537 Background: Biomarkers do not yet exist to triage patients with oligometastatic ccRCC for de-escalation strategies. Two promising biomarkers are kidney injury molecule-1 (KIM-1) and circulating tumor DNA (ctDNA). Methods: Patients with ccRCC and ≤5 metastases were enrolled on a single-arm phase 2 trial of metastasis-directed therapy (MDT) without systemic therapy (NCT03575611), powered for the primary endpoint of systemic therapy–free survival (STFS). Plasma samples for ctDNA and KIM-1 measurement were collected at baseline and 3-month follow-up. Personalized ctDNA detection panels (≤2000 somatic variants) were constructed from tumor whole-genome sequencing (Myriad Genetics). To create the Kidney Cancer OligoMetastasis Prognostic Assessment Systemic Score (K-COMPASS), we screened 24 candidate variables by elastic net-penalized Cox regression with 5-fold cross-validation repeated 100 times, with performance assessed by C-index. Predictors with nonzero coefficients were refit with Weibull regression for STFS. Results: Among 112 patients with KIM-1 measurements available, median baseline KIM-1 level was 127.0 pg/mL (IQR 71.5–228.0). KIM-1 and ctDNA were associated with STFS at baseline and 3 months in univariable and multivariable analyses (table). Progression-free survival (PFS) and overall survival (OS) were also associated with KIM-1 at baseline (PFS: HR=2.2, 95% CI 1.5–3.3; OS: HR=5.1, 95% CI 2.5–10.2, P <0.001) and at 3 months (PFS: HR=3.5, 95% CI 2.2–5.5; OS: HR=5.0, 95% CI 2.3–10.9) (all P <0.001). K-COMPASS construction selected baseline KIM-1, baseline ctDNA MRD, and 4 clinical variables (prior systemic therapy lines, ECOG performance status, number of metastatic lesions, time from diagnosis to metastasis). The complete model showed strong discrimination (C-index=0.76) and excellent calibration (slope=1). A user-facing K-COMPASS tool is available online (www.trialdesign.org). Conclusions: To our knowledge, this is the first evaluation of KIM-1 in oligometastatic ccRCC and the first to analyze KIM-1 and ctDNA in tandem for RCC. Both biomarkers were strongly and independently associated with outcomes in patients receiving MDT without systemic therapy. Integrating KIM-1 and ctDNA with clinical factors (K-COMPASS) yielded a well-calibrated model with high discrimination to support risk-adapted decision-making. External validation is planned. Univariable and multivariable association of baseline KIM-1 and ctDNA MRD status with systemic therapy free survival. HR (95% CI) Baseline 3-Month Follow-Up Univariable Multivariable Univariable Multivariable KIM-1(per log10[pg/mL]) 2.5 (1.5–4.1) P <0.001 1.9 (1.0–3.6) P =0.041 3.2 (1.9–5.4) P< 0.001 2.2 (1.1–4.5) P =0.028 ctDNA (MRD+ vs MRD–) 2.8 (1.3–5.9) P =0.0089 2.5 (1.1–5.6) P =0.032 4.4 (2.1–9.5) P< 0.001 2.7 (1.1–6.7) P =0.032

509 Background: Venous tumor thrombus (VTT) in patients with renal cell carcinoma (RCC) represents an aggressive disease feature associated with poor prognosis and management challenges. The efficacy of immunotherapy-based combinations in this subgroup remains insufficiently characterized. Methods: The PELET trial is an ambispective study enrolling adult patients with histologically confirmed advanced RCC and unresected VTT. Patients received lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was a ≥30% reduction in thrombus size. Secondary endpoints included changes in thrombus level, progression-free survival (PFS), and safety. Results: Twenty patients were included, predominantly male (85%), with a median age of 58.5 years. Most had clear cell histology (90%) and no sarcomatoid features. The median baseline thrombus size was 6.55 cm, which decreased to 3.0 cm after at least 12 weeks of therapy (p < 0.001). A ≥30% reduction in thrombus size was achieved in 45% of patients, meeting the primary endpoint. Moreover, 35% experienced a reduction in thrombus length > 50%, and 45% demonstrated a decrease in thrombus level by at least one level. Thrombus response was not correlated with baseline thrombus size. Median PFS was not reached at the time of analysis. Grade ≥3 adverse events occurred in 15% of patients. Conclusions: Twenty patients were included, predominantly male (85%), with a median age of 58.5 years. Most had clear cell histology (90%) and no sarcomatoid features. The median baseline thrombus size was 6.55 cm, which decreased to 3.0 cm after at least 12 weeks of therapy (p < 0.001). A ≥30% reduction in thrombus size was achieved in 45% of patients, meeting the primary endpoint. Moreover, 35% experienced a reduction in thrombus length > 50%, and 45% demonstrated a decrease in thrombus level by at least one level. Thrombus response was not correlated with baseline thrombus size. Median PFS was not reached at the time of analysis. Grade ≥3 adverse events occurred in 15% of patients. Clinical trial information: KCRB-092025-01.

96 Background: Preventing metastatic disease is the key goal of prostate cancer screening and local treatment. However, most evaluations of metastasis burden focus only on de novo metastatic disease at diagnosis and do not capture metastatic recurrences after local therapy, such as those based on cancer registries in the United States (U.S.). Methods: We inferred the full burden of metastatic prostate cancer in the Health Professionals Follow-up Study, a prospective cohort of U.S. male health professionals aged 40–75 years at enrollment in 1986 with follow-up in this analysis through January 2018. We captured three ways how metastatic prostate cancer manifested: (1) de novo metastases at initial diagnosis, (2) metastatic recurrences reported by participants during active follow-up, and (3) metastases were inferred from deaths attributed to prostate cancer, under the assumption that such deaths are almost invariably preceded by distant metastases. Cause-of-death adjudication assumed 90% specificity of coding, with a conservative 70% applied in sensitivity analyses. Absolute risk (cumulative incidence) of metastatic prostate cancer was estimated using the Aalen–Johansen method, accounting for death from other causes as a competing risk. Results: Our study population of 50,420 men had a median age of 54 years at enrollment (interquartile range, 46 to 63 years) when they were free from prostate cancer. The study population was predominantly of European descent (95%), with 2% Asian and 1% African American participants. Over up to 30 years of follow-up, we documented 8,305 prostate cancer diagnoses. Of these, 1,504 cases were adjudicated to be metastatic at diagnosis or to have metastasized after initial diagnosis. De novo metastatic disease accounted for only 249 (17%) of all metastatic cases. Conservative causes-of-death adjudication estimated 1,314 metastatic cases, with 19% being de novo metastases. The risk of metastatic prostate cancer among men was 0.8% (95% confidence interval [CI] 0.8, 0.9) by age 70, 2.4% by age 80 (95% CI 2.3, 2.6), and 4.0% (95% CI 3.8, 4.2) by age 90 years. Four in ten metastatic prostate cancers occurred after age 80 years. De novo metastatic disease risk represented about one-quarter of metastases by age 70, with lower relative contributions with advancing age. The risk of metastatic disease was particularly high in African-American men (3.6% by age 80, 95% CI 2.2, 5.8), while the risk among Asian men (2.3% by age 80, 95% CI 1.4, 3.7) was comparable to that among European men (2.5% by age 80, 95% CI 2.3, 2.6). Conclusions: One in 25 men in a widely PSA-screened population developed metastatic prostate cancer over the lifetime. Much of this substantial disease burden would remain hidden if using de novo disease as the only measure. Clinical and registry-based evaluations of early detection and local treatment need to capture the full burden of metastatic disease, which disproportionally impacts the oldest age groups.

LBA639 Background: PPARG is a master regulator of luminal lineage in UC with two-thirds of adv tumors classified as luminal. FX-909 is a first-in-class oral small molecule that potently and selectively inhibits both ligand-mediated and basal PPARG activity, offering a novel approach to targeting key cancer cell-intrinsic biology. Preliminary phase 1A data have demonstrated objective responses with FX-909 monotherapy (Gao, AACR Targets 2025). Here we report updated safety, tolerability, antitumor activity and predictive biomarker discovery to identify pts most likely to benefit from FX-909. Methods: 56 pts enrolled in a phase 1A open-label dose escalation study (30-100 mg PO QD, 28-day cycles), including additional 10 adv UC patients in 30 mg PO and 50 mg PO QD backfill cohorts. Baseline archival tissue (<30 months old) or a fresh biopsy collected for PPARG IHC (SP500 clone) and NGS correlative biomarker analysis. A provisional PPARG TPS cutoff was determined using linear regression modeling leveraging molecular real-world data (RWD) (N=2609 adv UC pts, Tempus xT). Serial blood samples collected for ctDNA analysis. Results: As of Nov 10, 2025, 46 pts with adv UC have been treated across four dose levels; 30 mg (17); 50 mg (16); 70 mg (11); and 100 mg (2). Median age was 71 (range 44-86), 71.7% ECOG PS 1, and 100% had mUC. Median lines of prior therapy was 3 (range, 1-8), including prior EV and anti-PD(L)1 treatment in 69.6%. Concordance between PPARG mRNA and TPS (r = 0.88, p<0.001) supported linear regression modeling, which inferred a provisional TPS cutoff of ≥60% (PPARG high ). Among 40 efficacy-evaluable adv UC pts, 35 had PPARG IHC results. 18/26 PPARG high pts showed tumor regressions, including 5 confirmed and 1 unconfirmed partial response. Decreases in ctDNA VAF occurred in 7/8 PPARG high pts with available results at cycle 2 (3 PR, 3 SD). Additional data demonstrating the relationship between PPARG high status, luminal subtype, and specific genomic alterations (PPARG(CN≥3), RXRA S427F and FGFR3) will be presented. At 30mg and 50mg doses, the most common ≥Gr3 TRAEs were anemia (18.9%), thrombocytopenia (16.2%) and fatigue (10.8%). Other common TEAEs were diarrhea (32.4%), hypertriglyceridemia (27%) and hyperglycemia (24.3%). The 30 mg dose was associated with fewer Gr3 TRAEs (35.3%), longer time to TRAE onset (52 days, range 44, 85), and fewer dose interruptions (29.4%) and dose reductions (11.8%). Conclusions: FX-909, a first-in-mechanism orally bioavailable PPARG inhibitor, demonstrates clinical proof-of-concept for targeting the master regulator of luminal lineage in heavily pretreated adv UC pts and may offer a novel therapeutic strategy for PPARG high adv UC. A randomized phase 1B expansion study is ongoing (NCT05929235). A combination study of FX-909/anti-PD1 is planned for early 2026. Clinical trial information: NCT05929235 .

TPS270 Background: ~15,000 men with metastatic prostate cancer (MPCa) receiving care in the Veterans Administration (VA) could benefit from germline testing to inform treatment options. However, there are insufficient genetics providers to arrange for germline testing. In 2021, the VA implemented multiple strategies to shift the task of germline testing to oncologists (i.e., mainstreaming) to increase guideline-concordant germline testing. These efforts led to improved adoption of germline testing by oncologists, and mainstreaming was more efficient and timely than genetics referral. However, germline testing remains low for many oncologists due to numerous barriers, e.g., lack of preparedness and confidence in germline testing, from identifying eligible patients to results-informed management. Methods: We will conduct a cluster-randomized trial comparing the effectiveness of implementation strategies to increase mainstreaming through randomization of oncologists not meeting a pre-specified test-order benchmark of 25%. Eligible participants include VA oncologists who: 1) have authored progress notes in oncology clinics for ≥10 patients with MPCa in the past two years, 2) are practicing at VA facilities with germline test orders in the electronic health record (EHR), and 3) <25% of their MPCa patients have had mainstream germline test orders. In the first 6 months, we will disseminate a germline testing handbook with provider education materials, information resources and EHR tools. At month 7, for oncologists who do not exceed the 25% benchmark, we will administer audit-feedback reports describing their germline testing rates compared to peers and the 25% benchmark. At month 12, oncologists whose order rates are <25% will be randomized to either continue audit-feedback or receive facilitation (interactive problem-solving and support) and audit-feedback. At month 24, we will stop the audit-feedback and facilitation strategies. Throughout the project, we will conduct semi-structured interviews to understand local germline testing workflows, challenges and enabling factors. We will assess fidelity to the implementation strategies and any adaptations made using the Longitudinal Implementation Strategy Tracking System. To evaluate the effectiveness of the implementation strategies on germline testing, we will use a mixed-effects model to account for the clustered nature of the data and the effect sizes of the implementation strategies. The project is informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. The study has not yet enrolled participants. There is no clinical trial registry number for this quality improvement project. This Department of Defense-funded project is a part of a greater quality improvement effort to increase guideline-concordant germline testing in the VA.

13 Background: Penile squamous cell carcinoma (PSCC) is a rare tumor with limited therapeutic options in advanced disease. Given the role of PD-L1 as a prognostic biomarker in many cancer subtypes, assessing its value in PSCC may inform prognosis and guide the use of immune checkpoint inhibitors in metastatic disease. In this systematic review and meta-analysis, we evaluate the prevalence of PD-L1 tumor expression in PSCC and assess its prognostic association with overall survival (OS), cancer-specific survival (CSS), and lymph node metastasis (LNM). Methods: We searched PubMed, Embase and Cochrane for relevant studies. The primary outcomes were OS, CSS, and LNM, analyzed using HRs or ORs, each with 95% CIs. Outcomes were prespecified in the PROSPERO protocol (CRD42019129410). Random-effects meta-analyses (restricted maximum-likelihood estimator) were performed using inverse-variance weighting. Heterogeneity was assessed by Q, τ², and I² statistics. Publication bias was examined by Egger’s test and funnel plots. Results: Fifteen retrospective studies were included (N = 1,445). Overall, 57% of tumors were PD-L1 positive (IQR, 44%–66%). Among 796 patients, PD-L1 expression was significantly higher in HPV-negative than in HPV-positive tumors (42% vs 13.5%). Eight studies (N = 930) evaluated OS, nine studies (N = 1,091) assessed CSS, and five studies (N = 622) investigated LNM. PD-L1 positivity was associated with reduced OS (HR 1.52; 1.12–2.05; I² = 6.8%) and CSS (HR 1.61; 1.16–2.23; I² = 38.3%), and with higher odds of LNM (OR 2.94; 1.28–6.78; I² = 57.3%). In meta-regression, HPV adjustment significantly strengthened CSS associations (QM = 7.13, p = 0.008; HR = 2.06, 1.21–3.51), accounting for all observed heterogeneity. Other moderators (sample size, adjustment status, tumor stage, study location, tumor-cell vs TIL scoring) were non-significant. Conclusions: PD-L1 expression is more frequent in HPV-negative PSCC and is consistently associated with adverse clinical outcomes, including shorter OS, shorter CSS, and higher odds of LNM. These findings support PD-L1 as a potential prognostic biomarker in PSCC and underscore the importance of considering HPV status in prognostic and therapeutic stratification.

140 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and frequently persistent and debilitating toxicity of cancer treatment that greatly affects the quality of life of cancer survivors. There is an unmet need for effective treatments against established CIPN and for preventative approaches. The enzyme soluble epoxide hydrolase (sEH) converts epoxy fatty acids (EpFAs), which are polyunsaturated fatty acid (PUFA) derivatives with inflammation-resolving, analgesic and anti-cancer properties, into corresponding pro-inflammatory and hyperalgesic dihydroxy metabolites (diols). Thus, sEH is a master regulator of inflammation. The sEH inhibitor (sEHI) EC5026 has completed phase 1 studies in healthy volunteers, with no significant adverse effects noted. The EpFAs of the ω-3 PUFAs are particularly effective at promoting analgesia and resolution of inflammation, suggesting that a diet rich in ω-3 PUFAs would enhance the inflammation-resolving effects of a sEHI. Methods: We examined the prophylactic efficacy of the sEHI EC5026 in a mouse model of docetaxel-induced painful neuropathy, by measuring mechanical hind paw withdrawal thresholds (PWTs) using an electronic von Frey aesthesiometer (IITC, Woodland Hills, CA). EC5026 was formulated in the drinking water at a concentration calculated to provide the mice with a dose of ~5 mg/kg/day through their daily unrestricted water intake. In addition, we studied docetaxel-induced CIPN in adult sEH ( Ephx2 ) male homozygous knock-out (KO) mice and wild-type (WT) mice on a diet high in ω-3 PUFAs vs a diet high in ω-6 PUFAs (both from Research Diets Inc., New Brunswick, NJ), starting 3 weeks prior to beginning docetaxel treatment and continued throughout the duration of the experiment. We also measured the levels of non-esterified PUFAs and their corresponding EpFAs and diols by UPLC-MS/MS in mouse plasma. Results: Docetaxel decreased the PWT in male C57BL/6J WT mice, while prophylactic administration of EC5026 mitigated this neuropathic allodynia. After 3 weeks on the ω-3 vs ω-6 diet, the respective PUFAs and their corresponding dihydroxy metabolites were significantly enriched. As expected, genetic ablation of Ephx2 increased the plasma levels of the corresponding epoxides. Importantly, sEH KO mice exhibited less severe docetaxel-induced CIPN and recovered from it faster than their WT counterparts when fed a diet high in ω-3 PUFAs, but not when fed a diet high in ω-6 PUFAs. Conclusions: We propose that sEH is a druggable therapeutic target in CIPN pathophysiology. The benefits of targeting sEH can be augmented by a diet rich in omega-3 PUFAs.

604 Background: Serum tumor markers play an important role in risk classification, prognostication, staging, and monitoring of treatment in germ-cell tumors (GCTs). While alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) are validated prognostic markers, recent investigations have suggested a correlation with lactate dehydrogenase (LDH) and treatment response and survival. Here, we evaluated LDH levels and survival in patients with advanced seminoma. Methods: The prospectively maintained Indiana University (IU) testicular cancer database was queried for patients with metastatic seminoma treated with first-line therapy. Pts were assigned to having a LDH <2.5 upper limit of normal (ULN) or ≥2.5 ULN based on pre-treatment LDH levels. Baseline characteristics were summarized. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Results: 113 pts were included in the study. Median age at diagnosis was 39.21 (22.80-68.72). Primary site was testis in 104 (92%), retroperitoneum in 6 (5.3%), and mediastinum in 3 (2.7%). Metastasis sites were retroperitoneal lymph nodes in 85%, pelvic lymph nodes in 12.4%, lung in 7.1%. IGCCCG risk was good in 92% and intermediate in 8%. 68.6% of pts were treated with BEPX3, 19.8% with EPX4, 1.2% with VIPX4, and 9.3% with other regimen. Median hCG was 3.50 (0.5-11,600). Median LDH was 349 (34-6550). Median follow-up was 2.30 years (0.02-19.11). 61 pts had LDH <2.5 ULN, 52 pts had LDH ≥2.5 ULN. For those with LDH <2.5 ULN, 3yr PFS was 91.5% (78.7-96.8) vs. 62.8% (45.2-76.1) for those with LDH ≥2.5 ULN, p= 0.0050. However, 3yr OS for those with LDH <2.5 ULN was 100% (100-100) vs. 95.2% (82.0-98.8), p= 0.6218. Conclusions: Patients with metastatic seminoma and LDH ≥2.5 ULN had inferior 3-yr PFS compared with normal LDH, but there was no difference in OS.

33 Background: Historically, PSA DT can be prognostic for metastasis free survival in BCR (as defined on computed tomography (CT) and bone scan). PSA DT is also an important tool in risk stratification in BCR to identify which patients (pts) require therapy (e.g. pts with a PSA DT>6 months). The emerging use of PSMA imaging creates another tool to assess BCR pts, but there is no data on the association of PSA DT and PSMA findings. Methods: NCT05588128 enrolls BCR pts after definitive +/- salvage therapies. Pts must have a PSA>0.5 ng/ml, testosterone >100 ng/dL, and negative CT/bone scans. Lymph nodes (LNs) up to 1.5 cm and prior therapies are permitted. All patients undergo a baseline PSMA PET scan, along with measurement of PSA and PSA DT. Here we describe the relationship between baseline PSA metrics and baseline PSMA imaging findings in patients with BCR. Results: 130 patients are currently evaluable with a median age= 71 years, baseline PSA of 1.95 ng/dL (range: 0.5 to 71) and PSA DT of 10.6 months (range 1.2 to 132) off therapy. Of all participants, 16.9% (n=22) had findings limited to the prostate bed and 34.6% (n=45) had PSMA+ avidity in the prostate bed with other findings. 42.3% (n=55) had PSMA + LNs, and 13.8% (n=18) had PSMA+ bone lesions. Four patients had serosal deposits with PSMA avidity, and one patient had a PSMA+ lung nodule. Conclusions: These data are the first to compare PSMA imaging results with corresponding PSA levels and PSA DT in a large cohort of patients with BCR. Results show that pts with historically favorable/long PSA DT may have high volume/bone+ findings on PSMA. There is no data to suggest treatment escalation is required in BCR pts with high volume PSMA findings, but long/favorable PSA DT. These results highlight the caveats of using PSMA imaging alone to drive treatment decisions in BCR without further data for how baseline PSMA imaging corresponds with long-term outcomes. Clinical trial information: NCT05588128 . PSMA PET+ lesion locations by PSA doubling time in patients with BCR prostate cancer (total n=130). PSA DT # Pts Median PSA PSMA Neg Prostate+ only Lymph Nodes+ ≥ 4 Lymph Nodes+ Bone+ ≥12 mo 52 3.55 9 (17.3%) 16 (30.8%) 24 (46.2%) 12 (23%) 6 (11.5%) 9 to <12 mo 20 1.56 2 (10%) 4 (20%) 11 (55%) 3 (15%) 3 (15%) 6 to <9 mo 17 0.9 5 (29.4%) 0 (0%) 12 (70%) 8 (47.1%) 2 (11.8*) <6 mo 41 2.1 5 (12.2%) 2 (4.9%) 28 (68.3) 15 (36.6) 7 (17.1)

151 Background: ARTO (NCT03449719) is a multicentre, randomized phase II trial testing the benefit of stereotactic body radiation therapy (SBRT) addition on top of abiraterone acetate (AA) and androgen deprivation therapy (ADT) in first line Oligometastatic Castrate Resistant Prostate Cancer (omCRPC) patients. Results already showed significant benefit in favour of the experimental arm in terms of biochemical progression free survival (bPFS) and radiological PFS (rPFS) after a median follow up of 24.9 months. Here we present an updated analysis comprehensive of long-term overall survival (OS) and prostate cancer specific survival (PCSS) data. Methods: Patients affected by omCRPC (≤ 3 non-visceral metastatic lesions) were randomized 1:1 to receive either AA+ADT alone (control arm) or the same systemic treatment associated with SBRT on all sites of disease (treatment arm). No previous treatment for mCRPC was allowed. Cox regression analysis was performed to compare bPFS, rPFS, OS and pCSS in the different arms of treatment. Results: One hundred fifty-seven patients were enrolled in ARTO trial. After a median follow up of 53 months (IQR 43-60), 103 bPFS events were recorded (41 vs 62 in the experimental vs control arm, respectively), 100 rPFS events occurred (40 vs 60 in the experimental vs control arm, respectively) and 65 patients died (24 vs 41 in the experimental vs control arm, respectively). Significant benefit in terms of bPFS and rPFS in favour of the experimental arm was confirmed (43 vs 17 months, HR 0.49, 95% CI 0.33-0.73, p<0.001 and 44 vs 17 months, HR 0.48, 95% CI 0.32-0.72, p<0.001, respectively). In terms of OS and PCSS, significant benefit was detected in favour of the experimental arm (Not reached vs 50 months, HR 0.55, 95%CI 0.33-0.92, p=0.02 and not reached, HR 0.37, 95%CI 0.18-0.78, p=0.008, respectively). Results were confirmed after adjusting for stratification variables (performance status 0 vs 1; 1 vs > 2 lesions) (HR 0.54, 95%CI 0.36-0.81, p=0.003, HR 0.53, 95%CI 0.35-0.81, p=0.003, HR 0.6, 95%CI 0.36-0.99, p=0.04, HR 0.43, 95%CI 0.2-0.9, p=0.02 for bPFS, rPFS, OS and PCSS, respectively). No safety concerns emerged, with 64 vs 71 grade 1/2 and 13 vs 22 grade >2 adverse events in the experimental vs control arm, respectively. Conclusions: After more than doubling the median follow up in this updated analysis, a significant OS and PCSS benefit were detected in patients undergoing concomitant SBRT with AA and ADT treatment compared to AA and ADT alone. These results warrant for confirmation in phase III trials. Clinical trial information: NCT03449719 .