Rosenberg, Jonathan E.

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 .

TPS290 Background: Landmark randomized trials established the survival benefit of adding D to ADT in mCSPC. Building on this foundation, subsequent trials (PEACE-1 and ARASENS) demonstrated further survival improvements when androgen receptor pathway inhibitors (ARPI) were added to the ADT + D backbone. However, the independent contribution of D within the triplet regimen remains unclear given lack of prospective evaluation. Additionally, tumor suppressor gene (TSG) alterations involving TP53, PTEN, and RB1 are frequently observed in PC and are associated with aggressive biology and poor outcomes, providing an opportunity to enhance prognostic accuracy and optimize selection of candidates for treatment intensification. We hypothesize that adding D to ADT plus A will improve survival compared to ADT + A in mCSPC and stratification by TSG status may identify different treatment effects across molecular subgroups. Methods: ASPIRE is an open-label, two-arm, randomized phase 3 study to assess the benefit of D added to ADT plus A for patients with mCSPC. Eligible patients include those with confirmed adenocarcinoma of the prostate with evidence of distant metastatic disease on conventional imaging and are appropriate to receive D. Patients with metachronous low-volume disease or PSMA-PET only disease are excluded. Candidates must have next-generation sequencing (NGS) results from a CLIA-certified tissue test available for TSG status stratification at registration. Eligible patients will receive ADT plus A (240 mg PO daily) +/- D for up to 6 cycles until progression of disease by PCWG3/RECIST version 1.1 criteria. Prior therapy with ADT (with or without ARPI) initiated within 120 days before registration is permitted. The primary endpoint is overall survival (OS). Secondary endpoints include OS by TSG status; radiographic progression-free survival (rPFS); time to castration resistance; symptomatic skeletal event–free survival; time to worsening of disease-related symptoms (NCCN-FACT FPSI-17); safety and tolerability (CTCAE v5.0); PSA90 response at 6 weeks and 6 months; time to PSA progression; and objective response rate in patients with measurable disease. The study will enroll 1200 patients and is currently actively accruing patients. Clinical trial information: NCT06931340 .

TPS277 Background: Recent advances in genomic sequencing have deepened our understanding of the molecular complexity of metastatic castration-resistant prostate cancer (mCRPC), revealing multiple actionable alterations that now inform biomarker-driven treatment strategies. Accordingly, germline and somatic tumor profiling is recommended for all patients with mCRPC. Beyond DNA aberrations, gene expression profiling can uncover additional therapeutic targets and pathway activations. The phase 2 PREDICT trial is leveraging both DNA and RNA alterations to guide rationally designed, biomarker-based therapeutic approaches for patients with mCRPC. Methods: This multi-center, multi-arm, biomarker-driven phase 2 umbrella trial is evaluating rationally selected therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint is objective response rate in patients with measurable disease, with secondary endpoints including radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative biomarker analyses. Eligible patients must have progressive mCRPC of any histology, prior treatment with an androgen receptor pathway inhibitor (ARPI), and either prior or declined taxane chemotherapy, with both measurable and non-measurable disease permitted. Enrollment requires standard-of-care next-generation DNA sequencing from tissue or circulating tumor DNA performed in a CLIA-certified laboratory, and RNA-based allocation will use the CLIA-certified Caris MI Tumor Seek assay (whole exome and whole transcriptome sequencing) on tissue obtained within 12 months of study entry, with a real-time molecular tumor board reviewing results to confirm arm assignment. Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician’s choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977). Clinical trial information: NCT06632977 .