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Conventional-dose chemotherapy as first salvage in germ cell tumors: Outcomes from an Ibero-American multi-institutional cohort.
597 Background: In relapsed or refractory germ cell tumors, two salvage strategies are commonly used: conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) with autologous stem cell transplantation. Current evidence remains insufficient to define the optimal approach, and the predictive value of existing risk models has not been prospectively validated. This study describes oncological outcomes according to the International Prognostic Factors Study Group (IPFSG) classification in patients receiving CDCT as first salvage therapy in a multi-institutional Ibero-American cohort (Argentina and Spain), where access to HDCT is limited. Methods: We conducted a retrospective, multi-institutional cohort study including patients with germ cell tumors treated between 2009 and 2023. All received CDCT as first-line salvage therapy. Progression-free survival (PFS) and overall survival (OS) were evaluated according to IPFSG classification. Time-to-event outcomes were analyzed using Cox regression, adjusting for potential confounders. Results: We included 91 patients with a median follow-up of 21 months (IQR 6.7–51). Among them, 40 (47%) achieved complete or partial response with negative markers. Progression-free survival was significantly poorer in patients with high to very high Beyer classification than in those with very low, low, or intermediate risk (HR 2.17, 95% CI 1.07–4.49, p = 0.036). Similarly, overall survival was worse in the high to very high group (HR 2.46, 95% CI 1.22–4.90, p = 0.008). Median PFS and OS for patients refractory to first-line treatment were 11 and 17 months, respectively, versus 45 and 70 months for non-refractory patients. Conclusions: While CDCT remains a feasible option for salvage therapy in settings with limited HDCT access, prospective studies are needed to refine risk models and optimize strategies. CDCT appears appropriate for non-refractory and low-risk patients; however, alternative or intensified therapies are required for those with higher risk. Baseline characteristics (n = 91). Primary site Testis 79 (87%) Histology Non seminoma 74 (83%) Non pulmonary visceral metastasis Yes 20 (23%) Refractory to first line 1 Yes 44 (48,3%) IPFSG 2 Very Low 10 (11%) Low 9 (9,9%) Intermediate 31 (34,1%) High 30 (33%) Very High 10 (11%) Chemotherapy regimen TIP 3 72 (79%) 1 Patients were considered refractory to first-line therapy if the PFI was <6 months from the start of treatment. 2 International Prognostic Factors Study Group. 3 Paclitaxel, Ifosfamide, Cisplatin.
Unveiling sex-based disparities in advanced renal cell carcinoma: Insights from the real-world Meet-URO33 (REGAL) study.
526 Background: Sex-related biological differences may affect cancer immunity and outcomes with immune checkpoint inhibitors (ICIs). With conflicting evidence, female sex has been associated with higher rates of sarcomatoid dedifferentiation, worse OS in metastatic RCC, higher-grade toxicities, and greater steroid use. Other analyses suggest a survival advantage for younger women compared with men, supporting a possible hormonal role with a protective effects of estrogens. Methods: Meet-URO-33 (REGAL) is a multicenter ambispective observational trial including 1560 patients with advanced RCC treated with 1st line systemic therapy after January 2021. Data from electronic medical records included demographics, histology, metastatic sites, treatment, and response according to RECIST 1.1. Clinical-pathological features, hematological parameters (including NLR), toxicities, and outcomes were compared by sex and by menopausal age cut-off (<50 vs ≥ 50 yrs). Results: Among 401 females (F) and 1159 males (M), F presented with worse baseline characteristics, such as ≥ 2 metastatic sites (35% vs 27%, p = 0.012), liver metastases (18% vs 11%, p = 0.002), and sarcomatoid variant (20.3% vs 14.5%, p = 0.025). F presented with lower BMI ≤ 25 kg/m2 (52% vs 43%, p = 0.008), and NLR <4 (73% vs 67%, p = 0.027). First-line treatment distribution (IO–TKI, IO–IO, or TKI monotherapy) was well balanced. Grade 3–4 immune related adverse events (irAEs) were significantly more frequent in F (35% vs 28%, p = 0.012), with no sex-related differences in the pattern of irAEs, but a greater need for steroids (18% vs 12%, p = 0.025). Discontinuation rates were similar in F and M (20.5% vs 19.3%, p = 0.63). No significant differences were observed for F in PFS (15.8 vs 18.5 months, p = 0.23) or OS (39.5 vs 41.9 months, p = 0.93). The presence of sarcomatoid features did not influence the sex–outcome interaction (p = 0.43 for OS, p = 0.95 for PFS). Stratifying outcomes by age, patients ≥ 50 years had similar results, but F < 50 years showed a markedly shorter PFS (8.5 vs 19.6 months, HR 2.02, p = 0.009). Conclusions: F presented with more adverse baseline features and higher severe toxicity rates, yet OS/PFS outcomes were similar, with unfavorable trends for F. The significantly worse PFS in younger F supports a possible hormonal influence, as the protective role of estrogens may vary before/after menopause. Higher steroid exposure, immune-related differences, and pharmacokinetics may also have contributed. The underrepresentation of F, consistent with other RCC trials, remains a limitation, reducing the reliability of subgroup analyses. These findings highlight the need to integrate sex and menopausal status into clinical practice and trial design. Dedicated translational research are essential to clarify biological and pharmacological mechanisms underlying sex-based disparities and to guide tailored strategies in advanced RCC. Clinical trial information: 33.
Fatigue Resistant Hydrogels Engineered With Twisting Hierarchical Structures
ABSTRACT Hydrogels hold significant potential for soft robotics and biomedical applications due to their high‐water content, tissue‐like softness, and biocompatibility, yet their practical utility remains limited by poor fatigue resistance during long‐term dynamic loading. Here, we present a twisting strategy that enhances hydrogel materials' mechanical durability through bioinspired torsion methodology, enabling efficient load transfer and energy dissipation. The resulting fibers exhibit improved tensile strength, stretchability, and unprecedented fatigue thresholds while maintaining structural integrity across prolonged cycling. Our strategy is also compatible with various hydrogel systems including poly(vinyl alcohol), alginate, cellulose and corresponding composite systems. This approach benefits from multiscale simulations, revealing that moderate twisting promotes uniform stress distribution through inter‐fiber sliding, while excessive twisting causes geometric locking. Proof‐of‐concept demonstrations include a frog‐tongue‐inspired actuator showing rapid yet reversible motion under high‐frequency cycling, highlighting its exceptional fatigue tolerance. This bioinspired architecture establishes a universal design paradigm for fatigue‐resistant hydrogel systems, unlocking their potential in demanding applications from implantable medical devices to adaptive soft robotics.
Evaluation of PSA decline patterns in the Chinese subgroup of LIBERTAS, a phase 3 study of apalutamide plus continuous versus intermittent androgen deprivation therapy in metastatic castration-sensitive prostate cancer.
154 Background: LIBERTAS is a global phase 3 study evaluating apalutamide (APA) plus intermittent versus continuous androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer (mCSPC). The study aims to determine reduces hot flash burden compared with APA + continuous ADT and whether APA + intermittent ADT provides noninferior radiographic progression-free survival (rPFS). Initial findings demonstrated that treatment with 6 months of APA + ADT resulted in rapid and deep PSA responses in most patients with mCSPC. This abstract presents PSA response results from patients enrolled in China. Methods: Overall, eligible mCSPC participants had ≤3 months of prior ADT, ECOG PS 0–1, and confirmed metastases by conventional or next-generation imaging. All received APA 240 mg/day + ADT during the initial 6-month treatment phase. In the main phase, 22 participants from China with PSA <0.2 ng/mL were randomized 1:1 to continuous or intermittent ADT. Primary endpoints: reduction of hot flash burden, measured by severity-adjusted hot flash score, and rPFS, measured by 18-mo event-free survival rate. Results: In total, 36 participants from China were enrolled from 8 sites, with 22 randomized to the main treatment phase. Median age was 71.0 years (range: 51–79) and median baseline PSA was 64.7 ng/mL (range: 2.6–2399.0). After 3 months of treatment with apalutamide plus ADT, 100.0% of participants achieved a ≥50% PSA decline (PSA50), 94.4% achieved a ≥90% decline (PSA90), and 30.6% achieved PSA <0.2 ng/mL (PSA0.2). Among those who completed the initial 6-month treatment phase, 100% achieved PSA50, 97.2% achieved PSA90, and 61.1% achieved PSA0.2. No new safety signals were observed in the Chinese subgroup. Conclusions: Participants enrolled in the LIBERTAS study had rapid and deep PSA responses to APA plus ADT, with patients in China having a similar rapid and deep PSA decline. The LIBERTAS results confirm the efficacy of APA + ADT in Chinese patients with mCSPC and aligned with the pivotal TITAN Phase 3. The safety profile of APA remained consistent with prior experience, supporting APA’s tolerability in this population. The LIBERTAS study remains on track for results readout in 2027. We would like to acknowledge Todd Simon for his statistical support. Clinical trial information: NCT05884398 .
Effect of programmed cell death protein ligand 1 nuclear translocation mediated by Enolase on urothelial carcinoma immune evasion.
788 Background: The efficacy of programmed death-ligand 1 (PD-L1)-based immunotherapy is limited in urothelial carcinoma (UC), one of the most aggressive solid tumors characterized by a lactic acid (LA)-enriched tumor microenvironment (TME) in favor of tumor immune evasion. In addition to protecting tumor cells from immune surveillance, PD-L1 can translocate to the nucleus and promote tumor development through diverse pathways. However, whether nuclear PD-L1 can impose an effect on LA accumulation in the TME to replenish the immune checkpoint function of membrane PD-L1 remains elusive. Methods: α-enolase (ENO1) expression in UC was analyzed via western blotting and immunohistochemistry using high throughput tissue microarray. The in vitro mechanism that ENO1 regulates PD-L1 nuclear translocation and subsequent transcriptional activation of monocarboxylate transporter 4 (MCT4) expression to facilitate LA secretion was investigated using immunofluorescence, nuclear cytoplasm separation, western blotting, Immunoprecipitation, mass spectrometry, GST pull-down assay, T cell cytotoxicity assay, and Seahorse experiment. In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with subcutaneous and orthotopic tumors, employed neutralizing antibody against CD8 and PD-1. Survival curves were constructed for the orthotopic model. Immunohistochemistry and flow cytometry analyzed local and systemic alterations in the tumor microenvironment (TME). Results: ENO1 physically interacts with PD-L1 and transports PD-L1 to the nucleus by recruiting Importin β (KPNB1) independently of its metabolic activity. Mutation of Leu432 and Lys434 in the C-terminal domain of ENO1 abrogates its binding to KPNB1 and subsequent PD-L1 nuclear import. Nuclear PD-L1 further transcriptionally upregulates MCT4 expression to facilitate LA secretion to the TME. Finally, targeting ENO1-mediated PD-L1 nuclear translocation alleviates LA accumulation in the TME, reinvigorates CD8+ T cells-mediated antitumor immune response, and potentiates anti-PD-L1 immunotherapy in UC. Conclusions: ENO1 is a feasible target for blocking PD-L1 nuclear translocation, thereby enhancing the efficacy of immunotherapy in UC.
Trends in prostate cancer mortality after the 2012 USPSTF PSA guideline: Comparisons with kidney cancer and racial disparities.
325 Background: In 2012, the USPSTF issued a Grade D recommendation against PSA-based screening for prostate cancer. While intended to reduce overdiagnosis, the change raised concerns about unintended effects on mortality. We evaluated national mortality trends to determine whether prostate cancer mortality declines stalled post-2012 and whether patterns diverged from kidney cancer, a comparator unaffected by PSA screening. Methods: Mortality data for U.S. men aged 45–85 years (1999–2020) were obtained from CDC WONDER. Prostate cancer deaths (ICD-10 C61) and kidney cancer deaths (C64–C65) were analyzed. Age-adjusted mortality rates (per 100,000) were stratified by race/ethnicity and age (50–69, the screening-eligible group, vs ≥70). Joinpoint regression estimated APC with 95% CIs; interrupted time-series models assessed slope changes. Results: Prostate cancer mortality declined significantly from 1999 - 2014 (APC - 3.51%, 95% CI - 3.61 to - 3.43). After the 2012 USPSTF recommendation, declines slowed: mortality plateaued in 2014–2018 (APC –0.69%, 95% CI - 1.15 to 0.00) and then increased in 2018 - 2020 (APC +2.63%, 95% CI - 1.12 to +7.06). This lag is consistent with delayed effects of reduced screening. Kidney cancer mortality showed no 2012-specific inflection, declining overall (2001 - 2015 APC - 0.74%, 95% CI - 0.76 to - 0.59) with a steeper drop in 2015 - 2018 and only a modest, nonsignificant uptick in 2018 - 2020, supporting its role as a negative control. Decline attenuation was most marked in men aged 50 - 69, while ≥70 showed little change. Black men had the highest absolute mortality and the most pronounced stall. Conclusions: The 2012 USPSTF Grade D PSA screening recommendation was temporally associated with a stall in previously steady prostate cancer mortality declines, particularly among Black men and those aged 50–69, whereas kidney cancer mortality continued to decline without similar interruption. This comparative, negative-control framework highlights how screening policies may inadvertently slow progress and widen disparities. Findings emphasize equity-focused, age-specific approaches in future screening guidelines and careful balancing of overdiagnosis concerns against risks of stalled mortality progress. Limitations include lack of individual-level data and heterogeneous policy implementation. Further studies are needed to validate mechanisms underlying these disparities.
Postoperative surveillance in non clear cell renal cancer: Is current practice best practice?
435 Background: Current American Urologic Association (AUA) and National Comprehensive Cancer Network (NCCN) guidelines do not differentiate between clear cell RCC and non–clear cell RCC (nccRCC), while European Urologic Association (EAU) does. Long-term recurrence data for nccRCC remains limited. We analyzed recurrence patterns after surgery for nccRCC and compared the prognostic performance of the guidelines. Methods: We identified 712 adults treated surgically for non-metastatic, non-hereditary nccRCC (2003-2015). Eligible histologies included papillary, chromophobe, translocation, mucinous tubular/spindle cell carcinoma, and unclassified RCC. Clinicopathologic factors, recurrence-free survival (RFS) and first-recurrence were recorded. Patients were classified by guideline risk categories. Model discrimination was assessed by concordance index (C-index). Model calibration was assessed by integrated Brier score (IBS), where lower values indicated better calibration and predictive accuracy. Results: Papillary RCC was the most common (420/712, 59%). Median follow-up was 120 months (IQR 108, 126). Recurrences were seen in 116 patients (16%) at a median of 26 months (IQR 9, 63). Intra-abdominal visceral organs or retroperitoneal lymph nodes were the most common sites of extra-renal recurrence (44/116, 38%), followed by lung (22/116, 19%). 5-year RFS was 85.8% (95% CI 83-89). When adjusted for stage, chromophobe was associated with lowest risk of recurrence (HR 0.20, 95% CI 0.11, 0.37). Most patients were AUA/EAU low risk (Table). RFS was significantly different by risk groups across all guidelines (Log-rank p<0.0001). AUA provided improved discrimination and calibration (C-index 0.74, IBS 0.110) compared to EAU (C-index 0.71, IBS 0.129) and NCCN (C-index 0.72, IBS 0.125) models. Late recurrences (>5 years post-op) were common (31/116, 27%), particularly among intermediate risk patients (Table). Conclusions: Recurrence after surgery for nccRCC is uncommon but its patterns of recurrence are unique. Contrary to ccRCC, nccRCC tended to recur in the abdomen more often than in the chest, which should guide imaging modality choice for surveillance. Late recurrences were common, highlighting the need for careful long-term surveillance. All three national guidelines stratify risk, but the AUA model may provide the most accurate discrimination and calibration. N = 712 (%) Recurrences (%) Late Recurrences (%) Time to 95% of Observed Recurrences (months) AUA Low Risk 303 (43) 27/303 (9) 26 144 AUA Intermediate Risk 241 (34) 27/241 (11) 59 159 AUA High Risk 115 (16) 25/115 (22) 20 113 AUA Very High Risk 53 (7) 37/53 (70) 8 90 EAU Low Risk 307 (43) 27/307 (9) 26 144 EAU Intermediate Risk 173 (24) 17/173 (10) 71 226 EAU High Risk 232 (33) 72/232 (31) 17 111 NCCN Stage 1 476 (67) 44/476 (9) 43 152 NCCN Stage 2 74 (10) 13/74 (18) 39 159 NCCN Stage 3/4 162 (23) 59/162 (36) 12 111
Redefining Separator Design and Water Activity for High‐Energy Zinc Batteries Using Covalent Organic Framework
ABSTRACT Despite zinc metal batteries offering attractions such as natural abundance, safety, and sustainability, their widespread adoption is hindered by a critical, underexplored limitation: intrinsically low device‐level energy density. While previous research has prioritized stabilizing zinc anodes to suppress dendrites, practical energy densities remain constrained by excessive inactive components (separators, electrolytes) that dominate device mass and volume. Conventional strategies, such as cell upscaling, exacerbate this issue by necessitating surplus electrolyte, leading to inflated electrolyte to capacity ratios (> 10 g Ah −1 ) and poor specific/volumetric energy metrics (e.g., ∼5 Wh kg −1 ). Current reporting practices, focusing on Ah or idealized active‐material metrics, further obscure true performance, masking the urgent need for holistic design innovations. Crucially, lean‐electrolyte operation, essential for high energy density, introduces unaddressed challenges like interfacial water depletion and activity mismanagement. This work bridges this gap by systematically unraveling failure mechanisms under lean conditions and pioneering a functional separator that optimizes water management and ion transport. By redefining hydrogen‐bonding networks to mitigate water consumption and enable rapid infiltration, the developed COF@PAN separator achieves unprecedented energy densities (54.0 Wh kg −1 , 185.3 Wh L −1 ) and cycle stability (over 800 cycles) in practical pouch cells. These insights and designs advance Zn metal batteries beyond lab‐scale promises, positioning them as viable contenders for energy‐dense, real‐world applications.
Twinning Strain‐Induced Pathway Switching on PtPdRuFe Nanoflowers Enables Efficient Formic Acid Oxidation
ABSTRACT Challenges in regulating formic acid oxidation reaction (FAOR) pathways have primarily compromised the output performance of direct formic acid fuel cells (DFAFCs). Herein, we leverage twin boundaries (TBs) engineering in PtPdRuFe nanoflowers (NFs) to deliberately steer the FAOR predominantly along the non‐CO dehydrogenation pathway. The introduced TBs induce localized tensile strain, effectively modulating the d ‐orbital electronic structure across all constituent metals, which is crucial for redirecting the formation of transition‐state intermediates. Specifically, a stronger adsorption affinity for HCOO * over COOH * on Pt and Fe sites is achieved, which reverses the situation that on the non‐twin PtPdRuFe counterpart and thereby preferentially prompts FAOR via a desirable dehydrogenation pathway. Concurrently, the conversion of CO * is also accelerated due to the enhanced adsorption of OH * on Ru/Fe sites, further eliminating the poisoning and deactivation issues induced by CO * . Profiting by these synergistic enhancements, the as‐fabricated twin‐PtPdRuFe NFs demonstrate markedly improved catalytic activity and durability, outperforming the non‐twin counterpart and benchmark Pt/C, enabling them to be among one of the best‐performing acid‐stable FAOR catalysts.
A randomised, multicentre, phase II trial of active surveillance with or without six months of apalutamide for prostate cancer.
363 Background: Active surveillance (AS) is standard of care for low-risk and selected intermediate risk prostate cancer (PC). However, 20 to 50% of patients (pts) will ultimately require a local treatment following AS. This study aims to assess whether apalutamide (APA) could reduce the proportion of patients requiring local treatment within 3 years. Methods: Multicentric, open label, non-comparative phase II study conducted in pts with low to intermediate risk PC randomized between APA 6 months (240 mg/d) with AS vs AS alone. The primary objective was to evaluate the proportion (π) of patients requiring a local treatment in the APA+AS arm with the aim of rejecting the null hypothesis π ≥ 30% with a 5% significance level, using an exact one-sided test for proportions. The secondary objectives were to assess pathological progression (pPFS: Gleason score or a higher % of positive cores against baseline), PSA progression (bPFS: rise in PSA levels ≥ 25%/baseline) and APA safety. Results: Between 09/2017 and 07/2021 51 pts were randomized in APA group (gp) and 40 in control (CTRL) gp. The median follow up was 36 mo (95%CI [36-37]). Median (range) age, PSA and PSA density were respectively 64 yrs (47-76), 6.8 μg/L (1.4-19.9) and 0.13 μg/L/cm³ (0.024-0.38); only 2 pts had ISUP 2 PC and 92% were d’Amico low risk group. In the APA gp, 1 did not receive APA (consent withdrawal), 4 discontinued early (<2 months) for AE and 46 received 6 mo of APA. Local treatment was performed in 37 % (90%CI, [25-50]) in APA gp and the primary objective was not achieved (p=0.88). In CTRL gp, the proportion was 44% (90% CI: [30–58]), not significantly different from APA gp (p=0.66). At 36 mo, bPFS was 55% (95% CI: [39–69]) for the APA gp vs. 42% (95% CI: [26–57]) for the CTRL gp (p= 0.07) and pPFS was 32% (95% CI: 18–46) for the APA gp vs. 11% (95% CI: [4–24]) for the CTRL gp (p= 0.01). APA toxicities (TRAEs) were observed in 98% of pts, with 14% grade 3 (G3) and 4% serious TRAEs (2% G3). Skin toxicity was observed in 30% (4%G3), 56% had asthenia/fatigue (4%G3), hypertension in 18% (4%G3), gynecomastia 62%, breast or nipple pain 36%, thyroid dysfunction 12% (2%G3), diarrhea 10%, nausea 14%, elevated transaminases in 24%. Conclusions: Apalutamide for low risk prostate cancer did not significantly reduce the proportion of patients requiring local treatment within three years. However, the results indicate improved pPFS in the APA gp. There were no new safety concerns. Clinical trial information: NCT03088124 .
Clinical, radiographic, and genomic predictors of response to neoadjuvant chemotherapy for high-risk localized upper tract urothelial carcinoma.
861 Background: Recent data support a pathologic response in 60-65%, including 10-20% with a pathologic complete response (CR) for patients treated with neoadjuvant chemotherapy (NAC, 4-cycles of cisplatin-based treatment) at definitive extirpative surgery; nearly 35% of patients do not respond. We evaluated clinical, radiographic, and genomic predictors of pathologic response to NAC. Methods: Patients undergoing definitive surgery for high-risk UTUC within 16-weeks of completing NAC between 2000-2024 were identified from an institutional database. Response to NAC was defined as < ypT2 N0 and non-response as ≥ypT2 N0/+. The association between clinical predictors and response was evaluated using Welch Two Sample t-tests, two sample tests of equality of proportions with continuity correction, and Fisher’s Exact tests (N = 144). The correspondence between post-NAC radiographic response and pathological response was tested using an Exact test (N = 127). Tumor genomic profiles were sequenced by MSK-IMPACT and alterations were filtered for oncogenic variants using OncoKB (N = 65). Results: Overall, 90% of patients were clinically stage as ≥cT2 at NAC initiation, with final surgical pathology identifying 65% (N = 94) responders and 35% non-responders. Nearly all patients (97%) received gemcitabine-cisplatin NAC, and 89% completed adequate chemotherapy (≥3-cycles). Demographics were similar between responders and non-responders. Of disease characteristics evaluated, only variant histology at pre-NAC biopsy was associated with non-response to NAC (p = 0.049). Non-responders more frequently harbored variant histologies at final pathology than responders (34% vs 2%, p = 0.003). Radiographic response was associated with pathologic response (p = 0.004), however, 9.3% patients with a radiographic CR were pathological non-responders. The mutational landscape of this cohort was enriched for TERT (60%), FGFR3 (43%), and histone methylation/chromatin remodeling gene (25-30%) mutations. Somatic mutation frequencies differed between responders and non-responders for TSC1 (0% vs 23%), EP300 (0% vs 17%), and HRAS (17% vs 0%), respectively. Conclusions: Limited clinical factors predict response to NAC; variant histology may predict for non-response to NAC. While radiographic response predicts pathologic response to NAC, it is not a sufficient surrogate for pathological CR. Genomic alterations in TSC1, EP300, and HRAS were associated with response to NAC and warrant further study.
A multi-institution analysis of outcomes with first-line ipilimumab and nivolumab for 514 patients with metastatic clear cell renal cell carcinoma by number of doses.
441 Background: Ipilimumab (IPI) and nivolumab (NIVO) are a standard first line systemic therapy option for patients with metastatic ccRCC. The regimen is administered in combination for 4 doses, followed by NIVO maintenance. Patients are often unable to receive all 4 doses of IPI due to toxicity. Whether this affects clinical outcomes is unknown. We assessed outcomes with IPI/NIVO by number of doses given in patients with metastatic ccRCC. Methods: We conducted a retrospective study of patients with metastatic ccRCC at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center treated with first line IPI/NIVO. We evaluated clinical outcomes starting at 12 weeks after initiation of therapy, including patients who were alive and being followed at that time point. We calculated time to second line treatment (TT2) and overall survival (OS) by the Kaplan-Meier method from the 12-week landmark for patients who received all 4 doses versus those who received < 4 doses for toxicity, excluding early progressors. Results: 514 patients initiated IPI/NIVO. 320 patients (62%) received all 4 doses, 193 (38%) received < 4 doses (73 - 3 doses, 71 - 2, 49 - 1), whereas 1 patient received 10 doses and was excluded. Most patients received < 4 doses for toxicity (106, 55%) or progression (47, 24%). In the TT2 and OS analyses, all 320 patients who received 4 doses and 106 patients who received < 4 due to toxicity were included. The two groups had comparable distributions of sarcomatoid and/or rhabdoid features (37% and 35%, respectively) and IMDC risk groups. NIVO maintenance was initiated in 251 (78%) of those who completed 4 doses and 25 (24%) in those who received < 4 doses. Median TT2 in 4 and < 4 dose group was 12.5 and 11.7 months, respectively. One-year TT2 rates are 51% and 49% with a 1-year difference of 2.6% (95% CI: -9.3, 14.6). Median OS in the 4 and < 4 dose group was 5.0 and 4.7 years, respectively. Two-year survival probabilities are 78% and 74% with a 2-year survival difference of 3.3% (95% CI: -6.8, 13.5). Median follow-up for survivors is 3.9 years. In a landmark Cox proportional-hazards model for survival adjusted for IMDC risk, sarcomatoid and rhabdoid features, the HR for 4 doses vs < 4 due to toxicity is 0.80 (95% CI: 0.56, 1.13). Conclusions: In this observational analysis, we found comparable TT2 and OS in patients who received 4 doses of IPI/NIVO compared to those who received < 4 doses due to toxicity. A prospective trial would help inform whether there is need for all 4 doses of IPI/NIVO in all patients. Four Doses of IPI + NIVO (N=320) Fewer Than Four Doses of IPI + NIVO for Toxicity (N=106) One-year TT2 rates 51% (95% CI: 46, 57) 49% (95% CI: 38, 59) Median TT2, months (95% CI) 12.5 months (95% CI: 9.5, 16.8) 11.7 months (95% CI: 6.8, 19.6) Two-year OS probabilities 78% (95% CI: 72, 82) 74% (95% CI: 64, 82) Median OS, years(95% CI) 5.0 years (95% CI: 3.9, 6.7) 4.7 years (95% CI: 3.0, 7.4)
Association between non-luminal molecular subtypes and complete response rates after neoadjuvant chemo-immune therapy for muscle-invasive bladder cancer: Biomarker analyses of NURE-combo and BLASST-01 phase 2 clinical trials.
845 Background: The BLASST-01 (NCT03294304) and NURE-combo (NCT04876313) clinical trials evaluated the use of neoadjuvant chemo-immune therapy before radical cystectomy (RC) in cT2-T4aN≤1M0 muscle invasive bladder cancer (MIBC) patients. Here, we evaluated associations between transcriptome-based molecular subtypes and outcomes in BLASST-01 and NURE-combo. Methods: BLASST-1 was a phase 2 trial evaluating neoadjuvant nivolumab + gemcitabine-cisplatin followed by radical cystectomy surgery (RC). NURE was a phase 2 trial evaluating neoadjuvant nivolumab + nab-paclitaxel followed by RC and 12 months of adjuvant nivolumab. Available TURBT specimens were analyzed with the Decipher Bladder Genomic Subtyping Classifier (GSC), a clinical-grade transcriptome-wide assay (Veracyte, San Diego, CA). Pathological complete response (PCR, ypT0N0) at RC was the primary endpoint and overall survival (OS) was the secondary endpoint. Multivariable logistic regression analyses for PCR were adjusted for patient age and sex and log-rank tests were performed for overall survival comparison. Results: Transcriptome-wide data were available for 37/43 (86%) of BLASST1 and 24/31 (77%) of NURE-combo patients. Median ages were 64 and 65 years, and male sex rates were 59% and 75% in BLASST-1 and NURE-combo, respectively. BLASST-1 was primarily cT2N0 (89% vs 25%), while NURE had more variant histology (48% vs 0%). Non-luminal subtypes were found in 77% (47/61) at a similar frequency in both trials. PCR rate was 65% in BLASST-1 and 58% in NURE-combo. We found higher PCR rate for non-luminal subtypes (47%, versus 14% for luminal subtype, X 2 p=0.058). From non-luminal subtypes, we found highest PCR rate among claudin-low subtype (62%) and multivariable analysis revealed a significant association between claudin-low MIBC and PCR (p=0.04). Two-year overall survival was 84% in patients with non-luminal MIBC vs. 100% in patients with luminal MIBC (Log-Rank p=0.18). Conclusions: Non-luminal MIBC is associated with highest PCR rates after neoadjuvant chemo-immunotherapy for MIBC. These results support clinical decision-making using Decipher Bladder in the neoadjuvant setting for MIBC. Clinical trial information: NCT03294304 & NCT04876313 .
Organic Metastable Hydrogels via In Situ Ionic‐Liquid Crystal Stacking for Latching Room‐Temperature Phosphorescence
ABSTRACT Stimuli‐responsive room‐temperature phosphorescence (RTP) materials offer notable potential in smart optoelectronic materials, yet their development is hindered by the persistent stimuli requirement. By drawing inspiration from inorganic metastable systems, we propose a strategy to fabricate organic metastable materials to address this critical challenge. By integrating supersaturated ionic liquids into a polymeric architecture, RTP hydrogels are obtained under transient stimulus, without requiring persistent stimulation. The soft hydrogels switch to a tough crystallized state via in situ stacking of ionic‐liquid crystals. A 10 fold enhancement in toughness and a 34 fold increase in phosphorescence lifetime are achieved, compared to their metastable counterparts. The mechanical reinforcement stems from confined segments and entangled chains caused by in situ stacked ionic‐liquid crystals, while the intertwinement of polymer chains further promotes the denser stacking of ionic‐liquid crystals to produce long‐lived RTP. Leveraging the advantage of 2D correlation spectroscopy in elucidating dynamic mechanisms, we map the microscopic response order of different groups in the crystallization process of ionic liquids and reveal the aforementioned mechanism at the atomic level. This work not only provides a design paradigm for addressing the challenge of transient response in existing stimuli‐responsive RTP materials but also charts a route for developing organic metastable materials to unlock unprecedented functionality.
Spin Polarization of Axial Oxygen‐Enhanced Ferromagnetic Single‐Atom Catalysts for Boosting Redox Kinetics in Room‐Temperature Sodium‐Sulfur Batteries
ABSTRACT Room‐temperature sodium–sulfur (RT Na–S) batteries are promising candidates for large‐scale energy storage owing to their high energy density and low cost, yet their practical deployment is hindered by sluggish sulfur redox kinetics and severe polysulfide shuttling. Here, guided by density functional theory (DFT) calculations, we develop a class of axially oxygen‐coordinated ferromagnetic single‐atom catalysts (SACs) with enhanced spin polarization to accelerate sulfur conversion. Among Fe‐, Co‐, and Ni‐based SACs, Co–N 2 O 3 is theoretically identified as the most effective configuration, featuring an optimized electronic structure with a minimal energy offset (0.26 eV) between the Co d ‐band and S p‐band centers, which facilitates Na + diffusion and lowers the activation barrier for polysulfide conversion. Experimentally, Co–N 2 O 3 atoms anchored on hollow mesoporous carbon spheres (Co–N 2 O 3 @MCS) exhibit outstanding catalytic activity as the sulfur host, achieving an ultrahigh rate capability (330.5 mAh g −1 at 10 A g −1 ) and excellent durability over 600 cycles at 1 A g −1 . In situ characterizations reveal that the enhanced ferromagnetism effectively suppresses polysulfide shuttling, underscoring the crucial role of coordination‐engineered spin polarization in boosting the redox kinetics of RT Na–S batteries.
ProTACT: A first-in-human, phase 1 dose escalation and expansion study evaluating the safety, tolerability, and anti-tumor activity of [ <sup>225</sup> Ac]Ac-FL-020, an anti-PSMA radioconjugate in patients with mCRPC.
TPS282 Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is an emerging treatment modality for metastatic castration-resistant prostate cancer (mCRPC). However, many agents targeting PSMA have resulted in quality of life-limiting toxicities, such as xerostomia, due to expression of PSMA in salivary glands and other organs. [ 225 Ac]Ac-FL-020 is a next-generation, PSMA alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. It is intended for the treatment of patients with mCRPC and aims to enhance tumor uptake while sparing radiosensitive organs, such as salivary glands, thus potentially leading to an improved therapeutic window. Methods: ProTACT (FL-020-001) is a first-in-human, open-label, multicenter Phase 1 study investigating the safety, tolerability, and preliminary anti-tumor activity of [ 225 Ac]Ac-FL-020 in patients with advanced PSMA-positive mCRPC. This study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2). Patients eligible for enrollment must be aged ≥18 years and have: histologically confirmed mCRPC, evidence of disease progression, ≥1 PSMA-positive lesion (uptake higher than liver) on PSMA positron-emission tomography/computed tomography imaging, an Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function. Prior treatment with androgen receptor signaling inhibitors or CYP17 inhibitors and ≥1 taxane-based chemotherapy is required, unless declined by the patient. Prior therapy with Lu-177 is allowed. Patients with extensive PSMA-negative disease are excluded. [ 225 Ac]Ac-FL-020 will be administered intravenously at the assigned dose every 6 weeks for up to 6 cycles. In Part 1, 5 eligible patients will receive 185 ± 20 MBq of [ 111 In]In-FL-020 for dosimetry evaluation ≥8 days prior to first dose of [ 225 Ac]Ac-FL-020. Part 1 will apply a Bayesian logistic regression model (BLRM) with overdose control to guide dose-escalation decisions. Dose cohorts of 1–3 patients (for Cohorts 1 and 2) and 3–6 patients (for Cohorts 3 and beyond) will evaluate ascending dose levels from 1–10 MBq to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Once the RP2D is established, 18 additional patients will be enrolled in Part 2 to further assess safety and explore early signals of efficacy. Primary endpoints include incidence of dose-limiting toxicities and type, frequency, and severity of adverse events/serious adverse events. Secondary endpoints include overall response rate, disease control rate, radiological progression-free survival, and pharmacokinetic parameters (eg, maximum plasma concentration). The study intends to enroll patients in Australia, Turkey, the United States, and China. Clinical trial information: NCT06492122 .
Antibody-drug conjugates in genitourinary malignancies: The clinical trial landscape and emerging efficacy benchmarks.
877 Background: Antibody-drug conjugates (ADCs) are increasingly likely to transform the treatment of genitourinary (GU) malignancies. To comprehensively map the strategic direction and evaluate the emerging evidence base, we analysed the global ADC clinical trial landscape in GU malignancies alongside recently published efficacy and safety outcomes. Methods: We performed a systematic search of the ClinicalTrials.gov database (Oct 2025) for all phase II-IV trials involving ADCs in GU cancers (n=151). Results were filtered to isolate a final cohort of ongoing and completed ADC studies. We extracted data on trial design, disease focus, therapeutic setting, ADC target, and sponsor geography. A corresponding systematic literature search was conducted to identify efficacy and safety benchmarks from the associated ADCs. Results: Our analysis identified 104 unique ADC trials in GU cancers. The pipeline is predominantly focused on urothelial carcinoma (UC; 73% of trials, n=76) and prostate cancer (PC; 18%, n=19). A significant strategic shift towards curative-intent therapy is evident in UC, with 37% (28/76) of trials investigating perioperative settings. Combination with immune checkpoint inhibitors is a dominant strategy (36% of UC trials). The most frequently studied ADC targets are Nectin-4 (n=25), HER2 (n=21), and TROP2 (n=17). Published data from pivotal trials have established key efficacy benchmarks: in first-line metastatic UC, ADC-immunotherapy combinations established a new median overall survival of 33.8 months; in the curative-intent muscle-invasive bladder cancer setting, a pathologic complete response rate of 57.1% has been achieved; and in pre-treated metastatic castration-resistant prostate cancer, promising objective response rates of ~41% are emerging for novel, non-prostate-specific membrane antigen targets. This is accompanied by substantial rates of Grade ≥3 treatment-related adverse events, with distinct, payload-dependent toxicity profiles emerging. Conclusions: The ADC clinical trial landscape in GU oncology is characterised by a strategic intensification in urothelial cancer, with a clear trajectory from metastatic to curative-intent settings driven by practice-changing survival data. A diverse and promising pipeline is emerging in prostate cancer against a portfolio of novel targets. The rapid evolution and maturation of this therapeutic class may continue to redefine treatment standards across the spectrum of GU malignancies.
Clinical and genomic characteristics of advanced urothelial carcinoma (UC) patients (pts) who fail therapy with enfortumab vedodin (EV) plus pembrolizumab (P).
685 Background: EV plus P has become the standard-of-care first-line therapy for most pts with advanced UC in the United States, based on results of the EV-302 study. However, primary progressive disease was noted in 8.7% of pts and median PFS was 12.5 months (mos) in the EV plus P treated pts on EV-302. Pts who fail to respond to EV plus P therapy or quickly lose response have a poor prognosis, highlighting the need for early identification of this pt cohort. Methods: This is a retrospective analysis of advanced UC pts, who initiated EV plus P at 5 academic institutions from 8/13/2018 to 7/21/2025. All pts had somatic next generation sequencing of their tumor tissue performed using a commercially available assay. Pts also needed to have at least 1 whole body scan to assess for treatment response, which was interpreted using RECIST criteria by the treating physician. Pts who had primary progressive disease or lost response to EV plus P within 6 mos of starting therapy were selected for this analysis. Extracted data included demographic, clinical, treatment, and genomic variables. Data was analyzed using descriptive statistics and Kaplan-Meier estimation. Results: A total of 29 were included, with 69% being male, 79.0% identifying as Caucasian, and a median age of 67 years [range, 27 to 92]. 76% had a primary bladder tumor, 20.6% had a primary upper tract tumor, and 3.4% had primary urethral tumor. At EV plus P start,14% had liver metastasis and 7.8% had peritoneal metastasis. Median duration of P therapy was 3.0 mos [range, 1.0 to 33.0], while median duration of EV therapy was 2.4 mos [range, 0.3 to 5.1]. Median progression free survival (mPFS) was 3.4 mos [IQR, 2.1 to 7.8], while median overall survival (mOS) was 12.0 mos [IQR, 8.3 to 24.0]. Median time to next therapy from EV plus P start, available in 25 pts, was 5.4 mos [range, 2.5 to 24.2]. Median tumor mutational burden (TMB) was 8 m/MB [range, 1 to 71] (available for 25/29 pts). Microsatellite instability (MSI) high status was 3.4% (available for 29/29 pts). HER2 immunohistochemistry (IHC) expression of 1+ or higher was noted in 86% tumor samples (available for 14/29 pts). HER2 positivity by fluorescence in situ hybridization (FISH) was positive in 21% of samples (available for 17/29 pts). Selected genomic alterations for all pts are listed in Table 1. Conclusions: This small retrospective dataset demonstrated a poor mPFS and mOS in pts with advanced UC who have primary progressive disease or loss of response within 6 mos to first-line EV plus P therapy. Low TMB/MSI-high status as well as frequent TERT variant promoter and FGFR2/3 alterations were noted. Further investigation into the genomic landscape of these tumors is needed. Selected genomic alterations of pts who fail EV plus P therapy. Genomic mutation % of pts FGFR 2/3 41 MTAP 6.7 TERT variant promoter 62 ERBB2 17 CDKN2A/2B 11
Impact of HER2 expression and <i>ERBB2</i> alterations on clinical outcomes in patients treated with enfortumab vedotin and pembrolizumab (EVP): UNITE study analysis.
794 Background: HER2 protein, encoded by ERBB2 gene, is the target of emerging therapies for patients (pts) with advanced urothelial carcinoma (aUC). High HER2 IHC expression (IHC 3+) is present in ~15% of pts with aUC, while >50% of pts have HER2 IHC 1+/2+/3+ expression. EVP is the preferred 1 st line regimen for pts with aUC, but the impact of HER2 status on EVP outcomes is unclear. Methods: We identified pts from the UNITE study with tumor samples tested for HER2 by IHC and another cohort with next-generation sequencing (NGS) data available. Outcomes were compared by HER2 IHC status (HER2 IHC 0/1+ vs 2+/3+) and separately based on ERBB2 status (alteration vs wild-type). X 2 test was used to compare observed response rate (ORR) and logistic regression was used to compare disease control rate (DCR). Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) from EVP start were evaluated using log-rank test and Cox proportional hazards models. Multivariate analysis (MVA) included age, sex, race, ECOG PS, neutrophil:lymphocyte ratio, albumin, hemoglobin, primary tumor site, tumor histology, prior lines of treatment, and metastatic sites as covariates. Results: Among 521 pts treated with EVP from 16 sites, 112 had HER2 IHC data and 313 had NGS. Median age was 71, 74% were men, 84% Caucasian, 82% had ECOG PS 0-1, 65% pure urothelial histology, and 73% received frontline EVP. HER2 IHC distribution (n=112) was 27%/21%/37%/15% for 0/1+/2+/3+, respectively. ERBB2 alterations were present in 14% (44/313). Baseline characteristics were similar in HER2 0/1+ and 2+/3+ pts, except more primary bladder tumors in 2+/3+ pts (83% vs 63%, p=0.01). For the overall cohort (n=521), with a median follow up of 7.3 mos from EVP start, ORR was 54%, DCR 81%, median DOR (mDOR) 8.5 mos, median PFS (mPFS) 8.5 mos, and median OS (mOS) 19.8 mos. Pt outcomes by HER2 IHC status are shown (Table). In univariate analysis (UVA), pts with HER2 IHC 0/1+ had longer mOS compared to HER2 IHC 2+/3+, but this was not significant in MVA (HR: 0.5; CI: 0.2–1.3, p=0.17). No significant differences were observed in other outcomes. Evaluating clinical outcomes by ERRB2 status, no significant differences were seen for ERBB2 -altered vs wild-type pts. Conclusions: In this retrospective study, no significant differences were seen in EVP treatment outcomes based on HER2 IHC status or ERBB2 status. These findings are hypothesis-generating and require validation in larger and prospective cohorts. HER2 0/1+ (n=54)* HER2 2+/3+ (n=58) OR (95%CI, p) HR UVA (95%CI, p) HR MVA (95%CI, p) ORR 49% (23/47) 55% (27/49) 1.3 (0.6-2.9, p=0.5) - - DCR 79% (37/47) 88% (43/49) 1.9 (0.7-6.2, p=0.2) - - mDOR 11.7 mos 10.4 mos - 1.3 (0.7-2.4, p=0.4) 1.2 (0.4-3.3, p=0.8) mPFS 5.9 mos 7.1 mos - 0.8 (0.5-1.4, p=0.5) 1.1 (0.5-2.5, p=0.9) mOS 42.4 mos 18.7 mos - 2.3 (1.1-4.5, p=0.02) 2.0 (0.8-5.4, p=0.2) *HER2 0/1+ used as reference.
A Dual‐Functional Artificial Interphase Design for High‐Efficient and Long‐Duration Anode‐Free Sodium All‐Solid‐State Battery
ABSTRACT Anode‐free solid‐state sodium batteries (AFSSBs) emerge as a highly promising next‐generation energy storage technology, offering exceptional energy density and significant cost advantages. However, their practical deployment remains challenging, primarily due to an insufficient understanding of Na dendrite formation and the absence of effective strategies to address the rigid multiphases interface, mitigate volume expansion, and reactivate inactive sodium. In this study, we systematically investigate the morphologies evolution of sodium at the interface between the Cu current collector and Na 5 SmSi 4 O 12 (NSSO) solid electrolyte. Building upon these findings, we design an iodinated polymeric elastic artificial interphase layer ( I ‐PIL) with dual functionality. This layer not only ensures conformal interfacial contact through photoinitiated polymerization and atomic bonding, but also reactivates dead sodium via spontaneous reaction with the incorporated I 3 − species. Consequently, Na|Cu half‐cells achieve remarkable cycling stability, remaining a Coulombic efficiency of 99.7% for over 1000 h at 1.5 mA cm −2 . When paired with Na 3 V 2 (PO 4 ) 3 cathode, the AFSSBs retain 85.8% capacity after 2000 cycles at 1.0 mA cm −2 and preserve 92.8% capacity over three months under high mass loading of 28 mg cm −2 . This work provides fundamental insights into sodium deposition and establishes a versatile and scalable interfacial design strategy for high‐performance, durable anode‐free solid‐state batteries.