Sensitivity analysis: non-MSI-H comparison. (A) Standardized mean difference is shown for features pre- and post- adjustment for the TMB10+ cohort. Propensity-adjusted comparison of ICI (tTMB≥10) vs. taxanes (any tTMB level) is shown for (B) TTNT and (C) OS among the cohort excluding MSI-H.

Figure S10 shows the ratio score of CXCL9+:NLRP3+ Macs is predictive of ICB response

BACKGROUND:For over a decade the Advanced Prostate Cancer Consensus Conference (APCCC) covers a variety of topics that greatly impact daily practice. In 2025, a dedicated event was organised to discuss key questions in clinical management of patients with prostate cancer (PC) related to diagnostic tools (APCCC Diagnostics). Here we present the voting results of the APCCC Diagnostics questions. OBJECTIVE; DESIGN, SETTING, AND PARTECIPANTS: APCCC Diagnostics 2025 is a pilot project. The scientific committee for APCCC Diagnostics 2025 developed 88 multiple-choice consensus questions on six different topics. Prior to the conference, the panel members (''panellists'') voted on these questions via a web-based survey. Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS:Consensus was only reached on 17 of 88 questions (19%), of which six (7%) received a strong consensus. Specifically, consensus was reached for two of 17 questions (14%) in "how to diagnose PC"; seven of 16 (44%) in "how to stage PC"; three of 14 (21%) in "Biochemical Recurrence Scenario"; two of 11 (18%) in "metastatic disease: what to do?"; zero of 18 (0%) in "monitoring metastatic PC"; and three of 12 (25%) in "radioligand therapy and imaging." CONCLUSIONS:The voting results and their discussion may assist physicians in navigating controversial areas of clinical management related to diagnosis, staging, and restaging in the different clinical settings for PC, particularly where high-level evidence is scarce or conflicting. The findings can also help funders and policymakers in prioritising areas for future research.

Figure S14. Luminal B phenotype is associated with higher MYC signaling and lower radiation response scores.

The therapeutic landscape for renal cell carcinoma (RCC) and urinary tract cancer (UTC) has transformed dramatically, creating complexity in treatment selection and sequencing. The 2025 Advanced Urologic Cancer Consensus Conference was convened to establish evidence‐based expert consensus recommendations for optimal management. A multidisciplinary panel of 51 experts participated in a modified Delphi process addressing questions developed through iterative consensus‐building covering RCC and UTC management. Voting occurred before and after the conference, and analyses focused on postmeeting responses. Consensus was defined as ≥75% agreement, with strong consensus as >90%. Strong consensus was found on the use of adjuvant pembrolizumab for higher risk RCC (pathologic T2 [pT2], grade 4; pT3–pT4, any grade; pTXN1; or fully resected metastatic disease) and on neoadjuvant therapy before cystectomy for localized UTC. There was strong consensus on the use of enfortumab vedotin plus pembrolizumab as frontline therapy for metastatic UTC and the use of platinum‐based chemotherapy postprogression in biomarker‐negative UTC. For RCC, there was consensus on the role of single‐agent vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy after progression on frontline immune checkpoint inhibitor/vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy or dual immune checkpoint inhibitor therapy. However, there was a lack of consensus on other critical areas in the management of RCC and UTC. The 2025 Advanced Urologic Cancer Consensus Conference provides evidence‐informed guidance for complex clinical scenarios while identifying critical research priorities. The group recognizes that the lack of consensus across multiple areas highlights the need for improved patient selection and prospective studies enabling optimal combination and sequencing approaches. This iterative annual process will address evolving treatment paradigms to optimize outcomes.

4555 Background: TiNivo-2 results showed that immune checkpoint inhibitor (ICI) rechallenge did not offer benefit to patients with mRCC, regardless of treatment sequencing ( Lancet , 2024; 404:1309). However, the data highlights activity for Tivo monotherapy in the post-ICI setting. Long term outcomes of the TiNivo-2 study are reported here. Methods: TiNivo-2 trial design and primary-endpoint results were previously reported: patients with mRCC were randomized to treatment with Tivo 0.89 mg once daily for 21/28 days plus Nivolumab (Nivo) at 480 mg every four weeks (Tivo/Nivo) or Tivo 1.34 mg once daily for 21/28 days. Here, long term progression free survival (PFS), overall survival (OS), and the safety profile are reported at final analysis. Results: At the data cutoff of 17 October 2025, 172 patients were randomized to Tivo (171 treated) and 171 patients were randomized to Tivo/Nivo (168 treated); median (m) follow up was 28.4 mo (95% CI 27.0-29.8) in Tivo versus 27.2 months (mo) (95% CI 26.1-28.5) in Tivo/Nivo. Survival outcomes and hazard ratios (HR) for the ITT population, 2L, and 3L populations are summarized in Table 1. In 2L, mPFS favored Tivo over Tivo/Nivo (9.23 mo [7.29, 11.04] vs 5.95 mo [5.42, 7.95]). Across subgroups, there were no differences in mOS. No new safety signals were observed with prolonged administration; the most common ≥ Grade 3 TEAE was hypertension occurring in 39 (22.8%) and 38 (22.6%) and of patients in the Tivo and Tivo/Nivo groups respectively. Other ≥ Grade 3 TEAEs included diarrhea (2.3% and 3.6%) and palmar-plantar erythrodysaesthesia (0.6% and 1.2%) in the Tivo and Tivo/Nivo groups respectively. Treatment Related SAEs occurred in 15 (8.8%) and 18 (10.7%) of patients in Tivo and Tivo/Nivo groups respectively. Conclusions: This final analysis of patients in the TiNivo-2 study highlights the sustained efficacy Tivo in mRCC with a consistent safety profile. Together, these findings support durable clinical benefit and tolerability of Tivo in the post-ICI treatment setting in RCC, an area of high unmet need (NCT04987203). Clinical trial information: NCT04987203 . Parameter By ITT 2L setting 3L setting Tivo (0.89mg) /Nivo (n=171) Tivo (1.34mg) (n=172) Tivo (0.89mg) /Nivo (n=111) Tivo (1.34mg)(n=105) Tivo (0.89mg) /Nivo (n=60) Tivo (1.34mg)(n=67) mPFS, months (95% CI) 5.72(4.37-7.43) 7.43(5.52-9.23) 5.95(5.42, 7.95) 9.23(7.29, 11.04) 5.45(3.15, 9.56) 5.44(2.10, 7.36) mPFS HR 0.96 (0.76, 1.21) 1.08 (0.80, 1.46) 0.77 (0.52, 1.15) mOS, months (95% CI) 23.85(19.71-NR) 22.93 (18.14-NR) 29.50(21.06, NR) 23.52(18.33, NR) 19.71(10.81, 31.90) 22.70(11.79, NR) mOS HR 0.95 (0.70, 1.28) 0.78 (0.53, 1.16) 1.13 (0.70, 1.81) NR, not reached.

Figure S4 shows plasma IL-6 and CSF-1 are elevated in UC and in ICB non-responders

Figure S18 shows IL-6 signaling selectively limits the differentiation of naïve CD8+ and CD4+ T cells into effector T cells

Figure S7. Expression of neuroendocrine genes across CTC phenotypes.

e17057 Background: Relugolix is an oral androgen deprivation therapy used for the treatment of advanced prostate cancer (PC). OPTYX (NCT05467176) is an ongoing multicenter, prospective, observational study of relugolix treatment in the United States. There is limited published literature regarding patients with metastatic PC (mPC) initiating relugolix monotherapy or combination systemic therapy. We report testosterone suppression, serious adverse events (SAEs), and adherence data from baseline through 6 months in a subgroup of patients with mPC initiating relugolix monotherapy or relugolix in combination with other systemic prostate therapies. Methods: Patients with PC were enrolled in OPTYX if they initiated relugolix ≤1 month prior to study enrollment and intended to remain on relugolix for ≥4 months. Six-month testosterone suppression, SAEs, and adherence were assessed in patients with mPC. Monotherapy or combination therapy categorization was based on baseline use. Adherence is assessed by the Simplified Medication Adherence Questionnaire. All patients have ≥6 months of data after enrollment. The study is ongoing and data will be collected for a minimum of 2 years with no mandatory study visits required. Results: A total of 255/999 patients enrolled in OPTYX had mPC. Median age at baseline was 71 years; 14.5% were Black and 0.4% were Asian. At relugolix initiation, 64.7% received monotherapy and 35.3% received combination therapy. Of patients with available testosterone data at 1 month (earliest timepoint assessed), 95% (n = 38/40) and 81% (n = 17/21) of patients who initiated monotherapy and combination therapy, respectively, achieved castrate levels ( < 50 ng/dL). All patients assessed at 3 months (monotherapy, n = 47/47; combination therapy, n = 28/28) and 92% (n = 55/60) and 97% (n = 33/34) of patients (monotherapy and combination therapy, respectively) assessed at 6 months achieved castrate testosterone levels. Overall, 7.8% (20/255) of patients (monotherapy, 9.1%; combination therapy, 5.6%) initiating relugolix experienced ≥1 SAE; most common SAEs were anemia (n = 2) and atrial fibrillation (n = 2). One patient in each group (monotherapy, 0.6%; combination therapy, 1.1%) experienced cardiovascular (CV)-related SAEs. Patient adherence was high at 6 months, with 96% of patients (monotherapy, 96%; combination, 95%) reporting taking relugolix at the appropriate time each day and 81% (monotherapy, 80%; combination, 83%) reporting never forgetting to take relugolix even once. Conclusions: Using clinical practice data, relugolix treatment led to successful testosterone suppression, low rates of documented SAEs and CV-related SAEs, and high adherence at 6 months in patients with mPC. These results were similar in patients initiating monotherapy and combination therapy. Clinical trial information: NCT05467176 .

TPS408 Background: Pelvic radiation therapy plays a key role in the treatment of most genitourinary (GU), gynecologic (Gyn), and gastrointestinal (GI) malignancies of the pelvis. Commonly, physicians instruct patients undergoing pelvic radiation therapy to present with a reproducibly full bladder for treatment with the hope that increasing the distance between the treatment target and normal tissues will limit toxicity. However, this is challenging for patients and often leads to uncertainties in radiation dose distribution to the adjacent pelvic organs, as the bladder volume varies during a treatment course. Retrospective data suggests that treating with an empty bladder has minimal impact on treatment-related toxicity, but prospective data is very limited. A phase III randomized trial is required to evaluate the relative merits of two bladder fill protocols in terms of safety and patient-reported outcomes. The goal of this trial is to identify the optimal bladder filling approach to minimize toxicity and maximize patient quality of life. Methods: The BEFORE trial (NCT06651697) is an investigator-initiated, multi-center, prospective, open-label, pragmatic, two-arm randomized phase III study enrolling patients undergoing pelvic radiation therapy. Patients of all genders planning to undergo pelvic radiation therapy with curative intent for a primary GU, Gyn, or GI malignancy of the pelvis are eligible. This trial aims to include 300 patients randomized to one of the two arms, empty or full bladder protocol, in a 1:1 ratio stratified by primary tumor site, treatment of lymph nodes, and prior prostatectomy. The primary endpoint is the physician-reported acute any attribution GU and/or GI grade ≥2 toxicity within 3 months post-radiation therapy. Secondary endpoints are radiation attribution acute GU and/or GI toxicity, any attribution and radiation attribution late GU and/or GI toxicity, patient-reported urinary and bowel quality of life, and percentage of treatment fractions requiring delay due to incomplete bladder filling in the full bladder arm. BEFORE has enrolled 89 of 300 planned participants. Clinical trial information: NCT06651697 .

162 Background: Clinical trial conduct in advanced prostate cancer has changed dramatically with the continued development of new imaging approaches, molecular phenotypes and genetic subtypes, prognosis assessments, and effective therapies across a range of disease states. This created a need to redefine terminology and best practices for clinical trials. Methods: We convened PCWG4, an international expert committee of multidisciplinary working groups, between 2016 and 2025 to update and expand PCWG2-3 recommendations based on emerging evidence and clinical trial data in an innovative biomarker and imaging context to provide guidance for clinical trial design, eligibility, and endpoint assessments. Results: PCWG4 redefines terminology around disease states and prior therapies in a patient-centric context, considering imaging modalities, with a particular focus on PET-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, imaging and non-imaging-based responses. We define delay/prevent endpoints including responses by pathology, ctDNA, circulating tumor cells, and PSA declines, and specify intervals for re-assessments including imaging, biomarker assessments, and patient reported outcomes. We propose new imaging-specific rPFS criteria including guidance with serial PSMA PET/CT imaging (Table). We provide recommendations in a biomarker-based context for the indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. Conclusions: PCWG4 expands guidance on patient and tumor profiling, as well as therapy development, to include both androgen deprivation therapy sensitive and resistant settings, reflecting today’s more heterogeneous and diverse patient population to optimize outcomes. PCWG4-defined radiographic progression by imaging modality for patients with metastatic disease. Pretreatment Scan On-treatment Scan #1(≥week 8) On-treatment Scan #2 All Subsequent Scans Bone scintigraphy Comparator Comparator for subsequent scansPOD never called here POD:PCWG3 criteria (2+2 additional new lesions) POD:≤5 new lesions: PCWG3 criteria 2 new lesions confirmed≥6 new lesions CT/MRI Any measurable disease Comparator PCWG3/RECIST PCWG3/RECIST PCWG3/RECIST PSMA PET Bones, and lymph nodes and lung metastases (non-RECIST qualifying by + on PET only) Comparator POD:≤5 new lesions: 2 new lesions confirmed on a subsequent scan≥6 new lesions Same as prior Same as prior Liver and non-pulmonary viscera Comparator POD:Any single new lesion that represents disease Same as prior Same as prior

Abstract Background Oligometastatic clear-cell renal cell carcinoma (ccRCC) is a biologically distinct, often indolent state where metastasis-directed therapy, including metastasectomy or SBRT, provides durable local control and delays systemic therapy. Randomized prospective trial evidence demonstrates a survival benefit with adjuvant programmed cell death-1 (PD-1) inhibition following surgical metastasectomy in oligometastatic ccRCC. However, the role of adjuvant PD-1 inhibition following stereotactic body radiation therapy (SBRT) has not been prospectively evaluated. SBRT induces immunogenic tumor cell death, enhances tumor antigen presentation, and promotes T-cell priming, providing a strong biologic rationale for evaluating PD-1 inhibition following SBRT. Beyond PD-1 blockade alone, lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint expressed on tumor-infiltrating lymphocytes in ccRCC and contributes to T-cell exhaustion and immune evasion. Dual PD-1 and LAG-3 blockade has demonstrated promising anti-tumor activity with acceptable tolerability in early-phase studies, supporting investigation of strategies to enhance the efficacy of adjuvant PD-1 inhibition following SBRT in oligometastatic disease. Methods LAG-BOOST is a 1:1 randomized, prospective, multicenter, investigator-initiated phase II trial. Eligible patients have histologically confirmed oligometastatic ccRCC, defined as ≤ 5 metastatic lesions by RECIST v1.1, all amenable to SBRT. Following SBRT to all visible lesions, patients are randomized to receive one year of adjuvant PD-1 inhibition (cemiplimab) alone or combined PD-1 and LAG-3 inhibition (cemiplimab and fianlimab). Treatment continues for up to one year or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients must be naïve to systemic therapy for metastatic RCC; prior adjuvant therapy for non-metastatic RCC is permitted in the absence of radiographic disease progression within 12 months of treatment completion. Stratification is based on International Metastatic RCC Database Consortium (IMDC) risk and metastatic burden: (1) favorable or intermediate IMDC risk with 3 or fewer metastatic lesions and no brain metastases versus (2) poor IMDC risk or 4–5 metastatic lesions or the presence of brain metastases. The primary endpoint is 1-year progression-free survival (PFS). Secondary endpoints include safety and tolerability (treatment-related adverse events per CTCAE v5.0), objective response rate by RECIST v1.1, duration of response, disease control rate, and overall survival. The study is powered for H0: 65% versus Ha: 85% 1-year PFS (α = 0.05, power=0.8), with an estimated enrollment of 72 patients. ClinicalTrials.gov identifier: NCT07223541. (Figure 1) Results This study addresses a critical gap in the management of oligometastatic clear cell renal cell carcinoma (ccRCC), a biologically distinct subgroup for which optimal treatment strategies remain undefined. Emerging data suggest that SBRT may potentiate systemic antitumor immunity, particularly when all metastatic sites are treated, yet the optimal immunotherapy combination and treatment sequencing remain unclear. Given the established co-expression of PD-1 and LAG-3 in the ccRCC tumor microenvironment and the proven efficacy of dual checkpoint blockade in other malignancies, the LAG-BOOST trial is uniquely positioned to evaluate a novel, mechanism-driven strategy integrating SBRT with dual PD-1/LAG-3 inhibition. Importantly, LAG-BOOST extends beyond a therapeutic investigation to establish a comprehensive translational platform incorporating LAG-3 and PD-L1 immunohistochemistry, multi-omic tumor profiling, and serial circulating tumor DNA analyses. These integrated approaches aim to distinguish predictive from prognostic biomarkers, refine patient selection, and address the heterogeneity of response to immunotherapy. The trial is currently open and actively enrolling patients. Conclusions N/A DOD CDMRP Funding no

Table S5 shows reagents and resources used in this study.