care across the clinical risk spectrum for Black men treated in community settings.
329 Background: Social environment impacts prostate cancer (PCa) care, particularly for Black men, but whether its effect remains constant across for the risk spectrum remains unclear. We aim to examine how social environment and race impact clinical risk-based treatment and metastasis-free survival (MFS) for Black individuals managed in community urology practices. Understanding these relationships may better inform community-based strategies to improve PCa care implementation. Methods: This observational cohort study evaluated individuals diagnosed with PCa from 1998 to 2022 across 38 community urology practices, academic centers, and VA hospitals. Participants included individuals with biopsy-proven, clinically localized PCa. Social environment was assessed using the census tract-level social vulnerability index, where rankings above the 75th percentile nationally was deemed “high vulnerability” communities. Risk-based treatment was defined as Radical Prostatectomy/Radiation Therapy (RP/RT) vs Active Surveillance/Watchful Waiting (AS/WW) or androgen deprivation therapy (ADT) for intermediate/high-risk PCa, and RP/RT/ AS/WW vs ADT for low-risk PCa. Multivariable logistic regression analysis examined associations between social environment, race, and risk-based treatment, adjusting for socio-demographics, comorbidities, and job status. Lifetable estimates, Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression assessed associations between risk-based treatment and MFS for intermediate/high-risk PCa. Results: Among the 8,841 men identified, 863 (10%) were Black, 4,030 (46%) had low-risk PCa, and 1,064 (12%) had high vulnerability. Most (7988, 90%) were treated in community urology practices. Half (52%) underwent RP, 26% RT, 9% AS/WW, and 13% PADT. For low-risk PCa, Black individuals (OR 0.41, 95% CI 0.27-0.63) and those in high vulnerability communities (OR 0.50, 95% CI 0.34-0.72) had lower odds of risk-based treatment compared to ADT monotherapy. For those with intermediate/high-risk PCa, Black individuals (OR 0.37, 95% CI 0.28-0.49) was associated with lower odds of risk-based treatment while high community vulnerability was not. Those who received risk-based treatment had lower 10-year MFS compared to those who did not (95% vs 91%, log-rank p<0.01). After adjustment, risk-based treatment was associated with lower odds of metastasis (OR 0.70, 95% CI 0.52-0.94) compared to ADT or AS/WW. Conclusions: Relationships between social environment, race, and risk-based treatment change across the clinical risk spectrum for Black individuals with PCa. These findings underscore the importance of using clinical risk and social environment to inform community-based interventions to address inequities in risk-based treatment and outcomes for Black men with PCa.
Evaluation of ancillary multiparametric MRI features in PI-RADS 3 prostate lesions and their association with prostate cancer.
26 Background: Prostate cancer (PCa) remains the leading malignancy among men in Colombia and a major cause of cancer-related mortality worldwide. Multiparametric MRI (mpMRI) has become a cornerstone in PCa detection and biopsy targeting. However, PI-RADS 3 lesions continue to represent a diagnostic gray zone, accounting for 20–30% of mpMRI findings, with reported clinically significant PCa (csPCa) detection rates ranging from 11–25%. Management of these indeterminate lesions remains a relevant clinical challenge. Our institution has observed higher-than-expected csPCa prevalence in PI-RADS 3 lesions, underscoring the need to evaluate mpMRI features and clinical parameters that may refine risk stratification. Methods: Retrospective, single-center study of men >18 years with PI-RADS 3 lesions on mpMRI who underwent targeted prostate biopsy at a low and middle-income country (LMICs) between January 2019 and December 2024. mpMRI were acquired on 1.5T and 3T scanners following PI-RADS v2.1 standards. Imaging was reviewed independently by two abdominal radiologists with ≥10 years of experience. Clinical (age, PSA, PSA density), imaging (lesion size, location, morphology, diffusion/ADC restriction, contrast enhancement), and histopathology (Gleason score, ISUP grade group) data were collected. Clinically significant PCa was defined as Gleason ≥3+4. Univariate, bivariate, and multivariate logistic regression analyses were performed to identify independent predictors of csPCa. Results: A total of 82 patients met inclusion criteria. Overall PCa prevalence was 58%, with csPCa in 42% notably higher than previously reported rates for PI-RADS 3 lesions. On multivariate analysis, low apparent diffusion coefficient (ADC) values, linear or irregular lesion morphology, and elevated PSA density were independently associated with csPCa (p < 0.05). Traditional mpMRI features such as T2 signal intensity, qualitative diffusion restriction, and early dynamic contrast enhancement did not show statistically significant associations. The predictive model demonstrated acceptable discrimination (AUC = 0.726). These findings could suggest that integration of quantitative ADC metrics, PSA density, and lesion morphology may enhance risk stratification and therefore clinical management. Conclusions: Ancillary imaging and clinical features, specifically quantitative ADC values, PSA density, and lesion morphology emerged as robust predictors of csPCa. Incorporating these parameters into diagnostic pathways could ameliorate the proper selection of patients requiring prostate biopsies while improving early detection of aggressive disease. Our results highlight the need to refine PI-RADS guidelines particularly in the PI-RADS 3 category, and adapt biopsy strategies to diverse healthcare settings.
Clinical outcomes with immune checkpoint inhibitor and/or enfortumab vedotin in patients with MTAP-deleted metastatic urothelial carcinoma.
757 Background: MTAP-deletion(d) in urothelial carcinoma (UC) is associated with tumor aggressiveness, higher rates of metastasis, and treatment resistance. We investigated the impact of MTAP-d on treatment outcomes of metastatic UC (mUC) treated with checkpoint inhibitors (ICIs), enfortumab vedotin (EV), or EV/pembrolizumab (EV/P). Methods: We performed a retrospective analysis of 65 patients with mUC who underwent NGS assessment of MTAP status and were treated with first-line (1L) or 2nd+ line (2+L) ICI, EV, or EV/P between 2019 and 2025. Median treatment duration (mTD), median progression-free survival (mPFS), and objective response rate (ORR) were compared between patients with and without MTAP-d using Welch t-test, log-rank test and Cox proportional hazards, and Fisher’s test. Results: 25 patients with MTAP-d and 39 patients with MTAP-proficient(p) tumors were identified (ICI: 28 1L, 17 2+L; EV: 2 1L, 28 2+L; EV/P: 10 1L, 9 2+L). Median age was 68.5 (48 males; 16 females). FGFR3 co-alteration was seen in 24% of MTAP-d vs 10% of MTAP-p tumors (p = 0.2). Overall survival was significantly shorter in MTAP-d group (HR 2.1 [95% CI 1.1-4.2], p = 0.04). In patients treated with 1L or 2+L ICI monotherapy (n = 45), mTD (2.1 vs 5.1 mo, p = 0.2), mPFS (HR 1.6 [0.80-3.24], p = 0.2), and ORR (27.8% vs 35.7%, p = 0.53) were numerically lower but not significantly different in MTAP-d compared to MTAP-p. Among patients treated with 1L or 2+L EV monotherapy (n = 30), mTD (4 vs 7.2 mo, p = 0.04) and mPFS (HR 2.4 [1.07-5.33], p = 0.02) were significantly shorter while ORR (6.7 vs 41.7%, p = 0.06) was numerically lower in the MTAP-d group. In patients treated with 1L or 2+L EV/P (n = 19), no significant difference in mTD (6.1 vs 5 mo, p = 0.6), mPFS (HR 1.78 [95% CI 0.45-6.96], p = 0.3), or ORR (40% vs 35.5%, p > 0.99) was seen between MTAP-d and MTAP-p. Among MTAP-d patients, mPFS was numerically longer with EV/P compared to EV or ICI monotherapy (5.1 vs 3.7 vs 2.9 mo, p = 0.7). Conclusions: Our results suggest that MTAP-d is associated with inferior treatment outcomes among patients treated with ICI or EV as monotherapy. However, there was no significant difference in outcomes among patients with or without MTAP-d receiving EV/P, although findings are limited by the small cohort. Further evaluation of the impact of MTAP-d in patients treated with EV/P is ongoing. Impact of MTAP-d on the clinical outcomes of patients with mUC treated with immune checkpoint inhibitor and/or enfortumab vedotin. MTAP-d (n=25) MTAP-p (n=39) p-value ICI mTD, months [IQR] 2.1 [0.9-7] 5.1 [2.9-10.3] 0.1 mPFS, HR [95% CI] 1.6 [0.80-3.24] 0.62 [0.31-1.25] 0.2 ORR (%) 27.8 35.7 0.53 EV mTD, months [IQR] 4 [2.3-6.6] 7.2 [3.6-15.5] 0.04 mPFS, HR [95% CI] 2.4 [1.07-5.33] 0.42 [0.19-0.94] 0.02 ORR (%) 6.7 41.7 0.06 EV/P mTD, months [IQR] 6.1 [3-9.6] 5 [3.4-6.1] 0.6 mPFS, HR [95% CI] 1.78 [0.45-6.98] 0.56 [0.14-2.21] 0.3 ORR, % 40 35.7 >0.99 a =0.05.
Manipulating Ion Chemistry in Biphasic Electrolytes Toward Durable High‐Energy Zinc–Bromine Batteries
ABSTRACT Zinc–bromine batteries (ZBBs) are considered a promising candidate for long‐duration energy storage, but their practical implementation is critically hampered by the crossover of polybromides. This bottleneck can be alleviated by deploying aqueous‐organic biphasic electrolytes, which leverage the pronounced difference in polybromide solubility between two immiscible phases to achieve effective confinement. However, a profound mechanistic understanding of ion‐specific functions in such systems remains elusive, and the full‐cell performance still falls short of commercial requirements. Herein, we systematically investigate the ion‐manipulated solvation environment and biphasic equilibrium of the electrolytes that correlate with the electrochemical behavior of ZBBs. Beyond anion‐driven phase separation, cations dictate ion‐pairing interactions that govern component distribution across the two phases. Compared to monovalent and trivalent counterparts, divalent cations strike an optimal thermodynamic–kinetic balance, achieving a trade‐off between polybromide confinement and electrode reaction kinetics. Furthermore, a dual‐functional zwitterion is demonstrated to concurrently suppress polybromide shuttle and stabilize zinc deposition. The resulting biphasic ZBBs deliver an energy density of 40.6 Wh L −1 and sustain a cycling life over 1000 cycles, considerably outperforming reported biphasic systems. Coupled with a low system‐level cost of ∼$100 kWh −1 , the biphasic ZBBs represent a compelling technology for grid‐scale energy storage.
Phase 2 trial of belzutifan in participants from China and Japan with von Hippel-Lindau disease-associated tumors: Results from LITESPARK-015 cohort B1.
494 Background: Von Hippel-Lindau (VHL) disease manifests with tumors including renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS-HB), pancreatic neuroendocrine tumors (pNET), pheochromocytomas/paragangliomas (PPGL), and retinal hemangioblastomas (R-HB). The LITESPARK-004 trial conducted in the US and Europe demonstrated robust clinical activity of belzutifan in VHL disease-associated RCC, CNS-HB and pNET. We report the results of China and Japan participants (pts) with VHL disease-associated tumors from Cohort B1 of LITESPARK-015 trial. Methods: This global single-arm phase 2 trial enrolled adult pts with VHL disease-associated localized tumors with ≥1 measurable RCC, pNET or PPGL to receive 120 mg belzutifan Q1D until disease progression, unacceptable toxicity, or withdrawal. For R-HB, ophthalmic evaluations including color fundus photography were performed. The primary endpoint was objective response rate (ORR) for VHL disease-associated RCC per RECIST v1.1 by blinded independent central review (BICR) in pts from China and Japan; the hypothesis was ORR >15% tested once at 20 months (mo). Other key endpoints included duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) (RECIST 1.1, BICR), time to surgery by tumor type, overall survival (OS) and safety. Results: At data cut-off (April 22, 2025), 44 pts (23 China, 21 Japan) were enrolled and treated. The median age was 38 years, 59% pts had family history of VHL disease, and 59% had type 1 VHL disease. Overall, 34 (77%) pts had RCC, 22 (50%) solid and cystic CNS-HB, 16 (36%) solid CNS-HB, 21 (48%) pNET and 6 (14%) PPGL. Seven pts had ≥1 R-HB by BIRC at baseline. At median follow-up of 25.1 mo (range, 20.7 to 28.1), the primary endpoint was met with ORR of 88.2% (95% CI, 72.5-96.7; p <0.001) in pts with RCC. ORR was 90.5% (95%CI, 69.6-98.8) in pNET, 59.1% (95% CI, 36.4-79.3) in solid and cystic CNS-HB, 81.3% (95% CI, 54.4-96.0) in solid CNS-HB, and 16.7% (95% CI, 0.4,64.1) in PPGL. DCR was 100% in all pts. The best overall response at pt level for R-HB was “improved” in 71% pts. Median DOR and PFS were not reached for all pts, with 24-mo PFS rates of 88.1% (RCC), 88.4% (pNETs), 90.4% (solid and cystic CNS-HB), 100% (solid CNS-HB), and 100% (PPGL). No pts had VHL tumor specific surgery or radiation while treated with belzutifan. All pts (100%) had a treatment-related adverse event (TRAE), with a serious TRAE in 1 (2%) pt. One (2%) pt discontinued and 28 (64%) had dose reduction due to TRAE. Nine (21%) pts had grade 3 TRAEs; the most common were increased alanine aminotransferase (9%) and anemia (4%). There were no grade 4 or 5 TRAEs. Conclusions: Belzutifan provided robust and clinically meaningful antitumor activity with durable responses in pts from China and Japan with VHL disease-associated tumors. Belzutifan had a manageable safety profile with no new safety signals. Clinical trial information: NCT04924075 .
A national analysis of the impact of opioid use disorder on clinical outcomes in hospitalized patients with urothelial carcinoma.
659 Background: Patients with urothelial carcinoma often require hospitalizations for peri and post operative management of major surgical interventions, such as cystectomies and nephroureterectomies, and disease complications. Opioid use disorder (OUD) is a growing public health issue with well-established adverse outcomes; however, there is minimal literature with regards to the intersection of OUD and urothelial carcinoma. Here we investigate the associations of OUD with clinical outcomes in hospitalized patients with urothelial carcinoma. Methods: We conducted a cross-sectional study using the 2018 National Inpatient Sample among adult (age > 18 years) hospitalizations with urothelial carcinoma. Descriptive data was used to compare demographic and clinical characteristics of patients with and without OUD. Clinical outcomes were identified with ICD-10-CM codes. The Charlson Comorbidity Index (CCI) was used to calculate comorbidities. Multivariable logistic regression was used to evaluate the association between OUD and clinical outcomes, adjusting for demographics, comorbidities, metastatic disease, type of admission, hospital location and other clinical risk factors. Survey weights were applied to generate national estimates. Results: Among 93,040 weighted hospitalizations, 830 (0.9%) involved OUD. Patients with OUD tended to be younger (mean age 66.0 vs 73.4 years), African American (13.3% vs 7.7%), have higher rates of Medicaid insurance (14.5% vs. 5.6%), increased length of stay (5 days vs 4 days), and have metastatic disease (41.0% vs 24.3%) compared to non-OUD hospitalizations (all p < 0.005). However, there was no significant difference with regards to urothelial surgery (p = 0.629). After adjustment, OUD was independently associated with increased odds of hospitality mortality (aOR 1.75, 95% 1.11-2.77), sepsis, (aOR 1.30, 95% 1.06-1.59), and venous thrombosis (aOR 1.52, 95% 1.10-2.10). Conclusions: In this nationally represented sample of hospitalized patients with urothelial carcinoma, OUD was associated with sociodemographic disparities and worse clinical outcomes. Patients with OUD were more likely to belong to a minority population and present at a later stage in disease process. After adjustment for possible cofounders, OUD was independently associated with increased odds of hospital mortality, sepsis, and venous thrombosis.
A novel cabozantinib formulation with reduced pharmacokinetic variability and the potential to improve safety in patients with renal cell carcinoma.
512 Background: Cabozantinib is a standard treatment for advanced renal cell carcinoma (RCC) which exhibits substantial pharmacokinetic (PK) variability and high rates of dose modification (>75% of patients) and treatment interruption. A novel cabozantinib formulation comprising an alternate salt form, has been developed to provide pH-independent solubility and reduced PK variability while achieving equivalent average systemic exposure. Methods: Two single-dose clinical studies in healthy participants evaluated bioequivalence and impact of food on a novel cabozantinib formulation compared to a reference formulation of cabozantinib 60 mg. Population PK models were developed using these data for a novel cabozantinib formulation and the reference cabozantinib formulation and applied to predict steady-state concentration (C avg,ss ) in a virtual cohort of 2,000 RCC patients with demographics and dose reduction patterns for the reference formulation consistent with the METEOR trial. Hazard ratios (HR) for clinically relevant safety endpoints were derived for the virtual population based on model-predicted exposure and published exposure-response relationships. Results: A novel cabozantinib formulation achieved bioequivalent systemic exposure to cabozantinib (34.5 mg ≈ 60 mg) with no food effect and reduced inter-subject variability relative to the reference formulation. Correspondingly, the distribution of simulated C avg,ss was narrower for a novel cabozantinib formulation, with fewer patients exceeding the toxicity threshold (>1,350 ng/mL). This reduced variability in exposure translates to reduced HRs for key safety endpoints comparing high exposure patients (90 th percentile) to median exposure patients (50 th percentile) for a novel cabozantinib formulation 34.5 mg relative to cabozantinib 60 mg. Conclusions: A novel cabozantinib formulation demonstrates bioequivalence to cabozantinib with reduced PK variability and no impact of food on exposure. Modeling predicts lower risk of exposure-related toxicities among high exposure patients, which has the potential to maximize dose intensity and long-term outcomes by improving safety and treatment continuity reducing the risk of compromising dose interruptions and reductions. Model-predicted hazard ratios for clinically relevant safety endpoints in high exposure patients (90 th percentile) relative to median exposure patients. Adverse Event Hazard RatiosNovel Cabozantinib Formulation 34.5 mg Hazard RatiosCabozantinib 60 mg % HR Comparison Reduction Palmar-plantar erythrodysesthesia (PPE) 2.46 7.08 65% Diarrhea 1.92 4.11 53% Hypertension 2.01 4.53 56% Fatigue/Asthenia 2.21 5.59 61%
Impact of piflufolastat F18 imaging on disease management for prostate cancer patients: Observations from the PYLARIFY Registry study.
339 Background: PSMA-PET imaging is widely accepted as preferred to conventional imaging (CT, MRI, SPECT) for the management of patients with prostate cancer (PCa). PSMA-PET imaging has demonstrated the ability to more accurately stage patients with PCa. Such information is critical to physicians when determining an appropriate disease management plan for their patients. The long-term impact of PSMA-PET imaging on PCa management in real-world clinical settings has yet to be fully established. In this real-world observational registry study preliminary data on change in management following PSMA-PET imaging were evaluated. Methods: The PYLARIFY Registry (NCT 05712473), conducted under SoNaR, a Cardinal Health Specialty Networks Registry, is a 5-year prospective, multicenter, United States based observational study that follows patients receiving PSMA-PET with piflufolastat F18 imaging as part of their routine PCa management. The registry includes newly diagnosed treatment-naïve patients (Cohort 1) and patients with biochemical recurrence (BCR) (Cohort 2). To evaluate the impact of PSMA-PET with piflufolastat F18 on clinical decision-making, physician-reported treatment plans before and after imaging were assessed. Disease management for the first 325 enrolled patients was characterized and the overall impact of piflufolastat F18 imaging results on changes in management was quantified by calculating the Jaccard Index for both patient cohorts. Treating physicians also rated the confidence in their management plan following piflufolastat F18 imaging. Results: Among the 161 patients in the newly diagnosed cohort, the Jaccard Index was 0.437, indicating a 56.3% variation between pre-imaging and post-imaging treatment plans. Similarly for the 164 patients in the BCR cohort, the Jaccard Index was 0.430 reflecting a 57.0% variation in disease management strategies before and after imaging. These findings are comparable to the 63% change in planned management observed within a BCR cohort in the CONDOR clinical study. Overall, physicians reported increased confidence in their disease management plans for 97.8% of patients following piflufolastat F18 imaging. Conclusions: Present findings support the clinical utility of piflufolastat F18 in guiding real-world clinical decision-making in both newly diagnosed and BCR prostate cancer patients. The observed changes in treatment plans demonstrate a substantial shift in management strategies following PSMA-PET imaging. Our findings are consistent with those of a clinical trial and further underscore the clinical value that piflufolastat F18 provides to physicians and patients in a real-world setting.
Tuning Solution‐State Aggregation for Shearing‐Induced Alignment and High Mobility Transport in Conjugated Polymers
ABSTRACT Clarifying the evolution of solution‐state aggregation of conjugated polymers into ordered thin films under external forces remains one of the key issues in developing high‐performance polymer electronics. Here, a strategy is provided to tailor the polymer aggregation and their responsiveness to solution‐shearing forces by tuning intermolecular interactions, aiming for efficient charge transport. Using a typical n‐type conjugated polymer as the model system, we systematically modulate the balance between backbone–solvent and side chain–solvent interactions to design distinct aggregate structures. In the backbone‐selective solvent of 1‐chloronaphthalene, enhanced backbone solvation at elevated temperatures leads to loosely packed, rod‐like aggregates that align efficiently under directional shear, yielding highly ordered films with electron mobilities up to 4.74 cm 2 V −1 s −1 . In contrast, in the side‐chain‐selective solvent of trimethylbenzene, polymer chains form disordered network‐like aggregates that resist alignment and produce less ordered films with mobilities of 2.20 cm 2 V −1 s −1 . Additionally, similar enhancements in charge‐transport mobility are also observed with two other representative polymers using the same strategy. This work establishes the critical role of intermolecular interaction‐driven aggregate design in dictating shearing‐induced structural evolution, offering a robust framework for the fabrication of high‐mobility conjugated polymer films.
Initial results from CLIMATE, a prospective cohort study assessing the clinical utility of miR-371a-3p (miR-371) as a marker of minimal residual disease (MRD) in clinical stage 1 testicular germ cell tumour (TGCT): ANZUP 1906.
586 Background: Active surveillance (AS) remains a preferred option for clinical stage 1 (CS1) TGCT. Biomarkers to predict recurrence are limited by poor accuracy. Circulating miR-371 has high sensitivity and specificity for TGCT, and as a marker of MRD post-orchiectomy (orch), is a promising biomarker for predicting recurrence. Initial results from CLIMATE examine the discriminatory accuracy of baseline post-orch miR-371 in predicting recurrence in patients with CS1 TGCT undergoing AS. Methods: Patients from 12 sites in Australia and New Zealand, aged ≥18y, with histologically confirmed CS1 TGCT, no evidence of metastases and planned for AS, were enrolled ≤6w post-orch. Plasma and serum were collected at baseline (≤6w post-orch) and every 3mo for 24mo and at recurrence. Clinical and outcome data were recorded in iTestis, Australia’s TGCT registry. miR-371 was assessed using a qPCR assay based upon published methodology (Murray et al.) and deemed detectable if the mean of triplicate qPCR Ct was ≤40. Results: CLIMATE enrolled 200 patients from 2021 to 2025. 196 patients had assays run on baseline samples prior to data cutoff and were included in this analysis. Orch histology included 117 (60%) pure seminoma and 79 (40%) non-seminoma. With median follow-up (F/U) 18.9mo, there were 40 recurrences. miR-371 was detected at baseline in 42 (21%) plasma and 34 (17%) serum samples. Assays using plasma performed better than serum (AUC 0.77 v 0.69) and are reported hereafter. In predicting recurrence, baseline miR-371 demonstrated positive predictive value (PPV) 62%, negative predictive value (NPV) 91%. Detectable baseline miR-371 was associated with significantly poorer Recurrence Free Survival (RFS) compared to undetectable miR-371 (HR 10.28, p<0.001; 24mo RFS 32% v 89%). miR-371 outperformed existing biomarkers for predicting recurrence. For seminoma, with 10 (8%) recurrences and median F/U 18.4mo, miR-371 had superior discriminatory accuracy for recurrence compared to tumour size >4cm (AUC 0.86 v 0.57, p=0.02) and Boorman risk group (AUC 0.86 v 0.61, p=0.03). For non-seminoma, with 30 (38%) recurrences and median F/U 20.8mo, miR-371 had superior discriminatory accuracy for recurrence compared to presence of lymphovascular invasion (AUC 0.73 v 0.58, p=0.04), or embryonal carcinoma (AUC 0.73 v 0.53, p<0.001). Sensitivity analysis of 84 (43%) pts with recurrence or >24mo F/U supported high discriminatory accuracy of miR-371 (AUC 0.80, PPV 90%, NPV 67%) and significant difference in RFS (HR 8.59, p<0.001, 24mo RFS 7% v 75%). Conclusions: In this initial analysis of CLIMATE, detectable post-orch miR-371 in CS1 TGCT is a marker of MRD with superior discriminatory accuracy for predicting recurrence. Its utility in guiding use of adjuvant chemotherapy warrants exploration. Clinical trial information: ACTRN12622000247774.
OncoEducate: A pilot study of generative AI to support patient education in GU cancer care.
713 Background: Genitourinary (GU) cancer care involves complex treatment plans and goals, which can be difficult for patients to understand and navigate. Limited understanding can lead to distress and avoidable care utilization. We developed OncoEducate, a generative artificial intelligence (AI) tool that produces patient-friendly handouts, and piloted its accuracy, feasibility, and acceptability. Methods: OncoEducate uses the Claude Opus 4.1 large language model. User inputs include patient’s diagnosis, treatment intent, and treatment regimen. Based on these inputs, the tool generates tailored, two-page handouts summarizing diagnosis, treatment intent, regimen details, side effects, and reasons to contact the care team. Information is drawn from reputable public sources and standardized language is used for key concepts (e.g., treatment intent). Feedback from patient advocates, oncologists, and pharmacists informed iterative refinement. We conducted a prospective two-phase pilot study (IRB exempt, University of Pennsylvania). Phase 1: Nine handouts for common palliative-intent regimens in advanced kidney, prostate, and urothelial cancers were generated and reviewed by five GU oncologists and an advanced practice provider for accuracy, completeness, and readability. Feedback informed prompt refinement, yielding Version 2. Phase 2: Patients initiating these regimens received Version 2 handouts. Surveys assessed usefulness, readability, and acceptability (7-point Likert scale items) and comprehension of treatment intent (validated item from Cancer Care Outcomes Research and Surveillance study). Analyses were descriptive. Results: Clinicians rated Version 1 handouts as highly accurate and appropriate (median 6-7/7 across domains). Over eight weeks, 20 out of 21 eligible patients enrolled and completed surveys. Most were male (n = 17, 85%) with urothelial (n = 11, 55%) or kidney (n = 6, 30%) cancer. Median age was 71 (range: 46-83). Enfortumab vedotin + pembrolizumab (n = 8, 40%) was the most frequent regimen. Patients strongly agreed that the handouts were informative, easy to read, and improved their understanding of treatment plans and care team contact (median 7/7 for all). Comfort with AI-assisted education was high (median 7/7, range 2-7). 65% (n = 13) of patients correctly identified their treatment intent as palliative - exceeding historical benchmarks (19-31%, Weeks et al, NEJM 2012). Conclusions: OncoEducate handouts were well received by clinicians and patients and may improve understanding of treatment intent. Despite small sample size, findings demonstrate the feasibility of generative AI to deliver concise, personalized education. Larger randomized studies are needed to assess impact on patient outcomes.
Use of ultra-sensitive whole genome circulating tumor DNA detection to predict early recurrence in high-risk localized RCC after nephrectomy: Preliminary real-world findings.
516 Background: Circulating tumor DNA (ctDNA) has emerged as a powerful tool for detecting molecular residual disease (MRD) across multiple solid tumors, but its application in renal cell carcinoma (RCC) has historically been limited by low ctDNA shedding. Recent advances in ultra-sensitive, tumor-informed whole-genome sequencing (WGS) assays capable of tracking up to 1,800 patient-specific variants now enable ctDNA detection at concentrations as low as ~ 1 part per million (PPM). This study evaluates the prognostic value of ultra-sensitive ctDNA following nephrectomy in high-risk localized RCC. Methods: This single-center retrospective cohort study included patients with localized RCC who underwent at least one ctDNA assessment using the Next Personal Dx WGS tumor-informed assay. ctDNA testing was performed within 3 months after nephrectomy (3-month landmark), and/or at 6 months (≥3 to < 7 months) post-surgery. The primary endpoint was recurrence rate based on ctDNA status at any timepoint. A secondary endpoint was recurrence rate in patients with persistent ctDNA negativity, defined as undetectable ctDNA at both landmarks assessments. Results: Twenty-two patients (42 plasma samples) were included, with a median follow-up of 7.0 months (range, 3.2 – 19.3). The cohort was predominantly male (77%), with a median age of 63 years and largely white. A total of 87% underwent radical nephrectomy, 95% had pT3 disease, with a median size of 6.4 cm, all patients were pN0/Nx, 91% clear cell, 9% unclassified, 18% G2, 50% G3 and, 32% G4, 14% had sarcomatoid features and 50% received adjuvant therapy. Median time to the 3-month landmark ctDNA draw and subsequent 6-month assessment was 1.4 and 4.8 months, respectively. At the landmark timepoint, 95% of patients had ctDNA collected, and 91% had 6-month testing. Three patients (14%) had ctDNA positivity at any timepoint (two persistent and one conversion, all < 100ppm). Two of these developed radiographic recurrence (1 and 4 months after first ctDNA detection). In contrast, only 1 of 20 patients with 3-month landmark ctDNA negativity recurred, and none (0/16) of those with persistent ctDNA negativity recurred during the follow-up. Conclusions: Ultra-sensitive ctDNA appears promising for identifying RCC patients at higher risk for recurrence, while persistent undetectable ctDNA correlates with a low observed risk. Prospective studies are warranted to test its use in disease monitoring or patient selection for adjuvant treatment.
Acute kidney injury to predict cardiovascular outcomes following radical cystectomy: A multicenter retrospective study.
725 Background: Acute kidney injury (AKI) is a common complication in patients undergoing radical cystectomy (RC). Although AKI has been associated with adverse cardiovascular outcomes in various clinical settings, its impact on cardiovascular outcomes in patients undergoing RC remains unclear. Methods: This multicenter retrospective cohort study included 919 patients with muscle-invasive bladder cancer who underwent RC. AKI was defined according to the KDIGO criteria. Patients were categorized into four groups based on AKI stage. Major adverse cardiovascular events (MACE) were defined as a composite of myocardial infarction, stroke, and cardiovascular death. Multivariable Cox proportional hazards regression analysis was performed to assess the impact of perioperative AKI on MACE-free survival. Results: The median age of the cohort was 70 years, and the median follow-up period was 54 months. Among the 919 patients, 366 (40%), 93 (10%), and 34 (3.7%) developed stage 1, 2, and 3 AKI, respectively. MACE-free survival was significantly shorter in the AKI group compared to the non-AKI group ( P = 0.012). Patients with stage 1 AKI did not show a statistically significant difference in MACE-free survival compared to those with stage 0 AKI ( P = 0.063). However, patients with stage 3 AKI had significantly shorter MACE-free survival than those with stage 0 and stage 2 AKI ( P < 0.001 for both comparisons). After adjusting for confounding variables, stage 3 AKI remained independently and significantly associated with shorter MACE-free survival. Conclusions: Severe perioperative AKI is independently associated with worse long-term cardiovascular outcomes in patients undergoing RC, regardless of preoperative renal function. Multivariable analysis for MACE-free survival. Factor P value Hazard ratio 95% CI Age Continuous 0.185 1.019 0.991–1.049 Body mass index Continuous 0.741 0.989 0.927–1.056 Hypertension Presence 0.011 1.886 1.156–3.078 Dyslipidemia Presence 0.708 1.100 0.668–1.813 Diabetes mellitus Presence 0.370 1.257 0.762–2.072 History of CVD Presence 0.004 1.964 1.240–3.110 Preoperative eGFR Continuous 0.002 0.980 0.969–0.992 AKI Stage 0 Reference - Stage 1 0.306 1.275 0.801–2.031 Stage 2 0.227 1.550 0.761–3.155 Stage 3 0.049 2.430 1.005–5.877
Proton Sponge Tailoring of Interfacial H‐Bond Networks Enables Seawater Electrosynthesis for Concomitant Alkenol and Mg(OH) <sub>2</sub>
ABSTRACT Seawater electrolysis provides a sustainable hydrogen source for electrocatalytic semi‐hydrogenation (ECSH) of alkynols, but it suffers from severe hydrogen evolution and a lack of effective interfacial management. Here, we construct a proton sponge (1,8‐bis(dimethylamino)naphthalene) modified PdIn intermetallic metallene (Pd 1 In 1 ene@DMAN). In situ FTIR and ab initio molecular dynamics simulations reveal that this modification disrupts the hydrogen‐bond network of interfacial water molecules, while DFT calculations indicate facilitated water dissociation and enhanced generation of active hydrogen species. The Pd 1 In 1 ene@DMAN achieves a Faradaic efficiency (FE) of 94.43% for 2‐methyl‐3‐buten‐2‐ol (MBE) production at −100 mA cm −2 , a dramatic increase from the 44.93% attained by the Pd 1 In 1 ene, with an operational stability over 500 h. In a membrane‐electrode assembly (MEA) electrolyzer, it enables the efficient conversion of alkynol to alkenol at a current of 2 A, delivering a FE of 84.16%, a selectivity of 98.54% toward MBE, and excellent stability for up to 200 h. Concurrently, the cathodically generated OH − selectively precipitates Mg 2+ as high‐purity Mg(OH) 2 by precise pH control, enabling the co‐production of value‐added MBE and Mg(OH) 2 . This work establishes a seawater‐based electrochemical system, which regulates the hydrogen bond microenvironment through molecular interface engineering, providing a new strategy for efficient electrochemical hydrogenation in complex media.