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Objectives To evaluate biochemical recurrence‐free survival (BRFS) and metastasis‐free survival (MFS) as potential intermediate clinical endpoints (ICEs) for overall survival (OS) in patients undergoing salvage radical prostatectomy (sRP). Patients and Methods Evaluable patients were selected from a retrospective dataset, resulting in a cohort of 879 patients with recurrent, non‐metastatic, hormone‐sensitive prostate cancer treated with sRP at 13 centres. ICE surrogacy was evaluated using a two‐stage approach: (i) at the individual‐patient level by fitting Clayton copula models and estimating Kendall's ( >0.7 indicating a strong association) and (ii) at the centre level, by fitting weighted linear regression of 5‐year OS on 3‐year BRFS and MFS. Results The two‐step analysis included 759 patients for BRFS (366 events) and 476 for MFS (137 events), with median follow‐up of 37 months (95% confidence interval [CI] 36–42 months) and 34 months (95% CI 31–37 months), respectively. At the individual‐patient level, MFS showed a strong association with OS (Kendall's 0.85, 95% CI 0.82–0.88), which was not observed for BRFS (Kendall's 0.63, 95% CI 0.56–0.69). At the centre level, neither 3‐year BRFS ( R 2 = 0.15; slope = 0.34, P = 0.2) nor 3‐year MFS ( R 2 = 0.21; slope = 0.26, P = 0.14) predicted 5‐year OS with sufficient explanatory power. Limitations include the fact that centre‐level analysis was based on single‐arm associations rather than on treatment‐effect surrogacy across arms, and retrospective data collection. Conclusions The BRFS should not be used as a surrogate endpoint in the sRP setting. MFS requires further validation in future prospective studies to confirm its association with OS. Patient‐reported outcomes, such as quality‐of‐life and treatment‐related toxicity, should be considered in parallel with OS.

ABSTRACT Background While guidelines state that patients with NCCN favorable intermediate risk (FIR) prostate cancer (PCa) may consider active surveillance (AS), there is a relative lack of longer term follow up data informing AS inclusion criteria of patients with Grade Group (GG) 2 prostate cancer in the MRI era. Here we evaluate patient outcomes from a MRI‐screened AS‐eligible cohort of FIR GG2 PCa receiving radical prostatectomy (RP). Methods Patients with prostate MRI, NCCN FIR GG2 PCa (PSA < 10 ng/mL, ≤ cT2a, < 50% core positivity), and no prior treatments who underwent RP from 2015 to 2023 were included from a prospectively maintained prostatectomy registry. Primary outcomes were adverse pathologic features (APF) at RP (GG3‐5, ≥ pT3a, or pN1) and biochemical recurrence (BCR). Logistic regression and Cox regression identified factors associated with APF at RP and time to BCR, respectively. Results Of 522 patients, 110 (21%) had APF at RP and 45 (9%) developed BCR with median follow up 2.4 years (IQR 1.3–2.8). On multivariable logistic regression, % Gleason pattern 4 (%GP4, %GP4 > 25% OR 2.14, 95% CI 1.28–3.58, p = 0.004) was independently associated with APF. On multivariable Cox regression for time to BCR, PSAD (HR 1.06, 95% CI 1.04–1.09, p < 0.001) and positive surgical margins (HR 1.06, 95% CI 1.09–3.78, p = 0.03) were independently associated with BCR. PIRADS, % core positivity, and specimen involvement were associated with neither APF nor BCR. Conclusions % Gleason pattern 4 > 25% and PSAD are the primary factors associated with adverse outcomes and should be considered for patients with FIR GG2 PCa considering active surveillance. PIRADS and measures of biopsy cancer volume were not associated with APF or BCR. These results may inform patient selection for active surveillance among patients with FIR GG2 PCa.

ABSTRACT Background Inflammation plays a critical role in cancer cell proliferation; however, the specific role of inflammasomes, multiprotein complexes that regulate inflammation‐associated signaling pathways, in prostate cancer (PCa) remains insufficiently explored. This study aims to characterize the expression of inflammasome‐related genes in PCa and evaluate their association with clinical outcomes. Methods De‐identified transcriptome data from the Decipher GRID RP, a cohort of 52,266 radical prostatectomy (RP) samples tested (2016–2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA), were retrieved from the GRID registry (NCT02609269). Expression analysis of 34 genes involved in inflammatory pathways was conducted to associate their expression with clinical and genomic variables. Outcomes analyses were conducted on a retrospective cohort of 855 patients treated with RP (META855). Results Analysis of inflammasome gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Additionally, higher expression of most genes was associated with Gleason Grade Group 4–5 and very high Decipher scores. On survival analysis of the META855 cohort, higher expressions of AIM2 and HSP90AB1 were significantly associated with worse metastasis‐free survival. Conversely, both high and low expression levels of NLRP3 were associated with better metastasis‐free survival outcomes following RP compared to average expression. On multivariable Cox regression analysis, higher expressions of AIM2 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP. Conclusions There is molecular heterogeneity within pro‐inflammatory genes among patients with PCa. Our findings showed there is a potential association between the expression levels of certain inflammasomes, such as AIM2, HSP90AB1, and NLRP3, and oncological outcomes following RP.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel’s discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

392 Background: Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, exerting both tumor-promoting and tumor-restrictive effects, and in some cases, dual roles. CAFs are heterogeneous and have been implicated in tumor progression, metastasis, and therapeutic resistance. Recent translational evidence suggests the existence of at least two CAF subtypes: CAV1+ CAFs and FAP+FN1+ CAFs. The clinical utility of subclassifying CAFs in prostate cancer remains undefined. In this study, we aimed to examine the correlation of CAF subtypes in localized prostate cancer with Decipher genomic classifier (GC) scores, Grade Group (GG), and the presence of adverse pathological features (APF). Methods: We retrieved de-identified transcriptomic and pathological data from 55,329 radical prostatectomy (RP) samples tested with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) between 2016 and 2024, available through the GRID registry (NCT02609269). A subset of 855 patients (META855 cohort) treated with RP was utilized for outcomes analyses. CAF subtypes were defined based on the expression of key biomarkers (FN1, FAP, and CAV1), normalized to total CAF estimates. Correlation analyses and multivariable Cox regression models were performed to evaluate the association of CAF subtypes with GC scores, GG, APF. Metastasis-free survival (MFS) estimates were generated using Kaplan–Meier methodology. Results: FAP and FN1 normalized expressions were highly correlated (r=0.61) and weakly correlated with CAV1 suggesting that they represent two distinct subtypes of CAF. Samples with high expression (top 25%) of FN1 (FN1+) and FAP (FAP+) were enriched with very high Decipher (> 0.85, VHD) and GG4-5. As such, 37% and 32% of FAP+ were VHD and GG4-5 respectively compared to ~18% for low FAP(low 25%). While for FN+ 33.9% were VHD, and 31.5% GG4-5. Patients with FAP+FN1+, 42.5% and 37.1% were VHD, and had GG4-5. Samples with high CAV1 (CAV1+) were associated with lower rate of VHD (15.5%) or GG4-5 (20.8%) compared to low CAV1 (35.4% for VHD and 24.5% for GG4-5). When evaluating VHD in FAP+FN1+CAV1- subgroup, 58% were VHD compared to 6.4% in FAP-FN1-CAV1+. The 5-year MFS was 78% in FAP+FN1+CAV- compared to 96% in FAP-FN1-CAV1+ (p<0.01). When evaluating the biological implications of FAP+FN1+, we found that FAP and FN1 expression is highly correlated to angiogenesis and EMT pathways, radiation sensitivity signature (PORTOS). Conclusions: FAP+FN1+CAV- is a unique subset of CAFs that is associated with aggressive prostate cancer behavior. Our findings may lay the foundation for future efforts to modulate CAFs in localized prostate cancer with existing therapeutics targeting FAP or FN1.

382 Background: Androgen receptor signaling drives prostate cancer (PC) progression, and genes involved in androgen production, uptake, and conversion (APUC) are key therapeutic targets. We previously defined a 6-APUC gene set ( HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, and CYP17A1 ), that identified metastatic PC with favorable prognosis and predict docetaxel benefit. However, the expression landscape and clinical relevance of APUC genes have not been interrogated in localized PC. Methods: We analyzed the expression of 21 APUC genes in 55,329 radical prostatectomy tumor samples that underwent Decipher prostate genomic classifier (GC) testing (Veracyte Inc) between 2016-2024. Baseline clinical/pathologic factors were retrieved from Decipher GRID database (NCT02609269). Associations between gene expression quartiles with PathoGenomic Risk Factors (PGRF) including Very High Decipher score >0.85 (VHD), Grade Group (GG) 4-5, LNI and SVI were examined. Associations with distant metastatic (DM) outcomes and metastasis free survival (MFS) were evaluated using logistic regression in Mayo545 and Cox regression in Meta855 RP cohorts, respectively. Results: High expression of SRD5A2 was associated with favorable PGRF (lower odds ratio (OR), p<0.0001), lower rate of development of DM (OR 0.36, p<0.05), and longer MFS (Hazard ratio (HR) 0.51, p<0.05). HSD17B6 showed similar results for PGRF (lower OR, p<0.0001), DM (OR 0.58, p<0.05) and longer MFS (HR 0.39, p<0.05) despite being associated with GG4-5 and SVI+ in samples with VHD. In contrast, high expression of SRD5A3 and HSD17B10 had high OR for PGRFs (p<0.0001). High expression of SLCO2B1 , an androgen uptake gene, had the strongest association with GG4-5 and SVI/LNI (p<0.001 for both). We noted that SRD5A2 lacked correlation with SRD5A1 and SRD5A3 , which instead correlated with each other. Compared to all APUC genes, SRD5A2 had limited correlations with almost all APUC genes, including ones that exhibited robust cross correlation with each other . Similar to our prior finding, most APUC genes demonstrated negative correlation with AR expression and AR activity signatures. Key outcomes were validated based on transcriptomic data from 492 samples from TCGA database. Conclusions: Comprehensive analysis of 21 APUC genes in over 55,000 PC identified distinct, context-dependent associations with metastatic outcomes and clinical and molecular risk factors. Notably, high SRD5A2 expression was associated with lower odds of high-risk features and metastatic outcomes, whereas SRD5A1 and SRD5A3 linked to adverse outcomes, suggesting critical yet divergent roles among 5-alpha-reductase family members. These findings underscoring androgen-metabolic heterogeneity and highlighting SRD5A2 as a potential biomarker of indolent biology in localized prostate cancer.

TPS892 Background: Enfortumab Vedotin (EV) plus pembrolizumab (Pembro) is now first-line therapy for advanced urothelial carcinoma (UC), yielding ~30% complete response (CR) rates; nevertheless, most patients (pts) progress within 1 year and median overall survival (OS) remains < 3 years. In muscle invasive bladder cancer, local consolidation after systemic therapy improves outcomes, suggesting that residual, treatment-refractory intravesical disease drives relapse. We hypothesize that cytoreductive cystectomy/nephroureterectomy (CC/U)—with metastasis-directed therapy (MDT) as needed—can consolidate responses to EV/Pembro and extend benefit in regionally advanced or metastatic UC. CAST-AI prospectively evaluates this multimodal strategy and integrates correlative studies of exosomal Nectin-4 and circulating tumor DNA (ctDNA) from blood and urine as predictive/MRD biomarkers. Methods: CAST-AI is a phase II, decentralized single-arm trial enrolling pts with histologically confirmed UC of the bladder or upper urinary tract with ≥N1 and/or M1 disease and ECOG PS 0–2 who are potential surgical candidates (planned n = 75). Treatment: EV 1.25 mg/kg IV D1 & D8 + Pembro 200 mg IV D1 q21d, ≥4 cycles; MDT permitted any time pre-surgery. Response assessments occur q9 weeks (±4) to 18 months, then q12 weeks (±4). Surgical eligibility requires: (A) fitness for surgery; (B) complete or partial response (CR/PR) or, for select low-burden/unmeasurable disease, urologist-adjudicated candidacy; (C) all distant sites addressed; and (D) procedure in pt’s best interest. Post-CC/U maintenance EV/Pembro is encouraged per clinical discretion and guided by definitive surgical pathology results, which provide true pathologic staging often unattainable through imaging after systemic therapy. Primary endpoint: 12-month progression-free survival (PFS). Secondary endpoints: Objective response rate (ORR), CR rate, down-staging at CC/U, PFS, OS, and safety (using CTCAE). Exploratory endpoints: longitudinal exosomal Nectin-4 and ctDNA dynamics as MRD and early relapse indicators; tissue–blood–urine Nectin-4 concordance; pt-reported tolerability (using CIPN20). Key exclusions: > 20% variant histology or disallowed subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine); prior chemotherapy for UC; contraindications to surgery/EV/ICI; or active uncontrolled comorbidities/infections. Status: Enrollment is open and ongoing, with 25 of 75 pts enrolled as of September 2025. The trial uses a decentralized model, allowing pts to receive EV/Pembro at their local facility, with central coordination, biospecimen shipping, and surgical evaluation at Mayo Clinic or affiliated sites. ClinicalTrials.gov: NCT06764095. Clinical trial information: NCT06764095 .