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Quantifying the hidden burden of metastatic prostate cancer.
96 Background: Preventing metastatic disease is the key goal of prostate cancer screening and local treatment. However, most evaluations of metastasis burden focus only on de novo metastatic disease at diagnosis and do not capture metastatic recurrences after local therapy, such as those based on cancer registries in the United States (U.S.). Methods: We inferred the full burden of metastatic prostate cancer in the Health Professionals Follow-up Study, a prospective cohort of U.S. male health professionals aged 40–75 years at enrollment in 1986 with follow-up in this analysis through January 2018. We captured three ways how metastatic prostate cancer manifested: (1) de novo metastases at initial diagnosis, (2) metastatic recurrences reported by participants during active follow-up, and (3) metastases were inferred from deaths attributed to prostate cancer, under the assumption that such deaths are almost invariably preceded by distant metastases. Cause-of-death adjudication assumed 90% specificity of coding, with a conservative 70% applied in sensitivity analyses. Absolute risk (cumulative incidence) of metastatic prostate cancer was estimated using the Aalen–Johansen method, accounting for death from other causes as a competing risk. Results: Our study population of 50,420 men had a median age of 54 years at enrollment (interquartile range, 46 to 63 years) when they were free from prostate cancer. The study population was predominantly of European descent (95%), with 2% Asian and 1% African American participants. Over up to 30 years of follow-up, we documented 8,305 prostate cancer diagnoses. Of these, 1,504 cases were adjudicated to be metastatic at diagnosis or to have metastasized after initial diagnosis. De novo metastatic disease accounted for only 249 (17%) of all metastatic cases. Conservative causes-of-death adjudication estimated 1,314 metastatic cases, with 19% being de novo metastases. The risk of metastatic prostate cancer among men was 0.8% (95% confidence interval [CI] 0.8, 0.9) by age 70, 2.4% by age 80 (95% CI 2.3, 2.6), and 4.0% (95% CI 3.8, 4.2) by age 90 years. Four in ten metastatic prostate cancers occurred after age 80 years. De novo metastatic disease risk represented about one-quarter of metastases by age 70, with lower relative contributions with advancing age. The risk of metastatic disease was particularly high in African-American men (3.6% by age 80, 95% CI 2.2, 5.8), while the risk among Asian men (2.3% by age 80, 95% CI 1.4, 3.7) was comparable to that among European men (2.5% by age 80, 95% CI 2.3, 2.6). Conclusions: One in 25 men in a widely PSA-screened population developed metastatic prostate cancer over the lifetime. Much of this substantial disease burden would remain hidden if using de novo disease as the only measure. Clinical and registry-based evaluations of early detection and local treatment need to capture the full burden of metastatic disease, which disproportionally impacts the oldest age groups.
Diagnostic performance of <sup>18</sup> F-flotufolastat PET/CT compared with conventional imaging for detection of pelvic lymph node metastases in men with newly diagnosed prostate cancer: Descriptive post-hoc analysis from the phase 3 LIGHTHOUSE study.
311 Background: 18 F-Flotufolastat is a prostate-specific membrane antigen (PSMA)-targeting PET radiopharmaceutical approved in the US for diagnostic use in men with prostate cancer. The Phase 3 LIGHTHOUSE study (NCT04186819) assessed 18 F-flotufolastat in men with newly diagnosed prostate cancer planned for radical prostatectomy (RP) and pelvic lymph node dissection (PLND). This post-hoc descriptive analysis aimed to compare the diagnostic performance of 18 F-flotufolastat with baseline conventional imaging (CT or MRI). Methods: LIGHTHOUSE enrolled patients with newly diagnosed unfavorable intermediate-risk (UIR) to very high-risk prostate cancer. Patients underwent PET/CT 50–70 min after 18 F-flotufolastat (296 MBq ± 20%) administration. 18 F-Flotufolastat scans were evaluated by three blinded independent central readers. Patients had baseline conventional imaging with CT, MRI or bone scan, within 60 days before screening or at least 24 h before 18 F-flotufolastat PET. Baseline conventional imaging was evaluated by local read. Histopathology was used as standard of truth (SoT), with ≥ 1 PET positive lesion and one histopathological confirmed lymph node (LN) classed as true positive (TP). Study endpoints included patient-level sensitivity and specificity for the detection of pelvic LN metastases. This post-hoc descriptive analysis explored the sensitivity and specificity of baseline conventional imaging with CT and/or MRI in LIGHTHOUSE with the sensitivity and specificity reported for 18 F-flotufolastat PET among the efficacy analysis population (EAP). Results: In total, 296 patients (33% with UIR disease) underwent 18 F-flotufolastat PET followed by RP and PLND (EAP). Within the LIGHTHOUSE EAP, the majority read patient-level sensitivity for detecting pelvic LN metastasis with 18 F-flotufolastat was 24% (23–30% across readers) and specificity was 96% (93–97% across readers). Comparatively, among the subset of patients who had baseline CT and/or MRI scans available (N=267), the majority read patient-level sensitivity and specificity for 18 F-flotufolastat were 23% (22–29% across readers) and 96% (93–97% across readers), respectively. Notably lower sensitivity values were observed for baseline conventional imaging – for CT and/or MRI, the patient-level sensitivity was 3% (CT, 4%; MRI, 0%) and specificity was 95% (CT, 95%; MRI, 93%; N=267). Conclusions: This post-hoc analysis demonstrated the superior sensitivity of 18 F-flotufolastat PET compared with baseline conventional CT or MRI for the detection of pelvic LN metastasis. The very low sensitivity of conventional imaging (3%) highlights that detection of pelvic LN metastasis in the population enrolled in the LIGHTHOUSE study is highly challenging. Clinical trial information: NCT04186819 .
Examination of Decipher prostate genomic classifier in patients with de novo metastatic disease from a large scale real-world clinical and transcriptomic data linkage.
224 Background: Prognostic gene expression testing of primary tumor tissue has become widely adopted for localized prostate cancer risk stratification. Recent retrospective analyses of clinical trials have examined such testing in metastatic hormone-sensitive disease, but little has been reported outside of this context. We aim to evaluate the prognostic value of the Decipher prostate genomic classifier (GC) in patients with de novo metastatic prostate cancer (mPC) in real-world clinical practice (RWD). Methods: Clinical and transcriptomic data from clinical use of the GC between 2016-2024 were linked with RWD aggregated from insurance claims, pharmacy records, and electronic health record data. Patients (pts) were anonymously linked between datasets by deterministic methods through a de-identification engine using encrypted tokens. A hierarchical claims-based algorithm was used to identify de novo distant metastasis in the patient’s record. De novo metastasis was defined using claims and diagnosis codes recorded within 90 days of initial prostate cancer diagnosis, excluding cases with other primary malignancies diagnosed within 90 days and omitting codes for unspecified or pelvic lymph node–only metastases. The distribution of GC scores was compared between patients with de novo metastases and (1) all patients with localized prostate cancer and (2) a matched subset of localized patients with comparable baseline clinical and pathologic features. Here we focus on comparison to the latter group. Results: 135,044 pts with Decipher prostate GC from biopsy tests were successfully linked to RWD. De novo mPC was identified in 509 patients and compared to a matched set of 10,689 pts with localized disease. Among pts with de novo mPC, the median age at Decipher testing was 71 years (IQR 65, 77), median percentage of positive cores was 75% (IQR 50-100%), median PSA was 17 ng/mL (IQR 6.8,73) and 75% had NCCN high or very high-risk disease at diagnosis. Compared to the matched set for localized pts, 29% of mPC pts had PSA > 50 vs. 6% for localized patients. Median Decipher score for mPC pts was 0.94 (IQR 0.71, 0.99) compared to 0.75 (IQR 0.5, 0.9) in the matched localized patient cohorts. Compared to localized prostate cancer pts, mPC pts exhibited a higher proportion of Luminal B subtype (65% vs 54%), and a higher prevalence of PTEN inactivity (25% vs 15%). Conclusions: Using the largest linkage of transcriptomic and clinical data to date, we developed algorithms to identify de-novo mPC from a cohort of patients tested with a GC. These pts tended to have higher PSA, higher rates of PTEN inactivity and luminal B subtype tumors, higher NCCN risk groups at time of diagnosis and had substantially elevated GC scores. The use of the GC test may enhance understandings of de novo metastatic disease biology, patterns of care, and treatment effectiveness.
A study of GSK5458514 administered alone or in combination with other anticancer agents in patients with prostate cancer.
TPS285 Background: Prostate cancer is the second most common cancer in men and the fifth leading cause of cancer-related deaths in men. Despite treatment advances, 5-year survival estimates for patients with advanced disease remain low, ranging from 26%–37%. Hence, there is an urgent unmet need to develop novel therapies that delay disease progression, improve or maintain quality of life, and prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). GSK5458514 is a bispecific immunoglobulin G-like T-cell engager designed to bind to prostate-specific membrane antigen (PSMA), a clinically validated tumor-associated antigen, on one arm and CD3 of the T-cell receptor complex on the other arm. Co-binding of GSK5458514 to CD3 and PSMA brings T cells and tumor cells in proximity, which is designed to trigger subsequent T-cell activation, cytokine secretion, and T-cell–mediated killing of PSMA-positive tumor cells. Methods: This first-in-human, open-label, multicenter, phase 1/2 trial (NCT06990880) opened on June 12, 2025, and aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK5458514 alone or in combination with other anticancer agents in adult patients who have histologically confirmed adenocarcinoma of the prostate classified as mCRPC, novel antiandrogen receptor therapy failure, and treatment failure with 1–2 taxane-based chemotherapy regimens. During the dose escalation phase, participants will be administered GSK5458514 using a step-up dosing regimen (step-up treatment period) to mitigate the risk of cytokine release syndrome, followed by a fixed-dose treatment period once the intended target dose is achieved. In part 1, the objectives are to determine the safety and tolerability of GSK5458514 and to inform the dose-expansion phase. Ascending dosing cohorts will explore different doses and dosing regimens to determine the maximum tolerated dose. The primary endpoints for part 1 are safety during the dose-limiting toxicity period (first 28 days), frequency of adverse events, and any subsequent dose modifications (duration of trial and follow-up). Secondary endpoints include objective response rate in patients with measurable disease and duration of response, pharmacokinetics, 50% decrease in prostate-specific antigen (PSA50) response, and immunogenicity (antidrug antibodies against GSK5458514). Expected enrollment for part 1 is ≈45 patients. Open sites are located in the United States, Japan, and Canada. Additional sites are planned to open in 2026 in Spain and France. Clinical trial information: NCT06990880 .
Building like a Coral—Parallelized, Multiscale Biofabrication
ABSTRACT Visible from space or residing in the depths of the ocean, scleractinian corals engineer vast ecosystems supporting high biodiversity and providing essential ecosystem services. By creating these ecosystems, corals address significant challenges in material science, generating skeletal materials that are stiff, strong, and inherently circular—even in conditions where energy and building resources can be scarce or energetically expensive to synthesize. Understanding coral skeletal materials has progressed due to their exceptional mechanical properties, potential biocompatibility, and, in case of cold‐water corals, their ability to be synthesized in darkness, at low temperature, and with limited energy resources. These natural, sustainable processes offer inspiring blueprints for the development of transformative new materials, which may drive radical innovations across biomedical and engineering applications. In this perspective, we synthesize the current state of knowledge on the biomineralization process of corals, including the two prevailing viewpoints—biologically controlled vs. physicochemical controlled biomineralization. We then recast coral growth as a multiscale, parallelized biofabrication process, that can catalyse the development of next‐generation materials technologies. These insights outline pathways to sustainable, self‐organising, and energy‐efficient manufacturing with broad relevance to structural materials, biomaterials, and regenerative engineering. Ultimately, we strive to answer: “How to build like a coral?”
Halide Electrolytes for All‐Solid‐State Sodium Batteries: From Fundamental Chemistry to Interface Engineering
ABSTRACT All‐solid‐state sodium batteries (ASSSBs) stand out as a transformative energy storage technology, combining sodium's natural abundance with enhanced safety and competitive energy density. Solid electrolytes are pivotal to this innovation, with halide electrolytes emerging as prominent candidates due to their unique strengths—superior deformability for intimate electrode contact, strong cathode compatibility, and promising Na‐ion conductivity. Despite recent progress, significant challenges persist in scalable synthesis, performance optimization, and mechanistic understanding of ion transport and interfacial interactions. This review comprehensively covers sodium‐based halide electrolytes, including their structural chemistry, ion transport, synthesis, modification, electrochemical stability, interfacial behavior, and computational insights. We further integrate a systematic framework to elucidate intricate synthesis–structure–property relationships, enabling a holistic understanding for rational material design. Crucially, this work distinguishes itself by distilling concrete design principles for Na‐halide conductors, providing quantitative insights into humidity stability, and establishing in‐depth correlations between interphases/degradation modes and full‐cell metrics. Moreover, a practical assessment of key performance metrics (energy density, power density, cycle life) and design guidance is presented. Finally, we pinpoint critical barriers (moisture sensitivity, anode incompatibility, and conductivity limitations) and outline a roadmap emphasizing compositional design, interface engineering, manufacturing scalability, machine learning, operando characterization, and standardized metrics to accelerate commercialization.
Phase 1b/2 KEYMAKER-U03 substudy 03C of belzutifan plus zanzalintinib or belzutifan monotherapy for recurrent clear cell renal cell carcinoma during or after anti–PD-(L)1 therapy.
TPS579 Background: Adjuvant pembrolizumab is a standard of care for patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence post-surgery. Novel treatment approaches for recurrence after adjuvant anti–PD-(L)1 therapy are needed. Substudy 03C of the open-label, phase 1b/2 KEYMAKER-U03 trial (NCT07049926) is designed to evaluate the safety and efficacy of belzutifan plus zanzalintinib or belzutifan monotherapy for recurrent RCC during or after anti–PD-(L)1 adjuvant therapy. Methods: Eligible participants (≥18 years) must have histologically confirmed unresectable locally advanced or metastatic clear cell RCC, measurable disease per RECIST v1.1 as assessed by investigator and verified by blinded independent central review (BICR), and Karnofsky performance status of ≥70%. The study will comprise a safety lead-in phase followed by an efficacy phase. In the safety-lead in, prior immunotherapy and a maximum of 1 prior vascular endothelial growth factor tyrosine kinase inhibitor for metastatic disease is permitted. Participants in the efficacy phase must not have received prior systemic treatment except for adjuvant anti–PD-(L)1 therapy and had recurrence during or ≤24 months after the last dose of adjuvant anti–PD-(L)1 therapy. Treatment will consist of belzutifan plus zanzalintinib (arm C1) or belzutifan monotherapy (arm C2). Additional treatment arms may be added on a rolling basis. In the safety lead-in phase, at least 10 participants will receive belzutifan 120 mg orally once daily plus zanzalintinib 60 mg (arm C1a) or 100 mg (arm C1b) orally once daily. The primary objective of the safety lead-in phase is to establish the recommended phase 2 dose (RP2D). In the efficacy phase, approximately 120 participants will be randomly assigned 2:1 to receive belzutifan plus zanzalintinib at the RP2D or belzutifan 120 mg orally once daily. Primary end points of the efficacy phase are safety and objective response rate per RECIST v1.1 by BICR. Secondary end points are clinical benefit rate, duration of response and progression-free survival per RECIST v1.1 by BICR, and overall survival. No hypothesis testing and no formal comparisons are planned. This study is currently enrolling. Clinical trial information: NCT07049926 .
Real-world (rw) first-line (1L) treatment (tx) patterns and overall survival (OS) in patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC) and frailty or comorbidities.
666 Background: Enfortumab vedotin + pembrolizumab (EV+P) is now the preferred 1L tx for la/mUC, showing superior OS vs platinum-based chemotherapy (PBC) in the pivotal EV-302 trial. EV is associated with distinct adverse events, and clinical factors have been proposed to identify pts who are potentially EV unsuitable (EVU) to minimize serious toxicity. This study analyzed rw txs of pts with frailty or certain comorbidities ineligible for EV-302. Methods: This retrospective cohort study analyzed data from pts diagnosed with la/mUC between Jul 1, 2020, and Aug 31, 2024 using the Flatiron Health Research Database. Based on proposed criteria, pts were divided into 2 hypothetical/mutually exclusive cohorts: EVU and EV suitable (EVS), and within each group, by 1L tx status (treated, untreated) and tx choice. EVU was defined as having ≥1 of these factors: hemoglobin A1c ≥11% or blood glucose > 200 mg/dL in 2 consecutive samples within 1 week; creatinine clearance or glomerular filtration rate ≤20 mL/min; liver impairment grade ≥2; ECOG PS ≥3; neuropathy; corneal or retinal abnormality. EVU prevalence, pt characteristics at index, and tx patterns were summarized with descriptive statistics. Kaplan-Meier method was used to estimate rwOS from index date (treated: 1L tx date; untreated: la/mUC diagnosis date) to death. Cox proportional hazards regression was used to compare rwOS between treated EVU and EVS pts. Results: This study included 3500 pts with la/mUC (median age, 74 years; male, 72%; ECOG PS 0-1, 55%; bladder as primary site, 77%; median follow-up, 7 mos). A total of 748 (28%) of pts were identified as EVU, of whom 24% were untreated. The most common EVU factor was neuropathy (14%). Median rwOS was shorter in EVU vs EVS untreated (2.4 vs 7.0 mos) and treated pts (9.3 vs 17.0 mos) regardless of 1L tx. Immunotherapy monotherapy (IO mono) was the most common agent in EVU (38%). In the treated EVU group, rwOS was not significantly different between EV+P, PBC, or IO mono groups (Table). EVU vs EVS pts had 67% higher risk of death. Conclusions: In this study, 28% of pts with la/mUC in rw practice were EVU, representing a population typically excluded from clinical trials, and 24% were untreated. In pts treated with standard therapies, rwOS was shorter in EVU vs EVS. As tx outcomes did not significantly differ in the EVU group, shared tx decisions that incorporate various factors, including patient goals and preferences, tx tolerance, financial issues and quality of life in the context of advanced disease, has become increasingly important for this vulnerable group. Treated EVU n (%) EVU rwOS, median, mos Adjusted HR (95% CI); P value) Overall 748 (28) 9.3 Ref EVS: 171.67 (1.50-1.87); p<.001 EV+P 90 (12) Not reached Ref PBC 257 (34) 10.9 1.14 (0.70-1.86); p=0.60 IO mono 284 (38) 6.4 1.60 (0.99-2.58); p=0.06 Other tx 117 (16) 8.8 1.57 (0.95-2.59); p=0.08
Real-world efficacy and safety of tivozanib in metastatic renal cell carcinoma in a diverse cohort: A multicenter study from the City of Hope enterprise.
477 Background: Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) approved refractory metastatic renal cell carcinoma (mRCC) after 2 prior therapies. However, the safety and efficacy of tivozanib in real-world settings of patients with mRCC in non-clinical trial settings are limited. Methods: We conducted a multi-center, retrospective study of tivozanib-treated patients with mRCC from the City of Hope Cancer Center nationwide. Clinical information and disease characteristics were recorded using electronic medical records. Data were used to analyze objective response rates (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were also recorded and graded per CTCAE v5.0. Results: Among 123 patients with mRCC treated with tivozanib, 83 had adequate follow up data and were included in this analysis. Among this cohort, 72% were male, and 18% were Hispanic. The median age at the start of tivozanib was 66 years (range: 29-85). Clear cell histology was the most common (96%), with non-clear cell histology representing 4% of patients. Sarcomatoid features were present in 16% of patients. At the start of therapy, the most common metastatic sites included lungs (81%), lymph nodes (46%), liver (37%), and bone (37%). 93% of patients previously had a nephrectomy, of whom 25% had prior adjuvant therapy. The median number of lines of therapy in a metastatic setting prior to tivozanib was 3 (range: 0-8). Among the 75 patients with available imaging, the ORR was 15% (11/75) with 1 complete response observed. The DCR rate was 48%. The median OS was 15.1 months (95% CI, 11.9-NE). The median PFS was 3.6 months (95% CI, 3.0-4.9). 87% of patients experienced any all-grade AE. The most common all-grade AEs were hypertension (36%), anemia (35%), hypothyroidism (31%), diarrhea (22%), and fatigue (19%). Common grade 3-5 AEs included fatigue (33%), diarrhea (8%), and hand-foot syndrome (8%). Treatment interruption and dose reduction occurred in 18% and 28% of patients, respectively. Six patients (7%) discontinued therapy due to an AE, among which fatigue (2%) was the most common AE leading to discontinuation. Conclusions: In this notably diverse cohort (18% Hispanic) of heavily pretreated patients with mRCC and frequent rates of visceral disease, tivozanib demonstrated clinical efficacy in this population. The toxicity profile remained largely consistent with prior experiences.
Effect of enzalutamide and bipolar androgen therapy on clonal hematopoiesis and clinical outcomes among men with metastatic castration resistant prostate cancer.
229 Background: Clonal hematopoiesis (CH) is frequently found in men with advanced prostate cancer and is associated with prior radiation, PARP inhibitors, and radioligand therapy. The effect of hormonal therapies on CH, the prognostic significance, and association with androgen receptor (AR) alterations in prostate cancer is not well established. Methods: This is a secondary analysis of the TRANSFORMER clinical trial (NCT02286921). 195 men with metastatic castration resistant prostate cancer (mCRPC) were randomly assigned 1:1 to enzalutamide or bipolar androgen therapy (BAT). Only patients with paired samples (baseline and 3-month) were included in this study. The presence of CH was assessed from leukocytes using an ultra-deep duplex sequencing targeting 49 genes most commonly mutated in CH and myeloid malignancies. To minimize false positive results, our initial filtering strategy included only variants present at any timepoint at VAF ≥ 1%. The presence of the same variant at other timepoint was confirmed manually in VCF or BAM files. Results: 157 patients with paired samples were included and had more favorable outcomes than those who did not have paired samples. CH was detected in 84 (54%) patients and most (n=42) had a single CH clone. Mutations in DNMT3A (n=38), PPM1 D (n=18), TET2 (n=18), ASXL 1 (n=9), and TP53 (n=8) were the most common. There was no difference in the presence of baseline CH by treatment arm (55% in BAT arm and 53% in enza arm; P=0.8). Those with CH were older (median age 74 vs 69, P<0.01) and had poorer functional status (ECOG >0 64% compared to 36%, P=0.05). There was no significant difference in the progression or development of CH over 3-months (P=0.6) and no association with the presence of AR alterations at baseline. After adjusting for age, there was no difference in overall survival between those with or without CH at baseline for the cohort overall (HR 1.41, 0.88-2.25; P=0.15). However, among those who received BAT, either as initial therapy or crossover, CH at baseline was associated with a higher risk of death (HR 1.87, 95% CI 1.05 – 3.32; P=0.34) after adjusting for age and ECOG performance status at baseline. Conclusions: Short term treatment with enzalutamide or BAT do not influence CH dynamics in men with mCRPC. CH was associated with poorer prognosis among those who received BAT and may help identify patients less likely to benefit from BAT therapy.
Engineering Unequal Antipolar Displacement in Ferromagnetic Layered Oxide Heterostructures
Abstract Heterostructure engineering provides a versatile route for tailoring emergent functionalities that are often difficult to realize in single‐phase materials. In this work, the focus is on superlattices composed of the insulating and ferromagnetic double perovskites La 2 NiMnO 6 and Sm 2 NiMnO 6 , which constitute an intriguing model system. These layered structures are predicted to feature unequal antipolar displacements of the La and Sm ions; when combined with odd periodicity stacking, this structural motif is expected to give rise to polar behavior. The respective superlattices are grown with atomic precision and display robust ferromagnetism, as confirmed by in‐house magnetometry and synchrotron measurements. Scanning transmission electron microscopy combined with first‐principles calculations confirms the presence of the predicted unequal antipolar displacements, paving the way for the realization of hybrid improper ferroelectricity in such oxide heterostructures.
Digital monitoring of self-reported symptoms by patients treated with cabozantinib plus nivolumab for advanced clear-cell renal carcinoma (CANIQOL).
TPS570 Background: Cabozantinib plus nivolumab is a first-line standard treatment for advanced clear-cell renal cell carcinoma (RCC) based on the pivotal CheckMate 9ER trial (Motzer, Lancet Oncol 2022). However, clinical trial populations usually differ from real-life settings, and physician-reported adverse events (AEs) often underestimate symptom burden. Remote Patient Monitoring (RPM) of self-reported outcomes (PROs) can improve management of treatment-related toxicities and adherence. Methods: CANIQOL is a French prospective, multicenter, real-life, single-arm phase IV study evaluating the impact of RPM of self-reported symptoms on treatment management in patients (pts) receiving cabozantinib (40 mg PO daily) and nivolumab (240 mg IV q2w or 480 mg IV q4w) for advanced clear-cell RCC. Pts will report weekly PRO-CTCAE data using the RPM Cureety platform up to 6 months after start of the combined treatment. The RPM solution automatically generates alerts for the healthcare team, allowing adjustments for unplanned clinical actions and optimizing treatments management. This trial aims to assess the impact of RPM of self-reported symptoms on treatment management adjustments in pts receiving cabozantinib plus nivolumab for advanced RCC in real-life settings. The primary endpoint is the rate of pts with adjustment in treatment management (unplanned consultation, phone follow-up, advice, treatment discontinuation, hospitalization) within 3 months after combination initiation. Secondary endpoints include the evolution of self-reported side effects (PRO-CTCAE), fatigue (FACIT-F), quality of life (FKSI-10), anxiety/depression (HADS), the satisfaction regarding RPM (F-SUS), and the characterization of alerts. Duration of treatment, adherence to the oral treatment at 3 and 6 months (Girerd), and clinical outcomes (RECIST 1.1, objective response rate at 3 and 6 months, IMDC subgroup analysis) will also be assessed. Assuming the rate of adjustment of treatment management within 3 months after the combination start is around 25%, 70 assessable pts are required to estimate this rate with a 95% confidence interval (CI) of width 20%. We plan to enroll 83 pts to anticipate 15% of non-assessable pts, over 36 months of inclusion. The first patient was enrolled in October 2025. Follow-up is 6 months per patient. CANIQOL will provide real-world evidence on feasibility and clinical utility of RPM of PRO (side effects and quality of life) in pts receiving cabozantinib plus nivolumab for advanced RCC, assessing its impact on toxicity management, adherence, and quality of life. Trial registration: NCT07028125. Sponsor: Centre François Baclesse, Caen, France. Funding: IPSEN; logistical support – Cureety. Clinical trial information: NCT07028125 .
Use of genomic dedifferentiation signature to predict clinical outcomes with doublet vs triplet therapy in the phase III COSMIC-313 trial.
523 Background: The Genomic Dedifferentiation Signature (GDS) has previously been shown to differentiate clinical outcomes to immune checkpoint inhibitor (ICI)-based combinations and anti-VEGFR monotherapy in patients with metastatic renal cell carcinoma (mRCC; Salgia et al. Cancer Cell. 2025). COSMIC-313 is a randomized phase III trial evaluating cabozantinib-nivolumab-ipilimumab (C/N/I) vs nivolumab-ipilimumab (N/I) in mRCC. Here, we evaluated the prognostic and predictive utility of the GDS in COSMIC-313. Methods: Bulk transcriptomic profiling (RNAseq) was obtained for 398 patients (pts) enrolled in COSMIC-313 and used to assign GDS scores by single sample gene set enrichment analysis. Pts were classified as GDS high or GDS low based on median GDS expression. Clinicopathologic variables and objective response rates (ORR) were compared using Wilcoxon Rank-Sum and Fisher’s Exact Tests. Progression-free survival (PFS) and overall survival (OS) analyses employed Kaplan-Meier estimates and Cox proportional hazard models. Results: In the ITT population (both trial arms), GDS scores were significantly enriched in pts with IMDC poor vs intermediate risk (p = 0.0097) and in those with vs without sarcomatoid features (p = 2.2x10 -5 ). ORR did not significantly differ between GDS high and GDS low pts treated with C/N/I (48% vs. 58%; p = 0.21), though a non-significant improvement in ORR amongst GDS high vs. GDS low pts was seen with N/I (50% vs. 35%; p = 0.057). Among GDS low pts, C/N/I yielded a significantly higher ORR than N/I (58% vs. 35%; p = 0.0019), with no difference between arms in GDS high pts (48% vs. 50%; p = 0.98). PFS was not significantly different between GDS high and GDS low , pts in the ITT, C/N/I, and N/I cohorts, with HRs of 1.0 (95% CI: 0.81–1.3, p = 0.75), 1.2 (95% CI: 0.81–1.7, p = 0.4), and 0.88 (95% CI: 0.62–1.3, p = 0.48), respectively. OS was significantly worse in GDS high pts in the ITT population (HR: 1.3, 95% CI: 1.0–1.8, p = 0.043), with non-significant differences in the C/N/I and N/I arms (HRs: 1.4 and 1.2, p = 0.14 and 0.36, respectively). Conclusions: Front-line management of mRCC currently relies on ICI-ICI and VEGFR-ICI combinations, though no biomarker yet exists to determine which patients differentially benefit from each strategy. These results not only reinforce the negative prognostic capacity of the GDS, but also support the potential predictive utility of the GDS, suggesting that GDS low patients disproportionately benefit from the addition of VEGFR-directed agents to ICI-based therapy for the first-line treatment of mRCC.
Urologist-level variation in androgen deprivation therapy intensification in patients with metastatic hormone-sensitive prostate cancer: A retrospective, population-based cohort study in Ontario, Canada.
59 Background: Guidelines recommend androgen-deprivation therapy (ADT) intensification for individuals with de novo metastatic hormone-sensitive prostate cancer (mHSPC). Urologists frequently initiate ADT and influence early treatment decisions, yet the extent to which variation in intensification reflects physician practice versus patient factors remains unclear. Methods: We identified all patients diagnosed with de novo mHSPC and initiated on ADT by urologists in Ontario, Canada (2015–2022). For each urologist, we calculated the annual number and proportion of patients receiving treatment intensification. Intensification was attributed to the urologist if they either prescribed it directly or referred the patient to another specialist who subsequently intensified therapy, to capture appropriate referral practices. Multilevel logistic regression models clustered at the physician level were fit, and the variance partition coefficient (VPC) was used to estimate the proportion of variation in treatment intensification attributable to physician-level effects, adjusting for patient- and physician-level covariates. Caterpillar plots were constructed to visualize physician-specific random intercepts for ADT intensification. Results: The analytic cohort included 332 urologists treating 3871 patients. Overall, physicians intensified therapy for an average of 23% of their patients (median 21%, IQR 0–33%). Descriptive yearly analyses showed a steady rise in intensification: mean proportion per urologist increased from 15% in 2016 to 59% in 2022. In the complete cohort, physician-level clustering explained only 4.6% of variation in treatment intensification, with most variation attributable to patient characteristics. In a contemporary sub-cohort (2020–2022), physician clustering explained a somewhat larger share (VPC 7.8–8.5%). There was wide heterogeneity in physician-specific intercepts, with most urologists clustering around the null effect but a long tail of higher-intensifying physicians. Conclusions: From 2015–2022, ADT intensification among patients initiated on therapy by urologists rose substantially. Most variation was explained by patient factors, though physician influence became more apparent in later years as early adopters drove uptake. These findings imply that accelerating equitable adoption of intensification may require system-level supports and targeted efforts to bring later adopters in line with evolving standards.
Epigenomic alterations associated with androgen receptor pathway inhibitor response in metastatic castration-resistant prostate cancer.
220 Background: Androgen receptor pathway inhibitors (ARPIs) improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). However, some patients fail to respond, and resistance frequently emerges. While AR amplification and mutation are established genetic contributors to heterogeneous therapy response, the role of epigenetic mechanisms in modulating ARPI response remains poorly understood. In this study, we evaluated methylation features associated with duration of ARPI response in mCRPC and developed a predictive classifier to identify patients likely to progress within one year of treatment. Methods: We analyzed matched DNA methylation, genomic, and transcriptomic profiles from 117 mCRPC biopsies in the West Coast Dream Team cohort. Global methylation patterns were assessed by identifying highly variable recurrent hypomethylated regions, followed by unsupervised hierarchical clustering. In ARPI-naïve, AR -positive tumors (n = 36), differential methylation analysis was performed between patients in the top and bottom quartiles of radiographic progression-free survival (rPFS; n = 18 total) to maximize contrast in treatment response. Matched transcriptomic data were integrated to identify methylation changes correlated with gene expression. We then trained a random forest classifier using methylation profiles from all 36 samples to predict patients who would experience radiographic progression within one year of ARPI initiation. Results: Hierarchical clustering revealed global methylation patterns segregated by molecular subtype, with neuroendocrine tumors and those exhibiting a CpG methylator phenotype forming a distinct cluster. In multivariable Cox models adjusted for AR and AR upstream enhancer copy number, methylation of the downstream regulatory region was associated with longer rPFS (per 1%-unit increase: HR = 0.96, 95% CI: 0.93–0.99, p = 0.024). When dichotomized at the median, patients with high methylation showed significantly improved rPFS compared to those with low methylation (HR = 0.18, 95% CI: 0.07–0.44, p = 0.00023). Importantly, we have previously shown this region undergoes DNA amplification upon ARPI progression (Zhu et al., JCI 2024). Our random forest classifier distinguished good vs. poor outcomes on ARPI, achieving an F1 score of 0.86. Conclusions: We identified methylation changes and genomic regions, including a putative enhancer downstream of AR , associated with ARPI response. We also developed a predictive classifier that accurately identified patients who progressed more rapidly on ARPI therapy. Validation experiments for this classifier and association analyses are ongoing. These findings highlight a novel link between epigenomic alterations and ARPI response and support the development of methylation-based biomarkers for patient stratification in mCRPC.
Guest‐Induced Activation of Multicolor Photoluminescence in Naphthalene Bisimide Liquid Crystals
ABSTRACT Achieving color‐ and lifetime‐tunable emission in processable materials remains challenging, as most of the available advanced materials systems exist only in impractical solutions or hard‐to‐process crystals. Liquid crystals (LCs) represent a promising platform due to their processability, though previous work has mainly controlled emission color by external fluorophore doping. In this work, we present a supramolecular strategy to activate and tune both photoluminescence (PL) color and lifetime in naphthalene bisimide (NBI) LCs by embedding electron‐rich guests. The electron‐deficient NBIs form columnar hexagonal mesophases stabilized by nanosegregation of aromatic cores and aliphatic side chains, providing a suitable environment for charge‐transfer (CT) interactions. Incorporating electron‐rich polycyclic aromatics, carbazole derivatives, or square‐planar Pt(II) complexes yields emissive CT states with tunable emission from visible to near‐infrared (511–685 nm), covering short‐lived fluorescence to long‐lived delayed luminescence of coexisting thermally activated delayed fluorescence (TADF) and room‐temperature phosphorescence (RTP). Co‐assembling two complementary NBI hosts with one guest enables an energy‐transfer cascade that simultaneously supports green and red dual emission of fluorescence and TADF. This additive‐induced activation and host‐mixing approach greatly broadens the luminescence range accessible in LCs, combining tunable photophysical properties with intrinsic processability for next‐generation optical encoding and security labeling technologies.
Patient and physician preferences for treatment in advanced renal cell carcinoma (PEAR): An international, multi-centre discrete choice experiment (DCE).
443 Background: There are several treatment options for advanced renal cell carcinoma (aRCC) but limited evidence for treatment preferences in Asia-Pacific populations. This study evaluates patient and physician preferences for first-line aRCC treatment. Methods: A discrete choice experiment was conducted among 81 patients with aRCC, both clear cell and non–clear cell subtypes, and among 75 physicians with ≥5 years of experience managing aRCC in Australia, Hong Kong, and South Korea. Seven key efficacy and safety attributes were short-listed based on literature reviews, qualitative interviews and expert consultation: progression-free survival (PFS), overall survival (OS) rate at 3 years, complete response (CR) rate, duration of response (DoR), hospitalization for side effects, grade 3 or 4 lung inflammation, and grade 3 or 4 gastrointestinal (GI) perforation. Preference weights for attribute levels were estimated using a mixed logit regression model, and the relative importance score (out of 100%) for each attribute was calculated. Maximum acceptable risk (MAR), the additional adverse event (AE) risk patients and physicians would accept for incremental efficacy, was derived by dividing the benefit preference difference by the risk preference difference. Results: The median age of patients was 63 (interquartile range 55-68) years. All patients were receiving systemic therapy for aRCC at the time of survey; 73% reported treatment-related AEs. Among physicians, 55% had at least 16 years of experience managing aRCC. Patients placed the greatest importance on grade 3 or 4 lung inflammation (23%), followed by DoR (19%), OS rate at 3 years (18%), and CR rate (17%). PFS ranked the lowest importance (2%) among patients. In contrast, physicians placed the highest importance on OS rate at 3 years (29%), DoR (26%) and CR rate (15%), while PFS (14%) and AEs were relatively less influential. Grade 3 or 4 lung inflammation was given the lowest importance (2%) among physicians. MAR analysis indicated physicians were more willing to accept substantially higher lung inflammation risk for efficacy gains than patients but were more cautious about GI perforation. Conclusions: Both patients and physicians valued longer OS, higher CR, and longer DoR, but their benefit-risk trade-offs differed. Physicians prioritized efficacy parameters, and tolerated higher risk for lung inflammation, possibly due to their clinical experience in managing this AE, whereas patients were more risk-sensitive. Relative importance of attributes (%). Attribute Patients- Relative importance (%) Physicians- Relative importance (%) Inflammation of lung grade 3/4 23 2 DoR 19 26 OS rate at 3 years 18 29 CR rate 17 15 GI perforation grade 3/4 13 7 Chance of admission due to treatment S/E 8 7 PFS 2 14
Patient-reported outcomes in resected renal cell carcinoma: Active monitoring vs. durvalumab and tremelimumab in the RAMPART trial.
420 Background: Durvalumab + Tremelimumab (DT) given over one year (with Tremelimumab at Day 1 and Week 4), improved disease-free survival in patients with resected renal cell carcinoma at intermediate/high risk of relapse in the RAMPART trial. Evaluating quality of life (QoL) is key to understanding the overall impact of treatment. The primary QoL outcome in RAMPART was the change in overall health and quality of life (OHQL) from baseline to 15 months, and no difference was observed between participants assigned DT versus active monitoring (AM). We now present detailed QoL outcomes from the comparison of DT versus AM. Methods: This analysis includes participants randomly assigned (3:2) to AM or DT, who participated in the optional QoL sub study and completed the EORTC QLQ-C30 at baseline plus ≥1 follow-up (Week 16 or Month 15). Outcomes assessed include OHQL (Q29–30) at Week 16, five functional domains, eight symptom domains, and financial difficulties at both Week 16 and Month 15. Clinically meaningful differences (CMD) were predefined by item and scale. Results: A total of 254 participants were included (150 AM, 104 DT). Baseline characteristics were similar, with minor differences in sex distribution (male: 68% AM vs 74% DT) and performance status (PS 0: 80% AM vs 88% DT; PS 1: 20% AM vs 12% DT). At week 16, scores were worse in those assigned DT rather than AM for OHQL (–8.1; 95% CI: –12.8 to –3.4; p = 0.0008), role function (–6.0; 95% CI: –11.9 to –0.2; p = 0.04), fatigue (8.4; 95% CI: 3.2 to 13.7; p = 0.002), and insomnia (8.9; 95% CI: 1.3 to 16.4; p = 0.02). All exceeded the minimum threshold for a small CMD (CMD: OHQL 4–<10, role function 6–<19, fatigue 5–<13, insomnia 4–<13). At month 15, scores were worse in those assigned DT rather than AM for pain (8.8; 95% CI: 1.4 to 16.2; p = 0.02) and cognitive function (–5.8; 95% CI: –11.5 to –0.2; p = 0.04), both exceeding the predefined thresholds for a small CMD (CMD: pain 6–<13, cognitive function 3–<9). No other domains, symptom scales, or single items met both statistical and clinical thresholds at either timepoint. Conclusions: DT was associated with worse QoL at week 16 than AM, particularly in OHQL, role function, fatigue and sleep, all reaching clinically meaningful thresholds. These effects appeared to improve by month 15. At month 15, pain and cognitive function were worse in the DT arm. These findings should be considered alongside the DFS benefit when discussing treatment options with patients. Clinical trial information: NCT03288532 .
Real-world (rw) safety of first-line (1L) systemic regimens for locally advanced or metastatic urothelial cancer (la/mUC): Updated results from the ELEVATE UC-I study.
680 Background: The rw safety of contemporary 1L treatment (tx) regimens for la/mUC has been previously reported. This updated analysis, including additional patients (pts) and an extended study period, provides a more comprehensive assessment of the incidence of rw tx-emergent adverse events (rwTEAEs). Methods: This retrospective cohort study identified adult pts diagnosed with la/mUC in the US from Jan 2020 to Jun 2024 using the Premier PINC AI Healthcare Database. Cohorts were based on 1L tx: enfortumab vedotin + pembrolizumab (EV + P), cisplatin- or carboplatin-based chemotherapy (± avelumab maintenance), and immune checkpoint inhibitor (ICI) monotherapy. To adjust for 1L tx exposure, rwTEAEs were calculated as the number of events per 1,000 person-days on tx. Analyses were descriptive. Results: 7,984 pts were included. Median age was 72 years (IQR, 64-78), 73% of pts were male, and 83% were White; mean Charlson-Deyo Comorbidity Index was 5.02 (SD, 3.40). Median follow-up was 140 days (IQR, 92-175). Most frequent rwTEAEs included infusion-related reactions (53%), anemia (33%), fatigue (20%), asthenia (20%), and nausea/vomiting (18%). Incidence of specific rwTEAEs of interest varied across 1L tx (Table). ICI monotherapy had the lowest overall rwTEAE rates, while platinum-based chemotherapies demonstrated higher rates of hematologic toxicities. EV + P had higher rates of fatigue, peripheral neuropathy, and rash. Conclusions: This expanded analysis from the ELEVATE UC-I study enhances understanding of the rw safety of contemporary 1L txs for la/mUC, highlighting distinct toxicity profiles. Findings may inform pt counseling, proactive mitigation of tx toxicity, and shared decision-making. Future research may further adjust rwTEAE estimates for clinicodemographic and disease characteristics and evaluate the associated healthcare resource utilization and economic impacts. Incidence of specific rwTEAEs of interest (rate per 1000-person days on tx) overall and by 1L tx regimen for la/mUC. 1L Tx Overall cohort(n=7,984) EV + P (n=343) Cisplatin-based chemo + avelumab (n=223) Cisplatin-based chemo alone (n=3,608) Carboplatin-based chemo + avelumab (n=201) Carboplatin-based chemo alone (n=1,250) ICI monotherapy (n=2,359) Median follow-up, days 140 147 298 139 278 112 154 Incidence rate (no. of events per 1,000 person-days on tx) Fatigue 2.38 3.87 2.41 2.21 2.90 2.16 2.37 Neutropenia 2.05 0.54 3.11 3.45 2.41 3.70 0.20 Diarrhea 0.75 1.23 0.49 0.74 0.55 0.68 0.80 Chemotherapy-induced peripheral neuropathy 0.67 2.52 1.69 0.65 0.57 0.62 0.36 Decreased appetite 0.43 1.06 0.33 0.40 0.62 0.67 0.32 Rash 0.40 1.91 0.15 0.20 0.30 0.18 0.54 Hyperglycemia 0.23 0.37 0.63 0.23 0.31 0.21 0.14 Chemo, chemotherapy.
Systemic therapy combined with radiotherapy versus systemic therapy alone for oligometastatic kidney cancer (STROKER): A multicenter, randomized controlled phase III trial.
TPS576 Background: The value of local therapy for oligometastatic renal cell carcinoma (RCC) remains undefined. Several single-arm phase II studies suggest that stereotactic body radiotherapy (SBRT) may delay disease progression 1,2 . In our previous phase II trial, SBRT + sunitinib improved response and PFS versus sunitinib alone 3 . However, these studies are constrained by small sample sizes and phase II methodology, limiting the robustness and generalizability of their conclusions. The phase III STROKER trial was therefore designed to verify whether combining SBRT with systemic therapy offers additional benefit over systemic therapy alone in patients with oligometastatic RCC. Methods: This open-label, multicenter, randomized phase III trial enrolls patients with oligometastatic RCC (≤5 lesions), an ECOG performance status of 0 to 2. Patients must have received definitive treatment of the primary tumor, and no more than two prior lines of systemic therapy. Key exclusion criteria include intracranial metastases, prior high-dose irradiation to target lesions, or target lesions unamenable to SBRT. Eligible patients are randomized in a 1:1 ratio to receive systemic therapy alone, consisting of tyrosine kinase inhibitors (TKIs) or TKIs combined with immune checkpoint inhibitors (ICIs), versus SBRT+ systemic therapy. The primary endpoint is progression-free survival (PFS). Based on existing clinical data, the median PFS is estimated at 12 months in the control arm and expected to reach 18 months in the experimental arm. With a two-sided α of 0.05 and 80% power, a total of 113 patients per arm is required. Accounting for a 10% dropout rate, 126 patients per arm (252 total) will be enrolled over 4 years with a 2-year follow-up. One interim analysis will be conducted after 60% of the total sample size has been accrued, applying the O'Brien–Fleming α-spendin g function for type I error adjustment. Secondary endpoints include overall survival, cancer-specific survival, local control, post-treatment PFS, PFS2, adverse events, and Health-related quality of life as measured with NFKSI-19 and EQ-5D-5L. The trial has been open for patient enrollment since December 2024. References: 1. Tang C, Msaouel P, Hara K, et al. Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial. Lancet Oncol. 2021;22. 2. Siva S, Bressel M, Wood ST, et al. Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-The RAPPORT Trial. Eur Urol. 2022;81. 3. Liu Y, Wei W, Zhang Z, et al. Preliminary results from a phase II study comparing sunitinib alone or with stereotactic body radiotherapy (SBRT) for newly diagnosed oligometastatic renal cell carcinoma. J Clin Oncol. 2023;41. Clinical trial information: NCT06726421 .