Citations

TPS909 Background: BCG-Exposed NMIBC (a high grade recurrence within 24 months of prior BCG, but not meeting “unresponsive” criteria) is a large patient population with a critical need for more effective treatment strategies that prevent the development of BCG unresponsive disease/progression. The current standard of care is re-treatment with BCG alone, but only ~50% of patients derive clinical benefit. While intravesical gemcitabine (with or without docetaxel) is sometimes used, multiple retrospective studies have found that GemDoce is no better than re-treatment with BCG alone for patients with BCG-exposed NMIBC. A chemoimmunotherapy strategy of intravesical Gemcitabine with BCG (GemBCG) combines the two most effective, inexpensive, and commonly used treatments for NMIBC. Based on compelling biologic rationale and preclinical data, a phase I/II (n=52) trial was initiated of GemBCG in BCG-exposed NMIBC (NCT04179162). GemBCG has minimal side effects (3.8% [2/52] with Grade 3 TRAEs (no grade 4/5 seen) with similar side effects and tolerability to BCG alone. GemBCG has a outstanding early efficacy signal (6-month complete response of 97% [28/29] in patients with CIS, compared to ~50% 6-month complete response w/ BCG alone for BCG exposed CIS). GemBCG has promising preliminary longer term efficacy (18-month HG-RFS of 76% compared to ~45-55% reported with BCG alone, GemDoce, and recombinant BCG in BCG exposed NMIBC). Correlative studies support the hypothesis that the addition of gemcitabine to BCG can favorably modulate the tumor immune microenvironment. Methods: Based on the above rationale, we initiated the “GAIN” trial (A032303/ NCT07000084), a prospective, multicenter, open-label phase III study for patients with BCG-exposed NMIBC randomized to either: re-treatment with BCG only (Arm A, SOC) or Gemcitabine + BCG (GemBCG, Arm B). BCG-exposed NMIBC is defined as a high grade NMIBC (Ta, T1, Tis/CIS) that has recurred within 24 months of prior BCG, but NOT otherwise currently meeting BCG unresponsive NMIBC. The primary objective is to compare high grade recurrence-free survival (HG-RFS) between the two treatment arms. Notable aspects of the trial include: (1) the reduced burden on investigators and research teams due to the NCI’s new streamlined data initiative, (2) liberal inclusion/exclusion criteria and pragmatic design to improve generalizability of results, and (3) Cystoscopic biopsies/TURBT at week 13/month 3 for all participants (both CIS and “papillary only”) for multiple reasons including to allow for earlier detection of BCG unresponsive disease for patient safety, increased rigor of the trial, and objectively evaluate urinary biomarkers/urinary tumor DNA. Clinical trial information: NCT04179162 .

TPS577 Background: Pembrolizumab (pembro) for one year following resection of localized high risk clear cell renal cell carcinoma (ccRCC) in a phase 3 trial resulted in improvement in relapse-free survival and overall survival (Choueiri, NEJM 2024). However, 20% of patients still experienced a relapse within 2 years with no biomarker yet identified to predict who will respond to or needs adjuvant therapy. Addition of a tyrosine kinase inhibitor (TKI) to immunotherapy (IO) is a standard of care in metastatic ccRCC, but to date no studies have addressed the addition of a TKI to IO in the adjuvant setting. Subsequently, phase 3 STRIKE! was developed to explore the benefit of 6 months of tivozanib (tivo) added to pembro vs pembro alone in the adjuvant setting for resected high risk ccRCC. Methods: Eligible patients have an ECOG performance status ≤2 and a histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features after complete resection of the primary tumor, with pathology revealing pT2 grade 4 disease or any grade ≥ T3 or TxN1. Patients are also eligible if they developed metastasis within a year after resection and then underwent resection, definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) with no evidence of active disease (M1NED). Patients will be randomized 1:1 to intravenous pembro for 48 weeks with or without the addition of tivo 1.34 mg by mouth daily D1-21 q28D for 6 months stratified by stage (T2T3 vs T4/N1 vs M1NED) . With no limit on dose holds or interruptions of tivo, dose reductions of tivo to 0.89 mg D1-21 q28D or tivo 0.89 mg every other day are allowed. No dose reductions of pembro are permitted. Following baseline imaging to confirm no disease, imaging is performed every 12 weeks for first year, every 16 weeks for second year, every 24 weeks for third year and then annually until 5 years after registration or progression. The primary endpoint will be disease-free survival (DFS) as assessed by investigator, with secondary endpoints being overall survival, safety and tolerability. The study will enroll 1040 patients to detect a minimum detectable hazard ratio of 0.67 (24-month DFS 84% in experimental arm) with 90% power. Quality of life analysis will compare global quality of life and fatigue between the two arms. Imaging and specimens will be banked for future research. The study opened to accrual in April 2025 and at this time 106 patients have enrolled. Clinical trial information: NCT06661720 .

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 .

TPS283 Background: Emerging evidence suggests that metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) can delay systemic therapy in oligometastatic castration-sensitive prostate cancer (omCSPC). However, the optimal timing of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) initiation in this setting remains undefined. While deferred ADT following MDT may preserve quality of life, early short-course ADT/ARPI may eradicate micrometastatic disease and extend progression-free survival. Extracellular vesicles (EVs) carrying PSMA-positive prostate cancer (PC) signals and circulating tumor DNA (ctDNA) may serve as real-time biomarkers of MRD and treatment response. Methods: DIVINE [NCT06378866] is an open-label, phase II, randomized trial enrolling men with omCSPC defined by 1–5 metastases (≥1 extrapelvic) on conventional imaging (CT/MRI and bone scan) and testosterone >100 ng/dL. PSMA PET may be obtained for correlative purposes but does not determine eligibility. Participants (N = 220) are randomized 1:1 to: Arm A (Early systemic): SBRT plus 6 months of ADT + ARPI. Arm B (Deferred systemic): SBRT alone with observation, reserving systemic therapy until radiographic progression not amenable to further SBRT (mrPD). SBRT is delivered per institutional standard; repeat SBRT is allowed until lesions become non-addressable. The primary endpoint, modified radiographic progression-free survival (mrPFS), is the time from randomization to death or radiographic progression not amenable to further MDT, defined by PCWG3 (bone) and modified RECIST 1.1 (soft tissue) criteria on conventional imaging. Soft-tissue progression requires ≥ 20% increase in measurable disease or a new lesion; bone progression requires ≥ 2 new confirmed lesions. Secondary endpoints include OS, biochemical PFS, time to local and distant progression, and grade 3–5 adverse events during systemic therapy. Exploratory endpoints evaluate EV and ctDNA kinetics as MRD markers, correlation of PSMA-positive EV burden with outcomes, and duration of response after short-course ADT/ARPI. Correlative analyses will longitudinally quantify PSMA-positive EVs and ctDNA at baseline, on treatment, and at progression to define MRD dynamics and resistance patterns. The trial uses Pocock–Simon dynamic allocation by EV strata and metastatic burden to ensure balance across arms. The trial is open and actively enrolling across all Mayo Clinic sites; as of October 2025, 35 of the planned 220 patients have been accrued. Clinical trial information: NCT06378866 .

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended 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. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Abstract Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of neurofibromatosis type 1 (NF1)–related tumors, caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Patients and Methods: The study design was a multi-institutional, open-label, Simon two-stage, phase II study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50 mg twice daily and sirolimus 4 mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: A total of 21 heavily pretreated patients [seven females; median age, 41 years (range, 16–72); and 14 with NF1] with advanced disease enrolled at five participating sites. Clinical benefit was observed in only one of seven in stage 1 and one of 14 patients in stage 2. The median number of cycles was two (range, 1–6). Most common adverse events (AE) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18F-fluorodeoxyglucose PET scan performed during cycle 1 demonstrated partial metabolic responses in five patients (24%), but these did not correlate with objective responses after cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusions: The combination was safe, with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.

Abstract Ferritin, consisting of ferritin heavy chain (FTH1) and light chain (FTL) subunits, is an essential intracellular iron storage protein fundamental for cellular function. However, the source and the biological role of extracellular ferritin (ex-ferritin) are less understood. Recent studies have linked elevated serum ex-ferritin with adverse outcomes in individuals with acute respiratory distress syndrome (ARDS). In this study, we demonstrate that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AMs) of individuals with ARDS, a phenomenon we successfully replicate in a murine hyperoxia-induced acute lung injury (HALI) model. We show that FTH1 is consistently upregulated in macrophages during lung injury development, and mice with a targeted deletion of FTH1 in myeloid (LysMcre) or resident lung macrophage (Cd11ccre) populations exhibit attenuated HALI. This reduced injury is linked to macrophage resistance to ferroptotic cell death, ferritinophagy, altered airway inflammatory responses, and lower lung extracellular iron and higher levels of FTL-ex-ferritin. Transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid to wild-type mice protected against HALI. The ratio of FTL-ex-ferritin to FTH1 in the serum of individuals with ARDS who died was higher than that of those that survived, suggesting that the balance between FTH1 and FTL may play a role in injury modulation. Our findings highlight macrophage ferritin as a key regulator of macrophage survival and the response of the lung to injury, presenting a potentially targetable pathway for ARDS treatment.

PURPOSE Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). METHODS Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. RESULTS Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP -mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP- mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02). CONCLUSION SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP -mutated PC support its consideration as a unique molecular subtype with prognostic implications.

Abstract The addition of pembrolizumab to preoperative radiotherapy (RT) improved disease-free survival (DFS) for patients with stage III undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS) in the randomized SU2C-SARC032 trial. To precisely identify patients who benefit from pembrolizumab and RT, we performed comprehensive multi-omics profiling of pre- and post-treatment tumor and blood samples, including bulk RNA-seq, flow cytometry, and cytometry by time of flight. Additionally, we built a single-cell RNA-seq atlas spanning 65,786 cells from UPS and LPS to recover single-cell states in bulk tumor samples using digital cytometry. Two opposing tumor microenvironments (TMEs), immune-cold sarcoma ecotype 1 (SE1) and immune-hot sarcoma immune class E (SIC E), benefited from pembrolizumab. Pembrolizumab combined with RT caused an overall increase in activated CD8 + T cells, CD56 low NK cells, and T cell receptor diversity, while diminishing matrix-remodeling stromal cells and sarcoma cells. Our findings identify different mechanisms of response to pembrolizumab in localized, high-risk UPS/LPS and suggest that sarcoma TME signatures may identify patients most likely to benefit from adding pembrolizumab to preoperative RT.