Browse Articles

Evaluating the association between bone pain and radiologic progression-free survival (rPFS) in patients with metastatic castration-sensitive prostate cancer (mCSPC).

94 Background: Previous studies have shown bone pain to be associated with worse survival in patients with metastatic castration-resistant prostate cancer (mCRPC). However, there are few data regarding bone pain and survival outcomes in patients with (mCSPC). In the current study, we evaluated the association between bone pain and rPFS in patients treated with mCSPC. Methods: rPFS were estimated by using the Kaplan-Meier method and the log-rank test was used for the comparison between different subgroups. Differences in baseline characteristics by bone pain status at mHSPC were evaluated with χ2 test for categorical variables. Results: Data from 205 patients were analyzed. A detail of the patient’s characteristics is shown (Table).The median rPFS for all populations was calculated as 24 mo. In univariate analysis, the median rPFS were 17 vs 29.5 mo in patients with bone pain presentations vs none-pain (p=0.001), 29 vs 20 mo in patients with ECOG PS 0 or 1≥ (p=0.09), 22 vs 14 mo in patients with DNA repair mutations absent and present(p=0.06), 27 mo vs 19 mo in patients with low volume presentation vs high volume (p=0.05), 15 vs 25 months in patients with or without liver metastases (p=0.003), 17 mo vs 27 mo in patients with hemoglobin levels <12 gr/dL or higher (p=0.002), respectively. In multivariate analysis, bone pain (HR 1.9; 95% CI 1.2-3.1; p:0.001), hemoglobin<12 gr/dL (HR 2; 95% CI 1.9 -3.1; p:0.005) were found to be an independent determinant of short rPFS. Conclusions: Bone pain is associated with short rPFS in mCSPC. The current study showed bone pain needs to be selected in the treatment choice or prognostic model in mCSPC. Baseline characteristics of patients. Variable Patients Presence of bone pain Absence of bone pain (n=104) (n=101) p value ECOG performance status, n(%), p 0 ≥1 34 (%32.7)70 (%67.3) 67 (%66.3)34 (%33.7) <0,001 Gleason score at diagnosis, n(%), p <8 ≥8 Unknown 31 (%29.8)66 (%63.5)7 (%6.7) 34 (%33.7)65 (%64.4)2 (%1.9) 0,723 Under/over 70 years old, n(%), p <70 years ≥70 years 40 (%38.5)64 (%61.5) 47 (%46.5)54 (%53.5) 0,242 High/low volume disease, n(%), p High volume Low volume 76 (%73.1)28 (%26.9) 29 (%28.7)72 (%71.3) <0,001 Metastasis at diagnosis, n(%), p Yes No 79 (%76)25 (%24) 64 (%63.4)37 (%36.6) 0,050 Metachronous metastasis, n(%), p Yes No 25 (%24)79 (%76) 36 (%35.6)65 (%64.4) 0,069 Liver metastasis at diagnosis, n(%), p Yes No 9 (%8.7)95 (%91.3) 0 (%0)101 (%100) 0,002 DNA repair mutation, n(%), p Positive Negative Unknown 10 (%9.6)38 (%36.5)56 (%53.9) 5 (%5)38 (%37.6)58 (%57.4) 0,436 Hemoglobin levels, n(%), p <12 gr/dL ≥12 gr/dL Unknown 30 (%28.8)61 (%58.7)13 (%12.5) 20 (%19.8)74 (%73.3)7 (%6.9) 0,073 PSA levels, n(%), p <17 ng/ml ≥17 ng/ml 46 (%44.2)58 (%55.8) 56 (%55.4)45 (%44.6) 0,094 First line treatment 0.08 Androgen receptor pathway inhibitor 43 (%41.3) 45 (%44.6) Only ADT 34 (%32.7) 42 (%41.6) Docetaxel 27 (%26) 14 (%13.8)

Treatment patterns of MIBC patients not receiving radical cystectomy: Results from a real-world survey in Europe.

738 Background: Neoadjuvant chemotherapy followed by Radical cystectomy (RC) is the current standard of care for muscle invasive bladder cancer (MIBC). RC is associated with significant risks and quality of life (QoL) implications. This real-world survey aimed to understand the drivers behind why patients (pts) do not receive RC, and alternative treatments initiated with curative intent. Methods: Medical oncologists and urologists across France, Germany, Italy, Spain, and the UK were recruited to the Adelphi MIBC Disease Specific Programme (DSP)™ to extract patient medical records for their next 4 consecutive pts with MIBC who did not receive RC. Data was collected Dec 2023 to May 2024. Results: 200 physicians provided data for 762 pts with MIBC who didn’t receive RC, of whom 388 (51%) refused RC; 357 (47%) were ineligible for RC; and 17 (2%) didn’t receive RC for other reasons. The mean (standard deviation) age of pts was 73.9 (9.3) years; 70.1 (9.2) for pts that refused RC and 78.2 (7.4) for RC ineligible pts. 78% of pts were diagnosed de novo MIBC, and 20% of pts progressed from non-invasive disease. When surveyed as to why their pts may refuse RC, the most common reason physicians reported was pts not wanting a stoma (80%), followed by QoL concerns (66%) and concerns with the risk of surgery (48%). When asked which factors they consider when determining a patient’s eligibility for RC, the most common were comorbidities (90%), physical performance status (87%), and cardiac status (68%). Of the 388 pts that refused RC, the top 3 reasons provided by patients for refusal were QoL concerns following RC (71%), not wanting to live with a stoma (59%), and concerns over the risk of surgery (37%). Amongst the 357 RC ineligible pts the most common reasons they were deemed as such were their comorbidities (40%), physical performance status (37%), and cardiac status (11%). Bladder sparing therapy with curative intent (BSTx) was received by 367 (48%) of non-RC pts, of whom 94% had only 1 line. Treatments received at 1 st line can be seen below. Alongside BSTx non-radical surgery was received by 78% of pts, most commonly transurethral resection (74%) or partial cystectomy (5%). Complete response to 1 st line BSTx was reported by physicians in 44% of pts. Among pts that refused RC 48% recorded a complete response whilst this was 36% for RC ineligible pts. Conclusions: In this analysis, a similar proportion of pts refuse RC as are considered ineligible. There is a need for novel approaches to improve the options available to pts without compromising outcomes. Treatments received at 1 st line BSTx n, (%). All non-RC ptsn=762 Refused RCn=388 RC ineligiblen=357 No RC - other reasonn=17 Chemotherapy only 151 (20) 90 (23) 59 (17) 2 (12) Radiotherapy only 52 (7) 19 (5) 32 (9) 1 (6) Chemoradiotherapy 134 (18) 97 (25) 35 (10) 2 (12) Treatments including immunotherapies 21 (3) 11 (3) 10 (3) 0 (0) Other treatments 9 (1) 6 (2) 3 (1) 0 (0) No BSTx 395 (52) 165 (43) 218 (61) 12 (71)

Development of a functional electrical stimulation cycling toolkit for spinal cord injury rehabilitation in acute care hospitals: A participatory action approach

The purpose of our study was to develop a toolkit to facilitate the implementation of functional electrical stimulation (FES) cycling for persons with a newly acquired spinal cord injury (SCI) in the acute care inpatient hospital setting. The researchers and community members used participatory action as a research approach to co-create the toolkit. We held two focus groups to develop drafts, with a third meeting to provide feedback, and a fourth meeting to evaluate the toolkit and determine dissemination strategies. Toolkit development followed the Planning, Action, Reflection, Evaluation cycle. We used an iterative design informed by focus group and toolkit consultant (SC) feedback. In focus group discussions, we included FES cycling champions (JK, DW) who led acute care implementation. Focus group members, recruited through purposive sampling, had to 1) have an understanding about FES cycling in acute care for SCI and 2) represent one of these groups: individual living with SCI, social support, hospital manager, clinician, therapist, researcher, and/or acute care FES cycling champion. Twelve individuals took part in four focus groups to develop a toolkit designed to facilitate implementation of FES cycling in SCI acute care in Edmonton, Alberta. Group members included an individual with lived experience, three acute-care occupational or physical therapists, three acute-care hospital managers, and five researchers. Two physical therapists also identified as clinical FES cycling champions. Following an inductive content analysis, we identified four main themes: 1) Health care provider toolkit content and categories, 2) Health care provider toolkit end product, 3) Collaborations between groups and institutions and 4) Infrastructure. Interested parties who utilize FES cycling in acute care for SCI rehabilitation agree that toolkits should target the appropriate group, be acute care setting-specific, and provide information for a smooth transition in care.

The long-term associations of childhood parental loss with attachment, creativity, and epigenetic regulation

Downregulation of E-selectin and contributions to immune restraining in prostate cancer.

257 Background: Immune surveillance in prostate cancer (PCa) relies on leukocyte trafficking into target tissues, a process mediated by endothelial adhesion molecules. This study investigates the role of E-selectin (SELE) in PCa immune evasion and patient outcomes. Methods: We analyzed transcriptomic data from 7,523 PCa samples (4,768 localized; 2,755 metastatic) molecularly profiled at Caris Life Sciences to assess SELE expression. Correlations between TNF and adhesion molecule expression were examined in normal prostate and PCa tissues. Survival analysis was performed based on SELE expression levels. Immunohistochemistry was conducted to evaluate SELE protein expression in tumor, benign prostatic hyperplasia (BPH), and stromal samples. Results: SELE was significantly upregulated in localized PCa samples compared to metastases (SELE: 0.83 vs 0.47 TPM, p<0.001), along with SELP (P-selectin) (3.15 vs 1.29 TPM, p<0.0001), ICAM1 (5.05 vs 3.70, P<0.0001) and VCAM1 (7.10 vs 5.41, P<0.001), while TNF expression was similar (0.48 vs 0.43 TPM, P<0.001). TNF positively correlated with SELE, with a stronger correlation observed in metastatic vs localized PCa samples, suggesting altered transcriptional regulation. High expression of SELE was associated with improved survival among patients with localized PCa (HR=0.61, p<0.0001), with no significant difference observed among those with metastatic PCa (HR=0.90, p=0.153). Among those with localized PCa, high expression of SELP was also associated with improved survival (HR=0.75, p<0.001), while worse overall survival was associated with high expression of ICAM1 (HR=1.58, p<0.0001), VCAM1 (HR=1.73, p<0.0001), and TNF (HR=1.23, p=0.004). Combined high SELE/low TNF demonstrated an enhanced survival effect compared to low SELE/high TNF (HR=0.44, p<0.001). Conclusions: Our findings suggest that downregulation of SELE in PCa contributes to tumor "coldness" by potentially reducing anti-tumor immune cell infiltration. This mechanism may explain the limited efficacy of immune checkpoint inhibitors in PCa. The strong association between SELE expression and improved survival highlights their potential for prognostic biomarker and therapeutic target in PCa.

Prognostic and predictive genomic biomarkers in metastatic clear cell renal cell carcinoma (mccRCC): A large retrospective analysis of real-world data from a US-based clinico-genomic database (CGDB).

473 Background: The absence of validated prognostic and predictive biomarkers constitutes a significant barrier to appropriate selection among immune checkpoint inhibitor combinations (ICI-C) for individual patients (pts) with mccRCC. Our study aimed to evaluate the prognostic and predictive value of single-gene alterations (GAs) and gene clusters in a large real-world case series of mccRCC. Methods: This study employed data from the US-based de-identified Flatiron Health-Foundation Medicine Inc. (FH-FMI) CGDB, comprising 858 mccRCC pts diagnosed between 2011 and 2022 in 280 US cancer clinics. The presence of GAs was determined using Foundation Medicine tests on tumor tissue specimens. The co-occurrence and mutual exclusivity of the most common GAs were assessed utilizing Fisher's exact test. The Louvain algorithm was applied to identify three co-occurring gene clusters (C) on the gene network graph: C1: VHL , SETD2 , PBRM1 , KDM5C , NFE2L2; C2: TP53 , TSC1 , TERT , DNMT3A ; C3: CDKN2A , CDKN2B , BAP1 , NF2 , MTAP . Pts were labelled as C+ if they had one or more mutations within a specific cluster and none in the others. Cox proportional hazard model was used to discern the prognostic and predictive value of GAs. Median overall survival (mOS) and progression-free survival (mPFS) were estimated using the Kaplan-Meier method. Results: The prognostic analysis encompassed 782 pts with mccRCC, while the predictive analysis involved 493 pts profiled with FMI genomic tests within 3 months of starting first-line systemic therapy (1L). GAs of seven genes ( CDKN2A , CDKN2B , TP53 , PTEN , NF2 , PIK3CA , MTAP ) correlated with a poorer prognosis, whereas PBRM1 mutants exhibited a favorable OS. C1+ pts had higher OS compared to C1- (mOS: 40 vs. 19 months; HR: 0.63, p <0.001), while C3+ was associated with worse OS (mOS: 18 vs. 27 months; HR: 1.36, p = 0.023). In 1L, 201 pts (40.8%) received antiangiogenic monotherapy (AAm) (mPFS: 7.0 months) and 172 pts (34.9%) received ICI-C (16.4% ICI+ICI, 18.5% ICI+AA) (mPFS: 6.8 months). 170 (34.5%), 43 (8.7%), and 71 (14.4%) pts were categorized as C1+, C2+, and C3+, respectively. TERT , TSC1 , and TET2 alterations were positive predictors of 1L-PFS for ICI-C vs. AAm (HR=0.44, 0.23, 0.20; p<0.05). C1+ favored AAm over ICI-C (HR=2.30, p=0.01) while C2+ favored ICI-C over AAm (HR=0.39, p=0.039). Among ICI-C, ICI+AA was more effective than ICI+ICI in pts with SETD2 alterations (HR=0.38, 0.020), and less effective in mutant TSC1 (HR=8.60, p=0.013). Conclusions: This study highlights the prognostic value of 8 GAs and 2 clusters of co-occurring GAs, and identifies 3 GAs and 1 cluster of co-occurring GAs to be positive predictors of 1L-PFS for ICI-C in a large mccRCC population. Prospective validation is required to confirm the prognostic and predictive role of these GAs and to tailor therapeutic strategies.

Treatment sequence (TS) and overall survival (OS) in patients with metastatic urothelial cancer (mUC): An observational, multicenter, real-life STATES-Bladder study.

724 Background: mUC remains of poor prognosis despite standard first-line platinum-based chemotherapy (PBC), maintenance avelumab for ptd non progressing PBC. Enfortumab vedotin (EV) and erdafitinib offers a promising option in later lines of therapy. However all patients will not receive the whole sequence and the attrition rate remains crucial. As the therapeutic landscape evolved over the last 5 years no recent data are available on an whole mUC population including responder and non responder to PBC. This study aims to evaluate OS and treatment outcomes in real-world practice across multiple centers in France. Methods: This retrospective study included 180 patients with mUC treated with first-line PBC between January 2020 and December 2023. The primary objective was to assess OS in the overall population. Secondary objectives included OS by treatment sequence, performance status (PS), and attrition rates across treatment lines. We analyzed OS in patients receiving maintenance avelumab, those progressing to second-line therapies, and attrition at each treatment line. Additionally, OS was compared between patients with WHO PS 0-1 and WHO PS 2-3. Results: The median age was 72 years (41-91), with 81% male. Synchronous metastases were observed in 52% of patients, while 48% had metachronous metastases. The most common metastatic sites were lymph nodes (68%), lung (33%), bone (32%) and liver (21%). 44% of patients received cisplatin-based chemotherapy, while 56% were treated with carboplatin. Among patients with WHO PS 2-3 (20%), median age was 73 years (41-91), with a greater proportion having liver (25%) and bone (42%) metastases. For the entire population, median OS was 22.4 months [CI95%,17.2-26.7]. Patients receiving avelumab maintenance had a median OS of 29.0 months [CI95%,22.5-NA], while those progressing to second-line therapy showed a median OS of 15.6 months [CI95%,12.4-24.4]. Median OS for patients treated with EV at any treatment line was 26.1 months [CI95%,22.5-NA]. 58% of patients received avelumab maintenance. Attrition rates were 57% after first-line, 37% after second-line, and 9% after third-line therapy. Patients with WHO PS 0-1 had a significantly better median OS of 26.4 months [CI95%,22.5-NA], compared to 7.2 months [CI95%,6.1-13.1] for those with WHO PS 2-3 (p<0.001). Conclusions: These real-world survival outcomes are consistent with large phase 3 trials. The particularly poor prognosis of patients with WHO PS 2-3 underscores the need for innovative treatment strategies, such as EV plus pembrolizumab, as highlighted by the EV-302 study, to potentially improve outcomes in this challenging subgroup.

Safety and efficacy of immune checkpoint inhibitor rechallenge in metastatic fumarate hydratase-deficient renal cell carcinoma: A retrospective study.

500 Background: Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare subtype of kidney cancer characterized by FH-inactivating alterations. Studies have revealed highly immunogenic features in this lethal disease, providing molecular evidence for implement of immune checkpoint inhibitor (ICI). Due to the lethal nature of FH-deficient RCC, a significant proportion of patients continue to have disease progression after receiving ICI combination therapy (ICI plus tyrosine kinase inhibitors, TKI). Herein, we aim to evaluate the safety and efficacy of immune checkpoint inhibitor rechallenge in metastatic fumarate hydratase-deficient renal cell carcinoma in real-world settings. Methods: A multicenter database of patients diagnosed with FH-deficient RCC, identified through IHC evidence of negative FH and/or positive 2SC, was explored. The study enrolled patients with metastatic FH-deficient RCC who received ICI combination therapy within three months of discontinuing prior ICI treatments between January 2018 and July 2023. Results: A total of 18 patients, each receiving at least two lines of ICI combination therapy, were included in the study. The majority of patients (n=15) experienced disease progression following prior-line immunotherapy. Among these, with 66.7% (10/15) showed progression in the original lesions, while 33.3% (5/15) developed new metastatic lesions. Three patients transitioned to later-line immunotherapy due to immune-related adverse events (irAEs) of grade 3 or higher. The incidence of grade 1-2 irAEs was comparable between prior and later-line therapies (28.15% vs. 27.30%, p=0.8932), as was the incidence of grade 3 or higher irAEs (0.86% vs. 0.29%, p=0.594). For the entire cohort, the median progression-free survival (mPFS) for prior-line ICI combination therapy was 16.2 months (95% CI: 5.565-26.835 months), and the mPFS for later-line ICI combination therapy was 15.2 months (95% CI: 3.915-26.485 months). The objective response rate (ORR) and disease control rate (DCR) for later-line therapy were 17% and 78%, respectively, compared to an ORR of 28% and a DCR of 67% for prior-line therapy. Conclusions: This cohort study demonstrated that ICI rechallenge achieved mPFS of 15.2 months and DCR of 78%, with a favorable safety profile in patients with FH-deficient RCC. Therefore, the resumption of ICI combination therapy may be a viable option for managing this lethal subtype of RCC.

Correction: Health and wellness in the Australian coal mining industry: An analysis of pre-post findings from the RESHAPE workplace health promotion program

Understanding in same- versus cross-race close relationships predicts the well-being of people of color over time

First line treatment of pancreatic metastases in metastatic renal cell carcinoma: Insights from the UK Renal Oncology Collaborative (UK ROC)—Tyrosine kinase inhibitors time to shine?

514 Background: Pancreatic metastases (PM) are a rare site of spread in metastatic renal cell carcinoma (mRCC). It has been suggested that patients with PM have improved survival outcomes and more angiogenic driven biology than other metastatic sites. We sought to define these outcomes and determine if TKI based combination is the preferred option in the first line treatment approach. Methods: UK ROC is a RWE multicentre study from patients starting SACT for mRCC in 17 UK centres. Retrospective analysis of patients with and without PM was performed. Survival data were compared using Kaplan–Meier curves, and the statistical significance of differences in outcome between the groups was assessed with the log‐rank test. Progression-free survival (PFS) and Overall Survival (OS) from the start of first-line therapy and initial diagnosis was assessed using Cox regression analysis comparing single agent TKI, IO/TKI and IO/IO combinations. Results: 1319 patients were identified, median age of 65. 90 (6.8%) patients within the cohort had PM. Of these 90, 11 patients had pancreatic only metastatic disease. There were no statistical differences in the distribution of the IMDC prognostic group (p=0.194), type of first-line treatment (IO/IO, TKI or TKI/IO) (p=0.189) or age (p=0.079) in patients with and without PM. Interestingly there was a significantly greater proportion of females in the PM group (37.8% vs 28.2%) (p=0.02). Patients with PM had a significantly greater interval from primary diagnosis to the date of first systemic treatment as compared to those without (median: 44 vs 5 months) (p<0.001). As expected, patients with PM in the overall population had improved OS from the primary diagnosis compared to non-PM [70 vs 28 months (HR 0.51, p<0.01)]. Similarly, PFS from diagnosis was significantly prolonged in those with PM (68 vs 19 months, HR 0.44, p<0.01). Importantly patients who have PM who receive either single agent TKI or IO/TKI have a significant improvement in survival compared to those without PM. The same significant improvement is not seen in PM patients who receive IO/IO combinations first line. Conclusions: As predicted based upon previous publications, our study demonstrated that patients with PM from RCC have relatively longer survival times than patients with metastatic RCC of other sites. More importantly though for decision making, patients who receive TKI based treatment have an improvement in outcome in patients with PM compared to treatments that do not contain a TKI. This would advocate TKI monotherapy or IO/TKI regimens in this patient group. Clinical trial information: (REC reference 24/SC/0038) IRAS project ID 338935 .

Real-world treatment patterns and outcomes of novel androgen receptor axis-targeted agents in non-metastatic castration-resistant prostate cancer: A multi-institutional retrospective study.

368 Background: Recently, three phase III trials have demonstrated that novel androgen receptor axis-targeted agents (ARATs) significantly improved metastasis-free survival (MFS) and overall survival (OS) compared to placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). However, the treatment patterns and outcomes of novel ARATs in real-world settings remain unclear. Methods: This multi-institutional retrospective study included 245 patients with nmCRPC treated between September 2003 and April 2024. Trends in the use of novel ARATs were evaluated. Patients were divided into two groups: those who were treated with any novel ARATs, including apalutamide, enzalutamide, darolutamide, and abiraterone acetate, during any line of nmCRPC treatment (novel ARATs group) and those who were not (control group). Multivariable Cox proportional hazards regression analyses were performed to evaluate the effects of novel ARATs on MFS and OS. Adverse events (AEs) associated with novel ARATs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Results: The median age and follow-up period after nmCRPC diagnosis were 77 years and 45 months, respectively. Of the 245 patients, 175 (71%) were treated with novel ARATs after nmCRPC diagnosis. Novel ARATs use in first line and any line was gradually increased from 2014 to 2023 (0% to 85% and 38% to 92%, respectively). The MFS and OS in the novel ARATs group were significantly longer than those in the control group ( P < 0.001 and P = 0.001, respectively). In multivariable analyses, a prostate-specific antigen doubling time (PSADT) and novel ARATs were independently and significantly associated with MFS and OS (Table). The rate of grade 3 AEs and discontinuation due to AEs were 1.1% and 6.0%, respectively. Conclusions: The use of novel ARATs for the treatment of nmCRPC increased over time. Novel ARATs use was safe and associated with improved oncological outcomes in a real-world setting. Multivariable analyses for MFS and OS. MFS Factor P value Hazard ratio 95% CI Age Continuous 0.003 0.956 0.928–0.984 Time of nmCRPC diagnosis Before 2014 0.706 0.917 0.584–1.439 PSADT <2.5 months <0.001 2.040 1.339–3.107 Novel ARATs Positive <0.001 0.364 0.238–0.557 OS Factor P value Hazard ratio 95% CI Age Continuous 0.418 1.014 0.980–1.049 Time of nmCRPC diagnosis Before 2014 0.626 0.883 0.537–1.454 PSADT <2.5 months <0.001 2.138 1.360–3.360 Novel ARATs Positive 0.001 0.479 0.306–0.748

Lutetium-177 PSMA radioligand therapy in taxan-naive first- and second-line metastatic castration resistant prostate cancer after first-line ARPI therapy.

79 Background: Lutetium-177 Prostate-specific membrane antigen (Lu-PSMA) radioligand therapy is EMA-approved for metastatic castration resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. However, its effect in taxane-naïve patients is under current investigation. Methods: We relied on the FRAMCAP database to elaborate Lu-PSMA therapy outcomes of progression-free (PFS) and overall (OS) in taxane-naïve mCRPC patients after previous ARPI treatment. Comparison was made against current standard of care with ARPI or docetaxel. Results: Of 269 patients, 11% received Lu-PSMA in first/second-line mCRPC vs. 57% ARPI vs. 33% docetaxel. Mostly no significant baseline differences between Lu-PSMA and ARPI patients were observed, while Lu-PSMA patients were significantly older, received less systematic treatments and ECOG1-2 proportions were higher, relative to docetaxel patients. In PFS (13.3 vs. 8.2 months, hazard ratio [HR]: 0.70, p=0.16) and OS analyses (68.9 vs. 39.1 months, HR: 0.64, p=0.2), Lu-PSMA was numerically more favorable than ARPI. In additional multivariable Cox regression models, Lu-PSMA was significant better regarding PFS and OS, relative to ARPI (both p<0.05). Compared to docetaxel, also significant better PFS (13.3 vs. 8.1 months, HR: 0.46) and OS (68.9 vs. 27.3 months, HR: 0.34, both p<0.01) was observed for Lu-PSMA treatment. The OS advantage was also observed after multivariable adjustment (p<0.01). Conclusions: Real-world evidence suggests that Lu-PSMA therapy provides significantly better PFS and OS outcomes in taxane-naïve mCRPC patients after previous ARPI treatment, relative to ARPI or docetaxel treatment and should therefore considered as an early mCRPC treatment. A B Characteristic N Overall N = 269 1 Lu-PSMA, N = 29 (11%) 1 ARPI, N = 152 (57%) 1 p-value 2 Docetaxel, N = 88 (33%) 1 p-value 2 Age at metastatic disease, years 256 71 (65, 77) 74 (69, 79) 72 (66, 77) 0.055 68 (62, 73) <0.001 Age at mCRPC, years 167 72 (67, 79) 76 (73, 83) 74 (68, 79) 0.083 69 (64, 75) <0.001 PSA at mCRPC, ng/ml 133 17 (6, 47) 23 (9, 82) 18 (5, 47) 0.2 12 (4, 40) 0.091 Systemic treatment lines for mCRPC 269 3 (2, 4) 2 (1, 2) 3 (2, 4) <0.001 3 (3, 5) <0.001 Received cycles 139 3 (2, 6) 3 (2, 5) 4 (2, 6) 0.2 PSA response, % 26 23 (4, 62) 20 (11, 30) 17 (0, 90) 0.9 41 (17, 62) 0.3 ECOG at mCRPC 87 0.13 0.017 0 40 (46%) 4 (24%) 17 (45%) 19 (59%) 1-2 47 (54%) 13 (76%) 21 (55%) 13 (41%) Cardiovascular disease 171 64 (37%) 9 (50%) 33 (34%) 0.2 22 (39%) 0.4 Gleason score 8-10 234 165 (71%) 16 (62%) 89 (69%) 0.5 60 (76%) 0.2 Local therapy 269 112 (42%) 12 (41%) 52 (34%) 0.5 48 (55%) 0.2 De Novo metastatic disease 259 140 (54%) 15 (54%) 86 (59%) 0.6 39 (45%) 0.4 High volume mHSPC 104 55 (53%) 6 (67%) 35 (54%) 0.7 14 (47%) 0.5 Metastatic sites at mCRPC 110 0.8 0.4 M1a 13 (12%) 2 (11%) 5 (10%) 6 (15%) M1b 91 (83%) 15 (79%) 42 (84%) 34 (83%) M1c 6 (5.5%) 2 (11%) 3 (6.0%) 1 (2.4%)

Fifteen-year outcomes of external radiation with or without 6 months of neoadjuvant deprivation therapy for intermediate risk prostate cancer.

388 Background: Our aim is to retrospectively compare survival outcomes in intermediate-risk prostate cancer (IRPC) treated with external-beam radiation therapy (EBRT) with or without neoadjuvant-deprivation-therapy (NADT). Methods: Retrospective analysis was performed on 566 IRPC treated with EBRT from 2004-2007. NADT was given to 336 patients, while 230 underwent EBRT alone. Median duration of NADT was 6 months. Median dose of radiation was 75.6 Gy to isocenter. Freedom-from-biochemical-failure (FFBF) was defined by the PSA nadir+2.0. Multi-variable analysis and Kaplan-Meier estimates were performed. Results: Median follow-up was 11.5 years in the NADT+EBRT vs 12.0 years in the EBRT alone group, with up to 19.8 years of follow-up. NADT+EBRT had more adverse factors of clinical stage (p=0.02), iPSA (p<0.01), Gleason group (p=0.02), %cores>50% (p<0.01). 15-year FFBF, metastases-free-survival (MFS), prostate-cancer-specific-survival (PCSS), and overall survival (OS) for NADT+EBRT vs EBRT alone was 52% vs 49% (p=0.41), 85% vs 83% (p=0.59), 91% vs 91% (p=0.67), 53% vs 51% (p=0.82). Conclusions: After 15 years of follow-up, IRPC treated with EBRT with or without 6 months of NADT experienced a high PCSS of 91%, despite a very high PSA failure rate of about 49-52% of the patients. It’s unclear if 6 months NADT in addition to EBRT can improve PCSS or overall survival for IRPC, or just merely delay PSA progression.

Fair food futures UK: Protocol for a mixed methods study exploring what approaches adopted by community food organisations are more likely to prevent the need for emergency food in two multicultural communities in Northern and Southern England

Introduction Food insecurity reduces people’s chances to live healthy and active lives and places a significant burden on healthcare systems. Levels have significantly increased in the UK since 2010, due to the impact of austerity and, more recently, the COVID-19 pandemic and the cost of living crisis. This increase is projected to continue. Households with children are amongst those at highest risk for food insecurity. A variety of community food organisations (CFOs), such as community gardens, community kitchens, food banks and social markets, have been essential in responding to rising food insecurity, including providing emergency food and other types of support such as welfare advice. However, beyond food banks, little is known about differing approaches to food aid in the UK, including how these organisations provide additional services to address the underlying issue that has led someone to seek emergency food support. Aim To understand what approaches used by community food organisations are most likely to help prevent the need for emergency food in two multicultural communities in the North (Bradford) and South (Tower Hamlets, London) of England, with high levels of ill-health and food insecurity. Research design, setting and participants This is a mixed methods study informed by complex systems theory. Methods include participatory systems mapping and qualitative longitudinal research. We will map the availability and type of help with food, and produce a typology of CFO approaches, using a survey, multiple local and national participatory system mapping workshops and interviews with local and national stakeholders (WP1). Then, we will conduct a longitudinal qualitative research using a ‘researcher in residence’ approach in up to 10 CFOs purposively sampled to reflect the diversity of prevention strategies adopted by CFOs. Research will include: a) a 12 month ethnographic study; b) three waves of ‘go along’ interviews with up to 35 families; and c) a visual study where the same families are invited to share photos and videos about their food thoughts via Indeemo research app. Outputs and dissemination Outputs will include: a) a toolkit on CFOs to support local and national policy and implementation decisions, b) a travelling exhibition with visual representations of people’s lived experiences c) publications in academic journals, d) blog posts, e) public talks, and f) policy briefs. Findings will help decision makers to invest in the most accessible, beneficial and culturally appropriate resources for communities.

Two-stream spatio-temporal GCN-transformer networks for skeleton-based action recognition

Detection of early-stage urothelial cancers using methylation patterns in urine cell-free DNA.

687 Background: Urine cell-free DNA (ucfDNA) has the potential to improve detection and monitoring of early-stage urothelial carcinoma (UC). We previously demonstrated the utility of ucfDNA methylation patterns to detect non-muscle invasive bladder cancer (NMIBC) in patients with suspicious bladder lesions (by cystoscopy or imaging). Based on those results, we trained a biopsy-free urine classifier for cancer detection. Here, we evaluate the performance of the urine classifier in an independent test set of patients with early-stage NMIBC or upper tract UC (UTUC). Methods: The urine classifier was trained using GRAIL’s biobank of plasma and cancer tissue, as well as prospectively collected urine from cancer and non-cancer participants (urine samples, n = 468). The locked classifier was evaluated at 95% and 98% target specificities on an independent test set of biobanked urine from patients with a new diagnosis of NMIBC (n = 49, 24 low grade and 25 high grade) and UTUC (n = 19, 9 low grade and 10 high grade), as well as age- and gender-matched non-cancer controls (n = 66). Results: The observed specificities in the test set at target specificities of 95% and 98% were 93.9% (62/66, 95% CI 85.2-98.3%) and 97.0% (64/66, 95% CI 89.5-99.6%), respectively. Observed sensitivity was the same at both target specificities. Of the 68 patients with a new diagnosis of either NMIBC or UTUC, 57 were classified as cancer, while 11 were classified as non-cancer. The urine classifier had a sensitivity of 100% for high grade NMIBC (25/25; 95% CI 86.3-100%) and 58.3% for low grade NMIBC (14/24; 95% CI 36.6-77.9%). For patients with UTUC, the urine classifier had a sensitivity of 100% for high grade UTUC (10/10; 95% CI 69.2-100%) and 88.9% for low grade UTUC (8/9; 95% CI 51.8-99.7%). Conclusions: A biopsy-free urine classifier based on ucfDNA methylation patterns is able to identify early-stage NMIBC and UTUC with high sensitivity at high specificity, particularly for patients with high grade disease. The classifier performance was validated in urine with an independent test set and did not require matched blood or tissue, highlighting the potential for a non-invasive and cost-effective method for UC screening. Current efforts are focused on evaluating urine classifier performance in prospective cohorts of UC patients undergoing both screening and recurrence monitoring.

Characterizing the clinical and genomic features of androgen indifferent prostate cancer.

222 Background: Androgen indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse and AIPC remains a poorly understood malignancy. This study aims to characterize the clinical and genomic features of AIPC. Our work ultimately seeks to identify biomarkers with diagnostic and therapeutic potential. Methods: Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we queried all prostate cancer (PC) patients, identified metastatic castrate resistant prostate cancer (MCRPC) samples, and aimed to enrich for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC) defined as having alterations in at least two of TP53, RB1, PTEN; neuroendocrine PC (NEPC) defined as small cell histology or NEPC signature score ≥ 0.25 (1); and double-negative PC (DNPC), defined as non-NEPC patients with low AR expression/AR signaling score. We compared clinical characteristics and genomic analysis of AIPC vs non-AIPC samples in patients who developed MCRPC. Clinical analysis was done using Wilcoxon rank sum test or Fisher's exact test. Gene expression analysis was performed using DESeq2 and GSEA. Results: Of 1,496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Median age at diagnosis for AIPC was 62 years and 85% were white, compared to 62 years and 87% for non-AIPC. Fifty-seven percent of AIPC patients had ECOG ≥1 at diagnosis vs 16% of non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs 15% for non-AIPC (p=0.003). TMPRSS2-ERG gene fusions were found in a significantly higher proportion of AIPC samples vs non-AIPC (38.5% vs 16%, p=0.014). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p=0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial mesenchymal transition (EMT), interferon response, and angiogenesis were significantly upregulated in AIPC vs non-AIPC samples. Conclusions: There was a significantly higher rate of de novo metastasis in the AIPC cohort. The downregulated androgen response and upregulated EMT pathways in AIPC suggest enrichment for androgen indifference with our methodology. Upregulated immune signaling and angiogenesis as well as higher MSI suggest opportunities for therapeutic investigation. Future directions include more focused in vitro and in vivo analysis to identify actionable targets. 1. Beltran H, et al. Nat Med . 2016;22(3):298-305. doi:10.1038/nm.4045.

Baseline fracture risk for prostate cancer patients initiating long-term androgen deprivation therapy.

122 Background: Androgen deprivation therapy (ADT) is essential for management of advanced prostate cancer, yet it carries risks including osteoporosis and fragility fractures. Antiresorptive therapy is recommended to reduce fractures for patients at high risk. However, precisely which patients should undergo formal screening with dual-energy X-ray absorptiometry (DEXA) at baseline has been relatively unexplored. This study aims to describe these baseline fracture risks, the utility of DEXA screening based upon Fracture Risk Assessment Tool (FRAX) scores, and the impact of specific risk factors in this population. Methods: We performed a retrospective cross-sectional study of patients at our institution with prostate cancer treated with ≥1 year of ADT between 2011 and 2024. Patients were excluded if their FRAX scores were incalculable or if they received antiresorptive therapy prior to starting ADT. Ten-year hip and combined major osteoporotic fracture risks were calculated using FRAX without femoral neck T-scores for all patients and with femoral neck T-scores for patients who received DEXA scans. A high fracture risk was defined as a 10-year hip fracture ≥3% or a combined major osteoporotic fracture risk ≥20%. Differences between dichotomous groups were assessed using independent samples t-tests, Chi-square tests, or Fisher’s exact tests. Results: We identified 515 patients with an average age of 70.1 years and average BMI of 29.5 kg/m 2 . Four hundred and forty-eight (87%) patients received leuprolide as ADT, 70 (13.6%) patients were on a prednisone-containing regimen, and 66 (12.8%) patients were active smokers. Based upon clinical data at ADT initiation (without including T-scores from DEXA), 201 (39.0%) patients had a high 10-year risk of hip or combined major osteoporotic fracture by FRAX. Among the 183 patients who did have DEXA scans, 85 (46.4%) met criteria for osteopenia while 14 (7.7%) had osteoporosis by T-score. Additionally, 48 (26.2%) patients had high 10-year fracture risks by FRAX and met criteria for initiation of antiresorptive therapy. The patients meeting criteria for antiresorptive therapy, in general, were older (73.3 years vs. 67.9 years) and weighed less (87.8 kilograms vs. 96.3 kilograms). Conclusions: In our institutional experience, nearly half of patients starting long term ADT have significant fracture risk warranting further risk stratification and risk mitigation strategies. This baseline data should inform systematic approaches to select those that do—and do not—require bisphosphonate or denosumab in the hormone sensitive setting.

Updated long-term follow-up from a phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for patients with high-grade upper tract urothelial carcinoma.

811 Background: We previously reported our multicenter phase II trial of neoadjuvant gemcitabine and split-dose cisplatin (GC) in 57 patients with high-grade upper tract urothelial carcinoma (HG UTUC), where 63% of patients experienced a pathological response (<ypT2 N0) at radical nephroureterectomy (RNU). Pathological response was associated with superior progression-free (PFS) and overall survival (OS) over a median 3-years of follow-up. Herein we report survival outcomes among the 50 patients treated at our institution with long-term follow-up. Methods: Patients with histologically confirmed HG UTUC and/or radiographically visible tumor stage T2-T4a N0/NX disease with a positive upper tract urine cytology were eligible. All patients received 4 cycles of split-dose GC followed by RNU and lymphadenectomy. The primary endpoints for this report were PFS (defined as metastasis or death from UTUC), cancer-specific survival (CSS) and OS, stratified by pathological response to NAC. Responders (<ypT2 N0) included both complete responders (CR, ypT0 N0) and partial responders (PR, ypTa/Tis/T1 N0/X); non-responders (NR) included ≥ypT2 Nany. Follow up started at RNU and patients were censored at the last occurrence of: clinical assessment, imaging study, or blood draw. Kaplan-Meier analyses estimated survival outcomes and log-rank tests evaluated for significant differences. Results: Of the 50 patients available for analysis, 32 (64%) were responders, of which 10 (20%) were CR. Baseline characteristics were similar between responders and NR. Forty-four of 50 patients tolerated ≥3 cycles of GC. Over a median follow-up among survivors of 5.7 years (interquartile range: 5.0, 7.9), 16 progression events, 11 cancer-specific deaths, and 16 total deaths occurred. Overall event rates were 63% and 63% for PFS, 77% and 70% for CSS, and 75% and 54% for OS, at 7- and 9-years, respectively. Estimated survival was higher among responders, compared to NR for PFS (log-rank p<0.001), CSS (log-rank p=0.002), and OS (log-rank p=0.002); corresponding 7- and 9-year event rates are presented in the table. Survival and event estimates were similar between CR and PR. Conclusions: These findings demonstrate a durable long-term progression and survival advantage of split-dose GC as NAC for HG UTUC among patients with a pathological response. Clinical trial information: NCT01261728 . 7- and 9-year PFS, CSS, and OS rates in patients treated with NAC, stratified by pathological response at RNU. Outcome Characteristic* 7 Years (95% CI) 9 Years (95% CI) PFS Responders 80% (64%, 99%) 80% (64%, 99%) Non-responders 36% (19%, 69%) 36% (19%, 69%) CSS Responders 89% (76%, 100%) 79% (60%, 100%) Non-responders 54% (33%, 88%) 54% (33%, 88%) OS Responders 87% (73%, 100%) 67% (46%, 99%) Non-responders 54% (33%, 88%) 32% (14%, 77%) *Responders were defined as <ypT2 N0/NX; Non-responders were defined as ≥ypT2 Nany.