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A phase Ib window of opportunity study of atezolizumab administered intravesically or direct injection in patients undergoing radical cystectomy for bladder cancer: Results of the single dose cohorts.

773 Background: BCG-unresponsive High-risk non-muscle invasive bladder cancer (HRNMIBC) tumours have an ominous prognosis and require effective, tolerable treatments. Uptake remains low for FDA approved agents (including systemic pembrolizumab, nogapendekin alfa inbakicept-pmln or N-803) due to toxicity concerns. We hypothesize direct intravesical administration of a PDL1 inhibitor could be effective with less systemic toxicity. However, it is unknown whether antibodies delivered via this route can reach tumor vasculature. INVEST is a phase Ib window of opportunity study investigating the safety and preliminary activity of passive instillation and direct injection of intravesical atezolizumab into the tumour/bladder wall. Methods: Eligible participants (ECOG performance status 0-2) are awaiting radical cystectomy (RC) for any stage urothelial cell carcinoma. Participants with muscle invasive bladder cancer, must be ineligible for/ refuse cisplatin based neo-adjuvant chemotherapy. Atezolizumab (600mg or 1200mg) is administered via direct injection into the tumour/bladder or by instillation into the bladder. The 3+3 design is utilised in the dose confirmation stages where participants receive either Single or Multiple (between 3 and 6) dose(s) of treatment before RC. Efficacy signals are derived from pathological complete response at RC and progression-free survival at 2 years. Primary endpoint, Dose confirmation stage: The number of dose-limiting toxicities (DLTs) observed from first dose of trial treatment to RC. Results: Enrolment began in May 2023. 13 participants were recruited to the single dose cohorts: 11 male, and 2 female. Age (Range; 43-86); median 70y, 9 NMIBC, 4 MIBC. 7 for direct injection (4 at 600mg and 3 at 1200mg dose) and 6 for passive instillation (3 at 600mg and 3 at 1200mg). Due to technical issues (syringe size) the first direct injection participant did not receive the full 600mg and were replaced. 12 participants received trial treatment as planned. There were no DLTs; 5 participants experienced non-trial treatment related SAEs (4 infections, 2 ileus, 2 renal impairment; 7/8 events occurred post-RC and all SAEs resolved). All participants underwent planned RC within the protocol stipulated timeline. Median time from last treatment to RC was18 days. 5 of 13 participants had downstaging of tumour in cystectomy specimen. Following independent Safety Review Committee review, recruitment is now open for the dose confirmation phase (Multiple 1200mg dose) in both treatment routes. Conclusions: Single dose atezolizumab treatment at a dose of 600mg and 1200mg in passive instillation and direct injection cohorts was well tolerated. Early efficacy data is encouraging. Multiple weekly doses of 1200mg in each treatment route are now being investigated within the INVEST trial. Clinical trial information: ISRCTN15842444 .

Using AI to identify optimal clinical, genomic, and radiographic prognostic features and novel risk classifiers compared to routinely available risk classifiers.

396 Background: This study investigated the use of artificial intelligence (AI) and traditional statistical techniques to identify and validate clinical (Clin), MRI-report-derived (MRIr), and genomic classifier (GC) features important for prognostic biomarker development and staging systems for prostate cancer metastasis. AI models were compared with conventional risk classifiers for prognostic accuracy. Methods: Data from 576 patients in a prospectively collected research registry, including 35 Clin, 1 GC, and 7 MRIr features, were used. Random forest (RF) classification and artificial neural networks (ANNs) using Leave-One-Out Cross-Validation evaluated the key features predictive of metastasis. Models with 35, 9, 6, or 0 Clin features were compared to those ± MRIr or GC features. ANN prognosticators from each model were fed into competing-risk regressions and compared to other established risk classifiers (CAPRA, STARCAP, 22-gene genomic assay (Decipher), Cell-Cycle Progression (CCP, Prolaris) score, and Combined Clinical Cell-Cycle Risk (CCR, Prolaris)) by the 5-year AUC (AUC5) for prognostic accuracy. Results: AI-derived models combining Clin ±GC +MRIr features (AUC5 range 0.72-0.76) outperform models excluding MRIr features (AUC5 0.66-0.71). AI models perform similarly to contemporary risk classifiers like Prolaris, CAPRA, STARCAP (AUC5 of 0.79. 0.77, 0.76, respectively (Table)). Models with 6 Clin, 4 MRIr, and a GC (Clin: Age, BMI, PSA, cT, alcohol use, and primary Gleason score; MRIr: prostate volume, max tumor diameter, extracapsular spread, and lymphadenopathy suspicion; GC: CCP score) performed as well as conventional classifiers. The classifier with the best ability to prognosticate early metastasis was Prolaris (AUC5 0.79). Conclusions: The findings indicate that AI biomarker discovery pipelines, integrating Clin, MRIr, and GC features, can successfully identify new and previously identified prognostic factors. AI-derived models have similar accuracy in predicting metastasis compared to contemporary risk classifiers. Adding MRIr and GC features improves risk prediction of early metastasis in AI-trained models. Lifestyle factors may have an important role in metastasis. Total # Features Genomic Features Radiographic Features Clinical Features Time-Dependent Competing Risk Regression 3-Year AUC 5-Year AUC 35 Clinical Feature AI Models (n=576) 43 1 7 35 0.70 0.72 42 7 35 0.69 0.72 36 1 35 0.64 0.66 35 35 0.62 0.65 11 Clinical Feature AI Models (n=576) 16 1 6 9 0.72 0.76 15 6 9 0.71 0.75 10 1 9 0.67 0.71 9 9 0.67 0.70 6 Clinical Feature AI Models (n=576) 11 1 4 6 0.73 0.75 10 4 6 0.73 0.75 7 1 6 0.61 0.64 6 6 0.62 0.65 0 clinical feature AI Models 7 1 6 0 0.66 0.68 6 6 0 0.65 0.67 Prolaris (n=570) 6 1 5 0.75 0.79 STARCAP (n=566) 5 5 0.72 0.77 CAPRA (n=570) 6 6 0.72 0.76 CCP score (n=576) 1 1 0.73 0.74 Decipher (n=25) 1 1 0.40 0.29

Updated efficacy, safety, and correlative analysis of a phase II trial in metastatic renal cell carcinoma with coordinated pembrolizumab and high dose IL-2.

554 Background: The CM 214 trial with Nivolumab-ipilimumab recently presented its long term follow up results with regards to efficacy and safety. In this abstract, we similarly present extended 6 year follow up results of efficacy, safety, and correlative data from the phase 2 clinical trial combining IL-2 and short course pembrolizumab (pembro) for patients (pts) with metastatic renal cell carcinoma (mRCC). Methods: This phase 2 study included pts with untreated clear cell mRCC and ECOG 0-1 status. Pts were treated with a maximum of four 9-week blocks of pembro/IL-2. Pembro was dosed every 3 weeks throughout all four blocks without subsequent maintenance dosing. High dose IL-2 was administered only during blocks 2 and 3. At fixed time points, proteomic data via Olink and gene expression data via Nanostring were obtained for correlative analysis. The Kaplan-Meier method was utilized to determine updated overall survival (OS), progression-free survival (PFS), and treatment-free survival (TFS). TFS was defined as the time from completion of pembro/IL-2 to initiation of next therapy, date of last follow up if no subsequent line of therapy, or death. TFS was used to subdivide pts into extreme responders ( > 5 years with no further treatment), non-responders ( < 6 months until next line of therapy), and others. Proteomics and gene expression in extreme responders, non-responders, and others were compared via Wilcoxon rank sum test and logarithmic fold change in expression. Results: 27 pts were enrolled in the study with 26 receiving treatment. The number of pts with IMDC risk of favorable, intermediate, and poor were 6, 19, and 1, respectively. The median time from the on-study date to last known alive or expired was 73 months (range: 13-86). OS probabilities for 1-, 3-, and 5-year intervals were 100% (95% confidence interval [CI]: 100-100%), 76.9% (CI: 55.7-88.9%), and 73.1% (CI: 51.7-86.2%) respectively. PFS at 1-, 3-, and 5-year intervals were 61.5% (CI: 40.3-77.1%), 42.3% (CI: 23.5-60.0%), and 42.3% (CI: 23.5-60.0%) respectively. TFS probabilities for 1-, 3-, and 5-year intervals were 76.9% (CI: 55.7-88.9%), 42.3% (23.5-60.0%), and 42.3% (23.5-60.0%) respectively. Of the 11 pts with durable disease control not requiring any further systemic therapy, none had persistent adverse events at the grade 2 or higher level. In a comparison of extreme responders to non-responders, IL-8 was found to have a 1.43 log fold change in expression with a p-value of 0.019 detected by the Nanostring assay. Additionally, ADA and GZMH showed -0.82 and -1.57 log fold change in expression detected via Olink assay with p-values of 0.002 and 0.039 respectively. Further correlative data will be presented at the meeting. Conclusions: Short course pembro in combination with high dose IL-2 allows for durable immune response. At 6 years median follow up, > 40% of pts have extended disease control without persistent toxicity or need for further systemic therapy. Moreover, we highlight select biomarkers that could be associated with this long-term response. Clinical trial information: NCT02964078 .

Healthcare utilization during acute medically attended episodes of respiratory syncytial virus-related lower respiratory tract infection among infants in the United States

Background Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization in the United States. Understanding healthcare utilization associated with medically attended (MA) RSV lower respiratory tract infection (LRTI) might inform research priorities aimed at reducing RSV-associated pediatric morbidity. We described healthcare utilization during acute MA RSV LRTI episodes within a geographically diverse cohort of infants in the United States. Methods We created retrospective cohorts of infants born in the United States from July 1, 2016 through February 29, 2020 in each of three de-identified insurance claims datasets: Merative MarketScan Commercial Claims and Encounters, Multi-State MarketScan Medicaid, and Optum’s de-identified Clinformatics ® Data Mart. We identified infants’ first MA RSV LRTI diagnosis during their first RSV season and followed them for 7 subsequent days to record outpatient, emergency department, and inpatient hospital utilization. We calculated the number of outpatient visits, emergency department visits, and inpatient hospital stays occurring during this acute episode and estimated the proportion of episodes involving ≥ 2 visits to a given healthcare setting. Results In the CCAE database, we identified 25,409 acute MA RSV LRTI episodes under the specific RSV definition and 69,068 under the sensitive definition. In the MDCD database, these totals were 67,357 and 170,744, while in the CDM database, they were 12,402 and 31,363, respectively. Across data sources, 34%–69% of infants’ first acute MA RSV LRTI episodes involve 2 or more visits to a healthcare setting within 7 days. The percentage of episodes involving at least 2 visits ranged from 34–62% among healthy term infants, 38–65% for Palivizumab-eligible infants, and 38–69% for infants with other comorbidities. Conclusions Within a week of their first MA RSV LRTI diagnosis, infants frequently experience at least 2 visits to one or more healthcare settings, regardless of their comorbidity profile. The percentage of MA RSV LRTI episodes involving at least 2 visits to a healthcare setting may vary by insurance claims database, even between commercial payers.

Spatiotemporal characteristics of gait when walking on an uneven surface in children with cerebral palsy

‘Devastating’ cuts to NIH grants by Trump’s team put on hold by US judge

Formula-01: A phase Ⅱ study of disitamab vedotin (RC48) intravenous injection combined with BCG intravesical instillation in high-risk non-muscle invasive bladder cancer with HER2 high expression.

TPS894 Background: Intravesical instillation of bacillus Calmette-Guérin (BCG) is the first-choice treatment for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). However, our previous study has demonstrated that HER2 was an independent predictor of poor BCG efficacy in NMIBC (Tan et al., European Urology Oncology, 2023). We found that high-risk NMIBC patients with HER2 high expression had the highest risk of disease recurrence and progression with 46.9% 2yr-RFS rate and 23.0% 2yr-PFS rate. Disitamab Vedotin (RC48) is an antibody-drugconjugate(ADC) targeting HER2 with a payload of MMAE. Formula-01 will evaluate the efficacy and safety of RC48 combining with BCG instillation in HER2 overexpression high-risk NMIBC patients. Methods: Formula-01 is an open-label, non-randomized, phase 2 trial. Patients must receive complete transurethral resection (TURBT) of bladder tumor (R0 resection) and did not accept BCG intravesical instillation and neoadjuvant chemotherapy or radiotherapy before. NMIBC was pathologically confirmed for all patients according to the 8th edition of the TNM staging system and the risk stratification was recorded basing on the American Urological Association (AUA)/Society of Urologic Oncology (SUO) guidelines.The pathology of NMIBC must be pure urothelial carcinoma and any divergent differentiation subtypes are excluded. This study is open at the Sun Yat-sen University Cancer Center (SYSUCC) and 70 patients are enrolled. The single-arm cohort will receive RC48 intravenous injection (2.0 mg/kg, iv drip, d1, Q2W, 8 cycles) combining with BCG intravesical instillation at least one year (D2PB302 strain, 1.2×10 8 CFU, 120 mg, dissolved in 40–50 ml of saline, 19 times in 1 yr). The primary endpoint is 2yr-RFS rate. Secondary endpoints include 1yr-RFS, 1yr-PFS, 2yr-PFS rate, bladder retention rate and safety. Exploratory analyses include determination of Her2 expression, molecular subtypes. The sample size calculation is based on the historical results of specific subgroup patients with 2yr-RFS rate of 46.9%, and we expected improvements to 70.0%. One-sample long-rank test was used to calculate the enrollment of 70 patients (α=0.05, β=0.8, lost-to-follow-up rate of 5.0%). The study began enrollment in February, 2024 and completed enrollment in October, 2024. Research approval was obtained from the SYSUCC Ethics Committee. Clinical trial information: ChiCTR2400080767 .

Impact of PSMA PET staging on initial treatment in newly diagnosed prostate cancer: An emulated randomized controlled trial.

350 Background: Prostate-specific membrane antigen (PSMA) PET/CT has become a common initial staging modality for localized prostate cancer due to its increased sensitivity and specificity over conventional staging. However, the causal impact of widespread PSMA staging on initial prostate cancer treatments has not been described. Methods: We used electronic medical record data from a national, diverse health system (Veterans Health Administration) to emulate a randomized controlled trial in which patients with newly diagnosed conventionally localized unfavorable intermediate, high, and very high-risk prostate cancer were allocated to either upfront PSMA staging or conventional imaging with technetium-99 bone scan and pelvic CT or MRI. Primary outcomes included the use of any androgen deprivation therapy (ADT), advanced androgen receptor pathway inhibitors (ARPIs), radiotherapy, and radical prostatectomy assessed in the year after diagnosis. We used the cloning, censoring, and weighting technique to estimate the causal effect of PSMA staging, controlling for potential confounders. In exploratory analyses, we extracted radiographic stage from PSMA reports using a natural language processing algorithm and assessed the influence of PSMA findings (N0M0, N1M0, or M1) on treatment patterns. Results: 9,049 patients met criteria for inclusion in the emulated trial, of whom 35% underwent PSMA staging and 46% underwent bone scan. In the emulated trial, PSMA staging was associated with higher rates of any ADT usage relative to conventional staging (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.19-1.44), higher ARPI usage (aHR 1.52, 95% CI 1.33-1.78), lower prostatectomy usage (aHR 0.69, 95% CI 0.56-0.83), and no effect on radiotherapy usage (aHR 1.10, 95% CI 0.99-1.25). Compared to patients with PSMA N0M0, ARPI usage was higher in patients with N1M0 (aHR 6.87, 95% CI 5.41-8.73) and M1 (aHR 10.13, 95% CI 8.16-1.2.58). Patients with N1M0 or M1 disease were less likely to undergo prostatectomy compared to N0M0. Similar patterns were seen in subgroup analyses within risk groups. Conclusions: In this emulated randomized trial, PSMA staging of localized prostate cancer was associated with increased rates of any ADT and ARPI use and lower rates of prostatectomy relative to conventional staging. The implications of these treatment changes on oncologic outcomes require further study.

PSMA-positive tumor vessels around renal cell carcinoma with high angiogenic potential as therapeutic targets and predictors of tumor recurrence.

561 Background: The expression of prostate-specific membrane antigen (PSMA) protein increases as prostate cancer advances and metastasizes. Recently, 68Ga-labeled PSMA PET has been used in diagnosing prostate cancer. Our previous studies demonstrated that PSMA-positive vesicles secreted by prostate cancer cells enhance the angiogenic activity of vascular endothelial cells, suggesting a role for PSMA in tumor angiogenesis. In this study, we focus on renal cell carcinoma, examining the relationship between PSMA expression in peritumoral blood vessels and clinical outcomes, particularly tumor recurrence, in surgically excised renal cancer specimens. Methods: Immunohistochemical analysis was performed on renal cell carcinoma samples from 45 patients who underwent nephrectomy or partial nephrectomy at our institution between January 2018 and December 2022. The correlation between PSMA expression levels in tumor-associated vessels and the rate of recurrence was evaluated. In addition, PSMA levels in human umbilical vein endothelial cells (HUVECs) treated with conditioned medium (CM) from renal cancer cell lines Caki1 and ACHN were analyzed by Western blotting (WB) and immunofluorescence (IF). Angiogenic activity was measured using a tube formation assay, and RNA sequencing (RNA-seq) was conducted to examine gene expression changes in endothelial cells influenced by vesicles secreted from renal cancer cells. Spatial gene expression analysis was performed to compare differences in gene expression between tumor vessels near and vessels away from the tumor. Results: Immunohistochemical staining for PSMA and CD31 revealed that only peritumoral vessels exhibited PSMA positivity. PSMA expression was categorized into three levels: weak (18 cases), moderate (11 cases), and strong (16 cases), with these levels corresponding to different recurrence rates. When the 10,000 g pellet fraction of CM from renal cancer cell lines was applied to HUVECs, they became PSMA-positive, leading to enhanced tube formation. RNA-seq analysis further demonstrated that HUVECs exposed to CM from renal cancer cells showed upregulation of pathways associated with angiogenesis. Conclusions: Vesicles secreted by renal cancer cells promote PSMA expression in vascular endothelial cells and boost angiogenic activity. Future research will aim to elucidate the mechanism by which PSMA becomes expressed in normal vascular endothelial cells, with the potential to pave the way for new anti-angiogenic therapies.

Re-treatment of metastatic castration-resistant prostate cancer patients with radium-223 therapy in daily practice.

183 Background: Radium-223 is a therapeutic option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and consists of up to 6 monthly injections. After the approved 6 radium-223 injections, treatment may be repeated. This study evaluated the safety and efficacy of radium-223 re-treatment in mCRPC patients in routine clinical practice. Methods: This multicenter, retrospective cohort study included patients with bone mCRPC who previously received 6 consecutive injections of radium-223 according to standard of care, and received at least one radium-223 re-treatment injection between 2014 and 2024. Patients with visceral metastases were excluded. Primary endpoint was safety (hematological and non-hematological adverse events (AEs), including skeletal-related events (SREs)). Secondary endpoints were the number of administered injections, overall survival, and alkaline phosphatase (ALP) and prostate-specific antigen (PSA) responses. Exploratory analyses intended to find variables associated with ALP response during re-treatment and completion of radium-223 re-treatment. Results: Across 7 Dutch medical centers, 61 patients were included. Median age was 75 years, 44% received prior chemotherapy, 87% previously received at least one androgen receptor pathway inhibitor and 51% received concomitant bone health agents. Median number of prior systemic therapies was 3. 81% of patients had an ECOG performance status ≥1. 95% of patients had at least one hematological AE, including 14% grade 3 hematological AEs. In total, 44 (75%) patients experienced at least one non-hematological AE during radium-223 re-treatment. No grade 4-5 AEs occurred. 11 (18%) patients developed a SRE during radium-223 re-treatment, including 2 (3%) patients with spinal cord compression. Time until first SRE was 9.5 months (95% CI, 6.2-12.8). The patients received a median number of 6 radium-223 re-treatment injections (IQR; 4-6). Overall survival was 16.9 months (95% CI, 11.9-21.9) from start of re-treatment. 56% of patients had a ≥30% ALP response and 25% had a ≥30% PSA response. Other than elevated ALP levels at baseline, no variables were associated with ≥30% ALP response during radium-223 re-treatment. High baseline hemoglobin levels, no prior chemotherapy and a PSA response ≥30% during the initial radium-223 therapy were predictors for completion of 6 radium-223 re-treatment injections. Conclusions: Radium-223 re-treatment was well tolerated and is therefore deemed safe in selected mCRPC patients. In addition, the high number of administered injections and the high ALP response rates suggest benefit in this cohort of advanced mCRPC patients. Further research should directly compare radium-223 re-treatment and other life-prolonging therapies to determine the position of radium-223 re-treatment within the therapeutic landscape of mCRPC.

Modelling protein-protein interactions for the design of vaccine chimeric antigens with protective epitopes

Ticks and tick-borne diseases are a growing burden worldwide and vaccines are effective control interventions. Vaccine formulations with tick antigens such as BM86/BM95 (BM) and Subolesin (SUB) have shown reduction in tick fitness and infestation in immunized hosts. However, antigen combination is a challenging approach to improve vaccine efficacy (E) against multiple tick species. Herein, in silico and in music algorithms were integrated to model BM-SUB protein-protein interactions to apply a quantum vaccinology approach for combining protective epitopes or immunological quantum in the chimeric antigen Q38-95. Cattle immunized with Q38-95 and infested with African blue tick Rhipicephalus decoloratus showed an 82% E similar to BM86 and higher than SUB. The immune mechanisms activated in cattle in response to vaccination with Q38-95 were mediated by anti-BM/SUB antibodies that interfered with BM-SUB interactions and through activation of other innate and adaptive immune pathways. The results support modelling protein-protein interactions affecting E to identify and combine candidate protective epitopes in chimeric antigens.

Author Correction: Cancer and One Health: tumor-bearing individuals can act as super spreaders of symbionts in communities

Quantifying the benefit of salvage radiation versus surveillance for biochemically recurrent prostate cancer after radical prostatectomy.

382 Background: The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) is heterogeneous, with most patients not progressing to metastasis. Determining the impact and optimal timing of salvage radiation therapy (SRT) remains challenging, particularly in the absence of prospective randomized trials with a surveillance control arm. Our objective isto quantify the oncologic benefit of SRT among men with BCR after RP. Methods: Patients who underwent RP at Mayo Clinic between 1990 and 2017 and developed BCR (PSA≥0.20ng/mL) were included. Patients treated with SRT were compared to those managed with surveillance using risk-set matching with time-dependent propensity scores, accounting for covariates at BCR and post-BCR. The primary outcome was metastases, analyzed via Kaplan-Meier and Cox proportional hazard models. The number needed to treat (NNT) with SRT to prevent progression was calculated using regression outputs at 5 and 15 years post-BCR. Interaction analyses identified factors modifying SRT’s effect on metastasis. Results: Of 6,881 patients with BCR, 2,109 received SRT. At a median follow-up of 10.2 years, 1,147 patients with BCR developed metastases. After 1:1 matching, SRT was associated with lower metastasis risk than surveillance at 5 years (12.7% vs 19.3%, p<0.0001) and 15 years (28.6% vs. 31.5%, p<0.001). SRT was independently associated with decreased metastasis risk (HR 0.75, 95%CI 0.63–0.90, p=0.002) on multivariable analysis, translating to NNT of 23 and 15 at 5 and 15 years, respectively (Table). Additionally, we noted a significant interaction between PSA at SRT and the association of SRT with metastasis (p-interaction=0.02), such that the reduction in metastatic progression with SRT vs. surveillance was restricted to the cohort of patients who received SRT for PSA>0.40ng/mL (HR 0.66, 95%CI 0.54–0.80, p<0.001). Conclusions: Most patients with BCR post-RP do not develop metastases. Indeed, the NNT with SRT to reduce metastasis versus surveillance indicates a generally indolent disease course. Further, the lack of a significant association of SRT with reduction of metastases in patients with a PSA≤0.40ng/mL underscores the importance of careful patient selection when considering early SRT. Our data establish the rationale for a randomized trial comparing early SRT versus surveillance for appropriately selected patients with BCR after RP. Hazard ratios of SRT after matching by propensity scores, and number needed to treat for systemic progression, prostate cancer specific mortality and overall mortality. DiseaseOutcome Hazard Ratio(95% CI) P value Number Needed to Treat* (95% CI) 5 years 15 years Systemic progression 0.75(0.63 – 0.90) 0.002 23(17 – 41) 15(11 – 27) Prostate cancer mortality 0.81 (0.64 – 1.03) 0.086 103(62 – 494) 26(15 – 124) Overall mortality 0.79 (0.70 – 0.89) 0.0001 38(29 – 62) 12(9 – 20) *Number needed to treat (NNT) calculated using regression based absolute differences in event free survival between salvage radiation therapy (SRT) and observation.

Safety and efficacy of FGFR inhibitors in urothelial carcinoma: A systematic review and meta-analysis.

782 Background: Urothelial carcinoma is the most frequently occurring bladder cancer and originates from urothelial cells lining the bladder and the urinary tract. Fibroblast growth factor receptor (FGFR) inhibitors are the emerging treatment option, due to their ability to alter FGFR signaling which plays a role in tumor proliferation, survival, and angiogenesis. This study aims to assess the efficacy of FGFR inhibitors for urothelial carcinoma. Methods: We conducted a systematic review and single-arm meta-analysis by systematically searching PubMed, Cochrane, and Embase for studies evaluating the efficacy and/or safety of FGFR inhibitors for urothelial carcinoma. The primary measures of effect were hazard ratios (HRs) and the proportion of events per 100 observations, both with 95% confidence intervals (CIs), pooled using a random-effects model with a generalized linear mixed model (GLMM). Heterogeneity was assessed using the I² statistic and Cochran’s Q test. Statistical analyses were performed using RStudio v4.3.3. Results: We included 19 studies, comprising two cohort studies and 17 clinical trials, five of which were randomized controlled trials (RCTs), with a combined total of 1,187 patients. The pooled median overall survival (mOS) was 8.77 months (95% CI, 7.28; 10.56), the pooled median progression-free survival (mPFS) was 3.46 months (95% CI, 2.73; 4.40), and the median duration of response (mDOR) was 5.38 months (95% CI, 4.72; 6.14). The grade ≥ 3 adverse effects rate was 49.43% (95% CI, 35.44; 63.51%). The overall objective response rate (ORR) was 24.16% (95% CI, 17.65; 32.14%), in the subgroup analysis of 218 patients using Erdafitinib ORR was 42.25%. The progressive disease and stable disease rates were 48.64% (95% CI, 38.88; 58.50%) and 26.07% (95% CI, 20.01; 33.21%), respectively. Conclusions: Our meta-analysis suggests that FGFR-targeted treatment regimens show promising clinical activity in urothelial carcinoma with a comparable safety profile to conventional treatment modalities.

Real-world evidence for factors associated with development of castration-resistant prostate cancer (CRPC).

92 Background: Androgen deprivation therapy (ADT) is foundational for advanced prostate cancer (PCa); luteinizing hormone-releasing hormone (LHRH) agonists and gonadotropin-releasing hormone (GnRH) antagonists are widely used. ~20% of PCa patients on LHRH analogs develop castration-resistant prostate cancer (CRPC) within 3 years. We evaluated factors associated with CRPC onset and time to CRPC onset for agonists vs. antagonist using real-world dataset. Methods: Data were collected from an EMR database purchased from Decision Resources Group. Analysis set included PCa patients who received ≥1 ADT 1991-2020 and excluded those who received both LHRH agonist and a GnRH antagonist and/or developed CRPC on the same day/before ADT initiation. CRPC onset date was defined as the earlier of 2 options: CRPC diagnosis or first CRPC therapy (standard of care treatments e.g., androgen pathway inhibitors, immunotherapy, chemotherapy, radiotherapy). Associations between CRPC and each available factor were evaluated using MV Cox regression. Time to CRPC onset was assessed for agonists vs. antagonist. Results: 41,379 patients were analyzed. Factors associated with MV HR >1.4, p<0.001 were oncology setting, metastatic disease, absence of diabetes, and no statin use (Table 1). Antagonist use had an adjusted HR of 1.4 (95% CI 1.06-1.85, p=0.02). Median time to CRPC onset after ADT initiation is 10.9 months for antagonist (n=238) vs. 17.3 months for agonists (n=5,231). Conclusions: Treatment-related (oncology setting; antagonist use) and comorbidity factors (older age, no diabetes, no statin use) were associated with CRPC onset. Oncology setting and antagonist use may reflect practice patterns in higher risk individuals. The association between diabetes and CRPC risk is under further evaluation e.g., whether antecedent diabetes therapies confer protection. Hazard ratio (95% CI) and P-value of CRPC for top 10 significant factors 1 in multivariable analysis. Multivariable (n=9,554) 2,3 Factors HR (95% CI) P-value Oncology vs Urology (Setting) 3.04 (2.56-3.59) <0.001 W vs W/o Metastasis (Baseline) 2.20 (1.58-3.05) <0.001 W/o vs W Diabetes 4 1.45 (1.22-1.73) <0.001 W/o vs W Statin 4 1.43 (1.25-1.63) <0.001 Antagonist vs Agonist 1.40 (1.06-1.85) 0.02 W/o vs W Hypertension 4 (HTN) 1.17 (1.01-1.36) 0.041 Decreasing ADT Exposure per Year 1.09 (1.05-1.13) <0.001 Increasing Age per Year (Older vs Younger) 1.02 (1.02-1.03) <0.001 1 Significant for multivariable analysis. 2 Excluded patients with CRPC on the same day/before ADT Start. 3 Excluded patients with both agonist and antagonist use; without BMI, PSA, and age data; non-white/black race; with unknown urology/oncology or with both urology/oncology setting. 4 Has taken statins/hypertension/diabetes medication or diagnosed with hypertension/diabetes disease.

Avelumab first-line (1L) maintenance therapy in advanced urothelial carcinoma: Final analysis from a real-world study in the UK.

723 Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab 1L maintenance therapy plus best supportive care (BSC) significantly improved overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) that had not progressed with 1L platinum-based chemotherapy (PBC). In the UK, initial access to avelumab was provided via the Early Access to Medicines Scheme (EAMS) from September 2020. This study reports 24-month real-world outcomes in patients treated with avelumab 1L maintenance via the EAMS in the UK. Methods: Patients aged ≥18 years who had been diagnosed with la/mUC, demonstrated at least stable disease following 1L PBC, and initiated avelumab since October 2020 were recruited consecutively from 10 UK hospitals. Primary outcomes included real-world OS, real-world PFS, and treatment patterns by 24 months. Recruitment was completed in June 2022, and all patients had completed 24 months of follow-up from avelumab initiation by June 2024. Results: Of 106 patients recruited, 78 (73.6%) were male. Median age at diagnosis of la/mUC was 72 years. Primary tumor site was bladder in 40 (78%), and the most common metastatic sites were lymph node in 64 (60.4%), lung in 31 (33%), and bone in 20 (21.3%). ECOG performance status was 0 in 35 (33.0%),1 in 36 (34%), 2-4 in 5 (4.7%), and not recorded in 30 (28.3%). 1L PBC was carboplatin/gemcitabine in 55 (51.9%) and cisplatin/gemcitabine in 49 (46.2%). Response to 1L PBC was partial or complete response in 63 (60.0%). From avelumab initiation, median OS was 16.8 months (95% CI, 11.6-23.4) and median PFS was 8.7 months (95% CI, 7.1-14.2). Median OS from the start of 1L PBC in this population without disease progression after 1L PBC was 21.8 months (95% CI, 17.0-28.9). In subgroup analyses of patients who had received 1L carboplatin/gemcitabine or cisplatin/gemcitabine, median OS from avelumab initiation was 14.4 months (95% CI, 10.1-not estimable [NE]) and 21.4 months (95% CI, 15.4-NE), and median OS from start of 1L PBC was 19.5 months (95% CI, 14.8-NE) and 26.7 months (95% CI, 20.5-NE), respectively. Conclusions: These results provide evidence of the clinical effectiveness of avelumab 1L maintenance therapy in patients who were progression free following 1L PBC in a UK real-world setting. Median OS was shorter than previously observed in the JAVELIN Bladder 100 trial, which may be due to the worse ECOG performance status and higher proportion of patients who had received 1L carboplatin-based chemotherapy in this real-world population.

Patient perceived weight stigma and patient-centered language use preferences: A cross-sectional mixed methods analysis conducted in a large academic medical center

Background Due to the rising prevalence of obesity and its impact on healthcare, patient-specific context is needed to optimize weight management with an emphasis on reducing health care-associated weight stigma. Our survey aimed to explore institution-specific patient experiences of weight stigma and preferences for patient-centered language use regarding weight management care. Methods This cross-sectional analysis adopted a concurrent mixed methods design with a sample of individuals who opted in to complete patient experience surveys after receiving care at a large academic medical center in the United States (U.S.). Categorical and continuous variables were assessed using Chi-squared and analysis of variance. We used classical content analysis to qualitatively analyze free-text data for thematic coding. Results After a 1-week survey fielding period, 3,219 of 16,758 patients completed the survey, yielding a response rate of (19.2%) with 2,816 having available electronic health record body mass index (BMI) data. Patients were comfortable discussing weight with their primary care providers but showed variation in the preferred approach and terms. Female patients with higher BMIs reported higher rates of delayed and canceled care due to prior weight stigma (25.6% and 12.2% for patients with class 3 obesity), and preferred a slower, gentler, and less direct approach with term preferences for “healthy eating plan” and against “obesity.” Qualitative analysis yielded 27 themes grouped into three domains: Emotional Hinderances, Perceptual Hinderances, and Perceived Helpfulness. Conclusions Findings from our large single institution cohort expand on the existing weight stigma literature by identifying patient language preferences and healthcare experiences according to patient weight class and sex. Given the potential impact of understanding context-specific patient language use preferences to reduce weight stigma, we recommend other healthcare systems use a similar process to address weight stigma as part of a coordinated health system improvement initiative to enhance patient-centered weight management care.

Low-intensity pulsed ultrasound induces multifaced alterations in chromosome segregation, cytoskeletal filaments and cell junctions

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Grade and volume progression and its association with the Decipher genomic classifier using patients enrolled in a prospective active surveillance protocol.

262 Background: The progression of prostate cancer through serial biopsies in patients on active surveillance is a multifaceted process, with grade and volume progression offering unique perspectives on disease advancement. The Decipher genomic classifier has been recognized as a valuable tool for predicting disease progression. This study examines the relationship between the Decipher score, and other GRID signatures and pathways, and grade and volume progression in prostate cancer patients, utilizing data collected prospectively from the Miami Active Surveillance Trial (MAST). Methods: We scrutinized 224 baseline samples from 124 unique patients participating in the MAST database. Progression was categorized into grade progression, volume progression, and no progression. For patients with multiple samples, the sample with the highest Decipher score was selected. We also evaluate the association between 11 prognostic signatures, including the Decipher score and an average genomic risk score combining the 11 signatures and 20 pathways available from the Decipher GRID. Results: Out of the baseline samples, 60 demonstrated grade progression, 51 volume progression, and 113 showed no progression. We found that the Decipher was not associated to our trial definition of progression, that combined grade and volume progression however we did find a statistically significant difference in Decipher scores from patients who experience grade progression (p=0.0005) as compared to volume progression (p=0.92) when comparing them with patients with no progression. A heat map evaluating prognostic signatures and pathways available on the Decipher grid found that the majority of prognostic signatures including the Decipher score and the average risk model were more associated with grade progression compared to volume or no progression. Conclusions: Our findings suggest that the Decipher score has a stronger correlation with grade progression than volume progression in prostate cancer patients. This highlights the potential of genomic classifiers like Decipher in enhancing our understanding of disease progression and in tailoring personalized treatment strategies. Further prospective studies are required to validate these findings. Clinical trial information: NCT02242773 .