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Design, synthesis, molecular docking and anticancer activity evaluation of methyl salicylate based thiazoles as PTP1B inhibitors

EORTC GUCG 2418 - STARBURST: Strategies for treatment adaptation following re-evaluation of the bladder after using primary neoadjuvant systemic therapies—An EORTC platform trial.

TPS880 Background: The standard treatment for patient with muscle-invasive bladder cancer (MIBC) consists of neoadjuvant systemic therapy (NAT) followed by radical cystectomy (RC) or trimodal therapy (TMT). Currently, patients are not routinely reassessed after NAT and proceed directly to local treatment, leading to a missed opportunity for patients with complete or near complete response to benefit from bladder sparing strategies. On the other hand, for the non-responders, it is a missed opportunity to early systemic escalation. The platform will involve multiple steps. First, Starburst-1 (SB-1) will aim to create an effective multimodal signature that can predict effectively pathological complete response to NAT. Once the signature is validated, we will develop Starburst-2 (SB-2) as a platform in which we will test different risk-adapted strategies based on the response post NAT. Methods: In SB-1, we will enroll in a phase II, single arm, prospective cohort, patients with newly diagnosed MIBC (pT2-T4a N0-1 M0). All patients will be treated with standard of care (SOC) NAT followed by RC. All patients will be assessed before NAT by a cystoscopy, TURBT, urine cytology, bladder multiparametric MRI (mpMRI) using the NacVi-RADS score, blood and urine liquid biopsy. After completing the NAT, each patient will undergo a cystoscopy (+/- biopsy), SOC clinical and radiological workup (TAP CT +/- PET-FDG), a mpMRI and blood/urine collection. The primary endpoint of SB-1 is to prospectively evaluate the accuracy of the NacVI-RADS score to predict the pathological complete response defined as the absence of muscle invasive disease (ypT≥2 vs ypT0/a/1). Kappa score agreement between the MRI staging and RC pathological staging will also be addressed. Secondary endpoints include the assessment of new biomarkers including blood circulating tumor DNA (ctDNA) and urine tumor DNA (utDNA), urine multiplex biomarkers, pathomics, radiomics and molecular alterations that could predict pathological response. In SB-2, de-escalation therapies and escalation therapies according to patients’ response to NAT will be tested in a prospective multi-arm cohort platform. NCT number: will be obtained before ASCO GU. Clinical trial information: Ongoing in clinical trials.gov.

Patient profiles as drivers of physician choice for first-line (1L) treatment (tx) in locally advanced or metastatic urothelial cancer (la/mUC): Perspectives from a US study.

719 Background: As the number of tx options for patients with la/mUC increases, physicians aiming to optimize tx choice and sequencing must make complex decisions. Although recommended options provide clinical benefits, each has a distinct toxicity profile that limits its use in routine clinical care. This study assessed physician perspectives for 1L la/mUC tx selection based on hypothetical patient and disease characteristics. Methods: Data were drawn from the Adelphi Real World mUC Disease Specific Programme, a cross-sectional survey that captured data from medical oncologists and urologists responsible for treating people with la/mUC in the US, from Jan-July 2024. Physicians self-reported which 1L tx option they would be most likely to prescribe based on patient and disease characteristics provided. Tx options presented were: platinum-based chemotherapy followed by avelumab maintenance (PBC & Ave), enfortumab vedotin plus pembrolizumab (EV & P), cisplatin/gemcitabine plus nivolumab (cis/gem & nivo), and other. Descriptive statistics were used for all analyses. Results: Of the 49 physicians who participated, 23 (47%) primarily worked in academic practices, 19 (39%) in community-based practices, and 7 (14%) in other care settings. At data collection, physicians were making tx decisions for a median of 24 patients with la/mUC (IQR, 10-44). Physicians most frequently reported that they would choose PBC & Ave for patients with liver disease (53%) and EV & P for patients with only lymph node involvement (55%). A breakdown of physician-reported 1L tx choices by patient/disease profile is presented in the Table. Conclusions: Despite the limited sample size, this real-world study provides contemporary insights into la/mUC tx choice among practicing US physicians in an evolving therapeutic landscape. We found heterogeneity in clinician-reported choices for 1L tx based on patient profiles, and inconsistency vs guideline recommendations. Multidisciplinary discussion and consensus are needed to support physicians in identifying patient profiles that may derive the greatest benefit from different 1L tx options while minimizing potential risks. Criteria that guide clinicians and inform policy decisions should evolve and gain broader acceptance as novel therapeutics are incorporated into routine care. Physician-reported 1L tx choice (N=49) Characteristic, n (%) PBC & Ave EV & P Cis/Gem & Nivo Other Liver disease 26 (53) 16 (33) 7 (14) - Visceral disease 18 (37) 25 (51) 6 (12) - Liver metastases 17 (35) 22 (45) 10 (20) - Frail/elderly patients 9 (18) 24 (49) 8 (16) 8 (16) Pre-existing peripheral neuropathy 15 (31) 25 (51) 3 (6) 6 (12) Diabetes 24 (49) 19 (39) 5 (10) 1 (2) Only lymph node involvement 19 (39) 27 (55) 3 (6) - Low tumor burden 15 (31) 21 (43) 12 (24) 1 (2) High tumor burden 20 (41) 19 (39) 10 (20) -

Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP).

TPS432 Background: Patients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR, defined by a prostate-specific antigen (PSA) increase with no evidence of metastases on conventional imaging. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) may detect lesions in patients with BCR. Patients with BCR are at high risk of disease progression, and lesions identified by PSMA PET/CT need effective treatment to delay progression. Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, significantly improved metastasis-free survival (MFS) and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (CRPC). ARASTEP (NCT05794906) will evaluate whether darolutamide when added to ADT improves radiologic progression-free survival (rPFS) by PSMA PET/CT vs placebo plus ADT in patients with BCR following primary therapy and PSMA PET/CT-positive lesions. Methods: Eligible patients were treated by primary RT or RP +/- adjuvant RT (ART) or salvage RT (SRT), present with high-risk BCR (PSA doubling time [PSADT] <12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), and must have ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone ≥150 ng/dL. Approximately 750 patients from 221 global sites will be randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, both with ADT, for 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients with detectable PSA values (≥0.2 ng/mL) after 24 months will continue study treatment until PSMA PET/CT progression by blinded independent central review (BICR). Stratification factors are PSADT <6 vs ≥6–<12 months, intent to treat baseline PSMA PET/CT lesions with image-guided RT/surgery (Yes vs No) and distant ± locoregional vs locoregional-only lesions. The primary endpoint is rPFS by PSMA PET/CT assessed by BICR. Secondary endpoints include MFS on conventional imaging by BICR, time to CRPC, OS, quality of life, and safety. As of October 2024, 248 patients have been randomized. Clinical trial information: NCT05794906 .

Understanding diversity and disparities in a real-world locally advanced/metastatic urothelial carcinoma (la/mUC): Clinical characteristics, genomic landscape, and self-reported social determinants of health (SDOH).

669 Background: Fibroblast growth factor receptor (FGFR) inhibitor therapy improves overall survival in LA/mUC patients with FGFR 2/3 alterations and prior systemic therapy including immune checkpoint inhibitors (ICI). The current treatment landscape is rapidly evolving with inequities in molecular testing and access to novel therapies. In the real-world, the genomic landscape, treatment patterns, and outcomes in LA/mUC have yet to be established. In this multicenter prospective cohort study, we examined the RW treatment patterns, outcomes, genomic profile, diversity, and SDOH in pts with LA/mUC. Methods: In this LA/mUC cohort, we assessed baseline characteristics, self-reported SDOH, clinical management patterns, and treatment outcomes (PFS, OS). Comprehensive genomic profiling (CGP), including FGFR1-4, of DNA and RNA from archived FFPE tissue were analyzed. Results: 42 pts with LA/mUC were enrolled from Apr – Sept 2024 (79% bladder; 21% upper tract). 93% (39/42) had distant metastases (18% visceral). Median age at diagnosis was 69 yrs and 79% were male. 23 (62%) completed a questionnaire. 96% self-reported as White/Caucasian, 4% as Indigenous. 26% live in a rural setting >1 hour from a cancer centre. 47% report financial stress. 30% report a family history of Lynch Syndrome related malignancies. In 35 pts who underwent CGP, 11 pts (31%) had FGFR alterations, comprised of FGFR1-3 fusions, amplification, or mutations (Table 1). 88% (37/42) of pts received first-line (1L) therapy, primarily CTx (78%), and 1 pt received an FGFR-inhibitor. 62% (23/37) received 2L therapy (83% ICI, of which 68% was maintenance avelumab). 8 pts received 3L (63% (5/8) antibody drug conjugate [ADC]). 2 pts received 4L (n=1 ADC, n=1 CTx); 1 pt received 5L (ICI). Median progression free survival (mPFS) was 7.6 mo (95% CI: 5.1 – 22.5), 6.6 mo [95% CI: 2.5 – NR] and 6.9 mo [2.1 – NR], for 1L, 2L, 3L, respectively, but not reached for 4L and 5L. 88% are alive with a median follow-up of 10.3 months. Overall survival was not yet reached. Conclusions: This RW analysis of pts with LA/mUC provides valuable insights into the genomic landscape, clinical characteristics, and SDOH within this population. The presence of targetable genomic alterations underscores the necessity for an equitable precision medicine approach in diverse LA/mUC pt populations to optimize outcomes. This study demonstrates the feasibility of collection of a comprehensive array of data and samples to guide a management for patients with LA/mUC. NGS results. FGFR Alteration (n=11) Number (%) FGFR1 amp (borderline) 1 (9) FGFR1::TBC1D22A fusion 1 (9) FGFR2::USP11 fusion 1 (9) FGFR3 mutation 3 (27) FGFR3::FGFR1 fusion 2 (18) Insufficient sample 3 (27)

Sea level since the Last Glacial Maximum from the Atlantic coast of Africa

Updated results from a phase I/II study of CBP-1018, a bi-ligand–drug conjugate (Bi-XDC) as late line therapy for patients with metastatic castration resistant prostate cancer (mCRPC).

161 Background: Patients (Pts) with mCRPC have a poor prognosis with limited treatment options, particularly those who have progressed after novel hormonal agents (NHA) and chemotherapy. CBP-1018 has demonstrated a well-tolerated safety profile based on 112 pts and preliminary efficacy in mCRPC at RP2D of 0.14mg/kg as shown in 2024ASCO and 2024ESMO. Here we report the updated safety data of 120 pts and efficacy at ≥0.14mg/kg including pts treated with prior 2 nd generation androgen receptor pathway inhibitor (ARPI) and taxane from the Phase I/II study. Methods: In this study, pts with progressive mCRPC after standard of care regardless of the number of prior therapies were enrolled. Response evaluation was undertaken per PCWG3 and RECIST v1.1. Primary endpoints were ORR, rPFS and safety. Results: As of cutoff date of 31-Aug 2024, a total of 120 pts were enrolled. 8.3% (10/120) of pts experienced treatment related adverse event (TRAE) leading to dose reduction and 4.2% (5/120) had TRAE leading to discontinuation. The AEs were consistent with the known safety profile, with the most common ≥G3 TRAE primarily being hematologic, which were transient and easily manageable. Typical common AEs seen with ADC were rarely observed; only 1 pt experienced treatment related visual acuity reduction and 11.7% (14/120) of pts experienced peripheral neuropathy. All of these TRAEs were G1. 76 pts were enrolled at ≥0.14mg/kg dose level (0.14mg/kg N=69; 0.16mg/kg N=7). 68.4% (52/76) with ECOG 1. 17.1% (13/76) had liver metastases and 15.8% (12/76) had lung metastases. Additionally, 67.1% (51/76) had received at least one prior taxane and at least one 2 nd generation ARPI, while 53.9% (41/76) had received ≥ 2 prior 2nd generation ARPIs. 21.1% (16/76) had received prior PARP inhibitors. Among 25 pts with target lesion (≥0.14mg/kg), ORR was 20% and DCR was 88.0%. Target lesion reduction was observed in 60% of pts. In the subset of 15 pts with prior taxane and 2 nd generation ARPI treated pts with target lesion (0.14mg/kg), ORR was 20% and DCR was 80%. Among 69 pts (0.14mg/kg), median radiographic progression-free survival (rPFS) has not yet been reached; 7-month rPFS rate was approximately 70%, and 12-month rPFS rate was about 60%. Among the 48 pts with prior taxane and 2 nd generation ARPI treated (0.14mg/kg), 7-month rPFS rate was around 66%. Conclusions: CBP-1018 shows potential as a viable therapeutic option for heavily treated mCRPC pts based on the superior rPFS and anti-tumor activity, warranting further evaluation in later phase III trials. Clinical trial information: NCT04928612 .

Relationship between androgen deprivation therapy and kidney function in patients with prostate cancer: An analysis of the RADICAL-PC study.

115 Background: Androgen deprivation therapy (ADT) is an effective treatment for patients with advanced prostate cancer (PC). However, its impact on renal function remains underexplored. We evaluated the impact of ADT on kidney function in a cohort of patients with PC. Methods: We analyzed the RADICAL-PC study (Role of Androgen-Deprivation Therapy in Cardiovascular Disease—A Longitudinal Prostate Cancer study, NCT04127631), a prospective study of patients with PC in 10 countries. ADT use was assessed at baseline and follow-up visits. We quantified kidney function using glomerular filtration rate (GFR), calculated using the CKD-EPI equation and creatinine measurements obtained at annual visits. We used a linear mixed-effects regression model to analyze the association between ADT and change in GFR (ΔGFR), adjusting for age, diabetes, hypertension, renal disease, heart failure, chemotherapy, medications, alcohol use, and smoking. Using a Cox regression model, we assessed the association between ADT and acute kidney injury (AKI) as reported by sites. Results: Our analysis included 4119 participants with a median age of 68 (IQR 63-74) years. In 1791 (43%) participants using ADT at baseline, the ΔGFR over 2 years was -0.64 [95%CI -1.05 to -0.22] ml/min/1.73m 2 /year. In 2328 (57%) ADT-naïve participants at baseline, the ΔGFR was -1.00 [95%CI -1.34 to -0.64] ml/min/1.73m 2 /year. There was no significant difference in ΔGFR between the two groups (p=0.20). Age (β=-0.58, p<0.001), hypertension (β=-1.98, p<0.01), and anticoagulation use (β=-3.92, p<0.001) were associated with GFR decline. When analyzed as a time-varying covariate, ADT use was associated with less GFR decline than no ADT use (-0.21 vs. -1.07 ml/min/1.73m 2 /year, respectively, p<0.01). Duration of ADT use was not associated with ΔGFR (+0.04 [95%CI -0.02 to 0.10] ml/min/1.73m 2 /month, p=0.18). AKI developed in 91 (2.2%) participants over a median follow-up of 25 (IQR 12-36) months. Baseline ADT use was associated with an increased risk of AKI in univariate analysis (HR 2.58 [95%CI 1.67 to 3.98], p<0.001), but was not significant after adjustment for covariates (HR 1.37 [95%CI 0.83 to 2.26], p=0.22). Conclusions: This analysis suggests that ADT use is not associated with GFR decline or AKI incidence in patients with PC, challenging previous literature concerning ADT-related renal dysfunction. Further studies with longer follow-up periods are needed to confirm these findings.

Natural history and risk-stratification of biochemical recurrence in prostate cancer treated with definitive radiotherapy.

348 Background: Biochemical recurrence (BCR) of prostate cancer following radiation therapy often does not result in clinically significant events, but a subset of patients may be at higher risk of developing metastatic disease or death. Identifying these patients is critical for clinical decision making, but unlike in the post-prostatectomy setting, no method has been externally validated for BCR after radiation therapy. This study characterized outcomes after post-radiation BCR and validated a proposed risk stratification heuristic. Methods: This was a retrospective, multicenter, nationwide cohort study of patients having post-radiation BCR treated in the United States Veterans Administration Health System. High-risk post-radiation BCR was defined as either Gleason score ≥8 or BCR occurring within 18 months of radiation therapy. BCR was defined as post-treatment PSA greater or equal to PSA nadir + 2 ng/ml, initiation of androgen deprivation therapy distinct from the initial treatment course, or development of metastatic disease, whichever occurred first. Results: Median time to BCR was 42.5 months (interquartile range 22.9-73.0). Among 7,126 patients who experienced BCR, 35.5% of patients developed metastatic disease and 17.4% died of prostate cancer at 10 years. 38.5% of patients had at least one qualifying high-risk feature of whom 23.3% had high-risk recurrence based on time to recurrence alone, 57.6% based on Gleason/Grade Group alone, and 19.1% based on both criteria. High-risk BCR resulted in higher 5-year rates of metastatic disease (42.0% versus 24.5%, hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.69-1.98, p < 0.001), death from prostate-cancer (18.7% versus 8.78%, HR 1.82, 95% CI 1.63-2.03, p < 0.001), and death from all causes (37.1% versus 30.8% rates, HR 1.18, 95% CI 1.11-1.26, p < 0.001). Conclusions: A simple, two-element risk stratification tool using existing clinically data is the first validated tool for identifying patients at risk of metastases or PCSM following post-radiation BCR. Most patients experiencing BCR in this context do not develop metastases or lethal prostate cancer, making such stratification essential for treatment decision-making and refinement of patient populations for clinical trials. Further work remains on risk-adapted therapy intensification.

Progressive T cell exhaustion and predominance of aging tissue associated macrophages with advancing disease stage in penile squamous cell carcinoma.

11 Background: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited understanding of the tumor immune microenvironment (TIME). The interplay between PSCC and the immune system across disease progression and HPV infection status remains poorly characterized. This study aims to assess the TIME changes from localized to advanced disease and between HPV-positive versus negative tumors, we hope to identify potential immune evasion mechanisms for advanced PSCC. Methods: scRNA-seq was performed on ten PSCC tissue samples from penile, lymph node and distant metastatic sites with four matched penile and lymph node samples to understand the cellular heterogeneity within PSCC tumors. Analysis of immune cell populations and transcriptional hallmarks were performed stratified by localized (pT1-3, N0) versus advanced (N1-3, M0 or any N, M1) disease states and HPV infection status. Results: Patients with advanced stage disease were found to have a TIME enriched with terminally exhausted C8+ T cells. The myeloid compartment showed an increase in aging and immunosuppressive M2-like macrophages. Additionally, hypoxia-induced response patterns were more pronounced in advanced stages. HPV-negative tumors exhibited a quiescent TIME characterized by low immune cell infiltration. Conclusions: We observed significant differences in immune cell infiltration between localized and advanced PSCC disease states. Advanced disease states demonstrated an exhausted immune phenotype, characterized by terminally exhausted CD8 + T cells, M2-like macrophages and hypoxic signature. HPV-negative tumors displayed low immune cell infiltration. These findings offer valuable insights into the evolving PSCC immune landscape, paving the way for the development of potential novel macrophage directed therapies for PSCC.

Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis

Nectin-4 targeted ADC, SHR-A2102, in patients with advanced or metastatic urothelial carcinoma: A phase 1 study.

657 Background: SHR-A2102 is a novel ADC that consists of a fully humanized IgG1 monoclonal antibody targeting nectin-4, a cleavable linker, and a topoisomerase I inhibitor payload with high membrane permeability and potent cell-killing efficacy. We have initiated a first-in-human phase 1 study to assess the safety, tolerability, and efficacy of SHR-A2102 in advanced solid tumors. Here, we present preliminary findings, focusing on urothelial carcinoma. Methods: Patients (pts) with locally advanced unresectable or metastatic urothelial carcinoma, who had failed or were intolerant to standard therapies, were eligible. SHR-A2102 was given intravenously at 1, 2, 4, 6, 8 mg/kg on D1 Q3W and 4 mg/kg on D1 and D8 Q3W during dose escalation. 6 and 8 mg/kg were selected for dose and efficacy expansions. Results: As of Aug 2, 2024, 73 UC pts were enrolled (median age: 65 yrs; ≥2 lines of prior systemic therapies: 57.5%; prior ADC: 42.5%). Efficacy outcomes were summarized in Table. Confirmed ORR was 38.4% (28/73; 95% CI, 27.2–50.5) in all pts, and was 32.3% (10/31; 95% CI, 16.7–51.4) in the 6 mg/kg dose group and 50.0% (16/32; 95% CI, 31.9–68.1) in the 8 mg/kg dose group. 6-mo DoR rate was 59.3% (95% CI, 23.1–83.0) in all pts, and was 66.7% (95% CI, 5.4–94.5) and 54.0% (95% CI, 12.7–83.2) in the 6 and 8 mg/kg groups, respectively. Of note, 31 pts had received ADC prior to study treatment; among them, 12 (38.7%; 95% CI, 21.9–57.8) pts achieved confirmed PR. Overall, TRAEs of grade 3 or worse occurred in 32 (43.8%) pts, with the most common (≥10%) being anemia (23.3%), decreased WBC count (19.2%), and decreased neutrophil count (17.8%). Conclusions: SHR-A2102 showed promising anti-tumor activity in pts with advanced or metastatic urothelial carcinoma, even after ADC therapy, along with manageable safety profile. Clinical trial information: NCT05735275 . Efficacy summary. All UC pts(N=73) 6 mg/kg(N=31) 8 mg/kg (N=32) ADC pretreated pts (N=31) Best overall response, n (%) Confirmed PR 28 (38.4) 10 (32.3) 16 (50.0) 12 (38.7) SD 30 (41.1) 18 (58.1) 10 (31.3) 11 (35.5) PD 12 (16.4) 3 (9.7) 3 (9.4) 7 (22.6) NE 3 (4.1) 0 3 (9.4) 1 (3.2) Confirmed ORR, % (95% CI) 38.4 (27.2–50.5) 32.3 (16.7–51.4) 50.0 (31.9–68.1) 38.7 (21.9–57.8) DCR, % (95% CI) 79.5 (68.4–88.0) 90.3 (74.3–98.0) 81.3 (63.6–92.8) 74.2 (55.4–88.1) 6-mo DoR rate, % (95% CI) 59.3 (23.1–83.0) 66.7 (5.4–94.5) 54.0 (12.7–83.2) 60.0 (12. 6–88.2) 6-mo PFS rate, % (95% CI) 41.4 (23.6–58.4) 54.7 (24.0–77.4) 38.0 (13.4–62.7) 39.1 (16.6–61.3)

Germline genetic variants in cancers of the urothelial tract and association with outcomes.

870 Background: Studies cite that 10-24% of patients (pts) with urothelial carcinoma (UC) have a pathogenic germline variant (var), but few have looked at association with outcomes. We aimed to identify the frequency of germline pathogenic vars (PV) in UC and hypothesized they would be associated with cancer-related outcomes. Here we present germline results from the largest reported, fully clinically annotated cohort of pts with UC. Methods: We performed a single center retrospective review of all pts with a diagnosis (dx) of bladder, renal pelvis, ureter, or urethra cancer who underwent clinical germline targeted panel genetic testing from 2018 to 2024. We also included all pts with the same dx enrolled on an institutional protocol that performed germline whole exome sequencing (WES) for research. We analyzed the 77 genes from WES most frequently included in the targeted panels. We classified all vars as pathogenic, variant of unknown significance (VUS), or benign. Results: We included 267 pts. Median number of genes tested was 77 (range 1-93) with 83.9% of pts completing a panel of ≥77 genes. Of 267 pts, 48 (18%) had a PV, 138 (52%) had a VUS without a PV, and 81 (30%) had no germline var. The most common PVs were in CHEK2 (n = 5/48 [11%]), ATM (9%), MUTYH (9%), MSH2 (9%), TP53 (7%) and MLH1 (7%). Among the 48 pts with a PV, 12 (25%) had Lynch syndrome and 25 (52%) had a non-Lynch DNA Damage Repair gene var. Of 256 pts with urothelial histology, 47 (18%) had a PV. Of 7 pts with pure squamous histology, 1 (14%) had a PV in ATM , 4 (57%) had a VUS. Three pts with rare histologies of small cell, rhabdomyosarcoma, and adenocarcinoma had a VUS in ATM, RET, or POLD1, respectively. Of 48 pts with a PV, only 12 (25%) ever developed metastatic disease. Comparing pts with PVs (n=48) to not (n=219), we found no significant difference in median age at dx, age at dx ≥ 60, sex, race, ethnicity, smoking history, median number of 1 st degree family members with a dx of cancer, or clinical stage at dx. Pts with a PV had no significant difference in primary tumor location, however pts with Lynch syndrome were more likely to have an upper tract tumor (p = 0.002). Adjusting for clinical stage, there was no significant difference in overall survival between pts with a PV compared to without. Three of 12 pts with Lynch received an immune checkpoint inhibitor (ICI) for non-muscle invasive, muscle invasive, or metastatic disease, respectively, and all had prolonged responses without recurrence at 44, 12, and 70 months of follow-up. Conclusions: Germline PVs were detected in 18% of pts with UC. We confirmed the association of Lynch syndrome with upper tract disease and favorable response to ICI. Germline genetics of rare histologic variants warrants further investigation. Our findings support genetic testing in all pts with UC, including early-stage disease. Further study of ICIs for early-stage UC in Lynch syndrome is needed. Analysis of a larger cohort and response to specific treatments is ongoing.

PSMA-based PET imaging in newly diagnosed, high-risk localized prostate cancer, a National Cancer Institute (NCI) Cancer Moonshot trial.

327 Background: Prospective randomized trials have suggested that prostate specific membrane antigen (PSMA)-based PET/CT may improve the detection of metastatic disease in patients with high-risk prostate cancer (HR-PCa) diagnosed by conventional imaging. Of patients with HR-PCa who undergo radical prostatectomy (RP), the majority will experience PSA recurrence within 5 years. PSMA-based PET/CT may improve patient selection for local therapy, suggesting that this imaging advancement may be integral to improving patient outcomes. Here, we present results from the NCI cohort of NCT03976843, which evaluated the use of 18F-DCFPyL PSMA- PET/CT in newly diagnosed HR-PCa prior to RP. Methods: Enrolled patients (pts) had HR-PCa (biopsy Gleason score [GS] ≥8, PSA >20, or ≥T3) with negative conventional imaging (CT & bone scan). Pts underwent 18F-DCFPyL PSMA PET/CT and prostate MRI prior to RP. The primary hypothesis was that the subgroup of patients with a negative pre-operative PET/CT would have improved progression-free survival (PFS) over historical controls. Progression was defined as a confirmed PSA ≥ 0.2 ng/mL and PET/CT at progression. Correlatives included IHC of RP specimens and expert NCI radiologic imaging review. Results: Forty patients enrolled, and 38 patients underwent RP. Of the 38, the median age was 68 years old (61-71 years old), median PSA was 8.15 ng/mL (5.75-16.25), median biopsy GS was 8 (8-9), and median RP GS was 7 (7-8). Pre-operative PET/CT demonstrated regional lymphadenopathy in 2 patients (5.3%), and the median SUVmax of the index lesion was 12.6 (6.6-17.1). At a median follow-up of 2.2 years, the 2- and 4-year PFS was 76% (63%-91%) and 45% (22%-95%), respectively. The median PFS was 3.2 years. Of the 11 pts who underwent progression restaging, 2 had recurrent pelvic nodal disease, and 9 had no visible disease. No AEs were observed. Conclusions: These results support 18F-DCFPyL PET/CT as a safe and effective pre-operative staging strategy with the potential to improve patient selection for local definitive therapy. Expert NCI radiologic review for this multisite study, with correlative molecular and genomic work, is ongoing. Clinical trial information: NCT03976843 .

Integrated efficacy and safety exposure response (ER) analysis of tivozanib (TIVO) for the treatment of renal cell cancer (RCC).

461 Background: TIVO is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) approved in the US for treatment of patients with RCC following ≥2 prior systemic therapies. The approved TIVO monotherapy starting dose is 1.34 mg once daily on days (D) 1-21 Q28D, with allowable dose modifications to manage adverse events. In the randomized TiNivo-2 trial, the addition of NIVO 480 mg to TIVO 0.89 mg D1-21 Q28D (lower dose of TIVO was studied given assumed risk of hypertension [HTN]) did not improve outcomes compared with TIVO 1.34 mg D1-21 Q28D. There was a trend toward worse progression-free survival (PFS) in the combination arm. Methods: Using a predeveloped population pharmacokinetic (PK) model, existing ER models based on Tivo-1 and Tivo-3 studies were augmented to characterize the relationship between TIVO at clinically relevant exposures and central reviewer–based PFS, tumor size (TS) reduction, and safety endpoints. TiNivo-2 trial results were integrated to update the PK and ER models for PFS (Cox proportional hazard), TS (sum of longest diameters longitudinal model), and HTN (logistic regression) and to simulate the ER-based risk/benefit profile of TIVO. Results: The visual predictive check of the PK model on TiNivo-2 PK data confirmed that the dose-proportional TIVO PK is unaffected by concurrent NIVO. The PFS range of 5.6-9.7 months and TS reduction models, with a range of −7.02% to −23.8%, showed a significant relationship with TIVO exposure (Table). Concurrent NIVO did not add discernible benefit to TIVO at the dose of 0.89 mg. An ER modeling analysis between maximum concentration and HTN showed that the predicted HTN incidence was similar between TIVO 1.34 mg and TIVO 0.89 mg (41.3% vs 38.8% for any-grade HTN; 23.8% vs 21.5% for grade ≥3 HTN). An effect term for NIVO in the ER model for HTN was nonsignificant. Conclusions: The efficacy ER models predicted that TIVO 1.34 mg would provide greater antitumor activity than the 0.89-mg dose, while the predicted HTN incidence (any grade and grade ≥3) was comparable at the 0.89- and 1.34-mg doses. The TIVO monotherapy dose selection of 1.34 mg is important, based on the ER analysis and its safety profile. The results from the TiNivo-2 data set further confirmed that re-challenge with immunotherapy does not add benefit and optimal dosing of TKI provides the highest clinical benefit. Clinical trial information: NCT04987203 . Efficacy endpoint TIVO average concentration, ng/mL n Observed value,combined studies (range) PFS 13.9-38.4 192 5.6 months PFS 38.4-47.9 191 7.3 months PFS 47.9-62.0 191 9.1 months PFS 62.0-177 191 9.7 months CFB TS 13.9-38.4 176 −7.02% (−16% to 1.93%) CFB TS 38.4-47.9 173 −11.7% (−21.3% to −2.05%) CFB TS 47.9-62.0 185 −17.3% (−26.4% to −8.27%) CFB TS 62.0-177 183 −23.8% (−33.5% to −14.1%) CFB, change from baseline.

Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia

Real-world time on treatment (rwTOT) with first-line (1L) enfortumab vedotin and pembrolizumab (EV+P) after U.S. Food and Drug Administration approval for advanced urothelial cancer (aUC).

731 Background: EV+P received accelerated approval (AA) for cisplatin (cis)-ineligible aUC patients in April 2023 (EV-103) and full approval (FA) for all previously untreated patients in December 2023 (EV-302). In EV-302 trial, median durations of treatment with EV+P was 9.4 months (7.0 and 8.5 months for EV and P, respectively). We previously demonstrated high uptake of EV+P post AA in the real-world. Here, we examine rwToT with 1L EV+P with nearly 1 year of follow-up post-AA. Methods: This descriptive, post-marketing, retrospective cohort study used the Flatiron Health longitudinal database derived from EHR records of US patients with aUC initiating 1L EV+P after April 5, 2023 (AA) but before December 15, 2023 (FA). rwToT for EV+P was defined as length from first administration date of EV+P regimen to 1L therapy discontinuation, defined as last administration date of either component (i.e., EV or P) if patient initiated a next line of therapy, died during therapy, or had a gap of >60 days between last recorded dose and last contact date. rwToT was also estimated for each EV+P component. If no discontinuation criteria were met, the patient was censored at data cut-off (March 31, 2024). The Kaplan-Meier method was used for analysis of rwToT, including median rwToT (months) and 30-, 90-, 180-day on-treatment rates (%). Results: We identified 111 patients with aUC who initiated 1L EV+P after AA but before FA (mean age: 73.9 y, 75.7% male, 77.0% white, 23.7% ECOG performance status ≥2, 75.2% cis-ineligible, and 84.7% from community practices). As of March 31, 2024, approximately 41.4% (n=46) discontinued both EV and P; 9.9% [n=11] began subsequent therapy, 27.0% [n=30] died, and remaining patients were censored at end of follow-up (58.6%, n=65). Median rwToT (95% confidence interval [CI]) for EV+P, EV, and P were 8.2 months (6.5-not reached [NR]), 7.2 months (5.2-NR), and NR (6.3-NR), respectively (on-treatment rates reported in Table). Among 1L EV+P treated patients receiving subsequent therapies, 72.7% (9/11) received gemcitabine and carboplatin as the first subsequent therapy. Conclusions: In this large and predominantly cis-ineligible cohort of advanced urothelial cancer patients treated with EV+P in contemporary practice, rwTOT approximated duration of treatment in clinical trials. Most 1L EV+P users receiving subsequent anticancer therapy received platinum-based chemotherapy. rwToT with 1L EV+P for patients with advanced urothelial cancer (N=111). EV+P EV P Discontinued, n (%) 46 (41.4) 52 (46.8) 47 (42.3) Censored, n (%) 65 (58.6) 59 (53.2) 64 (57.7) Median rwToT, months (95% CI) 8.1 (6.4-NR) 7.1 (5.1-NR) NR (6.2-NR) On-treatment rate, % (95%CI) 30-d 84.7(78.2, 91.7) 82.0(75.1, 89.5) 81.1(74.1, 88.7) 90-d 72.1(64.2, 80.9) 65.8(57.5, 75.2) 72.1(64.2, 80.9) 180-d 60.4(51.4, 70.9) 54.0(45.0, 64.9) 60.0(51.1, 70.4)

A phase II trial of dostarlimab and niraparib combination therapy in patients with stage III-IV recurrent or refractory penile cancer.

TPS14 Background: Penile squamous cell carcinoma (PSCC) is a rare and aggressive malignancy with limited therapeutic options, particularly for patients whose disease progresses despite platinum-based chemotherapy. The overall survival rate for these patients is less than five months with standard treatment, highlighting the critical need for new and effective therapies. Preclinical studies have demonstrated a synergistic effect between PARP inhibitors and immune checkpoint inhibitors in PSCC animal models. The combination of niraparib and dostarlimab holds promise in eliciting a robust antitumor immune response in patients with cisplatin-refractory PSCC. Methods: This is an open-label, multi-center, phase II study employing a Simon two-stage design to assess the efficacy and safety of niraparib and dostarlimab in patients with advanced relapsed or refractory PSCC. Patients must provide an adequate tumor tissue sample at screening for molecular and immune profiling. Blood samples are collected at cycle 1, day 1 (C1D1) for exploratory molecular analysis, at cycle 3, day 1 (C3D1), at the time of investigator-assessed partial response (PR) or complete response (CR), and at the end-of-treatment visit. Niraparib will be administered orally at a dose of 200 mg once daily from day 1 to day 21 of each cycle, continuing until disease progression or unacceptable toxicity. Dostarlimab will be administered intravenously once every three weeks for cycles 1 through 4 and then every six weeks thereafter. Eligible patients must have histologically confirmed stage III (unresectable) or stage IV penile cancer as defined by the American Joint Committee on Cancer (AJCC) staging system. They must have experienced disease progression or intolerance after one line of platinum-based therapy, possess a life expectancy of at least 12 weeks, and have an ECOG performance status (PS) of 0 or 1 (patients with an ECOG PS of 2 may be included upon discussion with the principal investigator). Additional eligibility criteria include measurable disease according to the Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST), adequate organ function, and no prior treatment with immunotherapy agents, cancer vaccines, adoptive cell therapies, or cytokine therapies. The primary efficacy endpoint is the investigator-assessed confirmed overall response rate (ORR), with tumor response evaluated according to iRECIST criteria. Patients who receive at least one complete dose of either study drug will be considered evaluable for response. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and duration of response (DOR), safety, and tolerability. Enrollment began in December 2022, and 14 of the planned 25 patients have been enrolled. Clinical trial information: NCT05526989 .

Functional and oncological outcome of primary nerve sparing retroperitoneal lymph node dissection in marker negative testicular germ cell tumors in clinical stage IIA/B.

641 Background: Guideline recommended treatment of choice for clinical stage IIA/B testicular nonseminomatous germ cell tumors (NSGCT) is the delivery of chemotherapy with 3 cycles PEB, 4 cycles PE. Despite its high curative efficacy, chemotherapy is associated with significant long-term toxicities. We evaluated the functional and oncological outcome of primary nerve sparing retroperitoneal lymph node dissection in marker negative NSGCT as a therapeutic option. Methods: Between 2018-2024 49 patients underwent primary RPLND for marker negative clinical stage IIA/B testicular germ cell tumors. All patients underwent nerve-sparing RPLND with a unilateral or bilateral template dissection. None of the patients received adjuvant chemotherapy. Follow-up was performed according to the EAU guidelines. The surgeries were performed by a single surgeon using an open transperitoneal approach. Results: The median age and median follow-up were 30.1 (17-35) years and 29.4 (11-47) months, respectively. The mean operative time, blood loss, and hospitalization duration were 131 (105-195) minutes, < 150ml, and 4.5 (3-9) days, respectively. 10 patients (9.18%) experienced a Clavien-Dindo grade 3a complication. Antegrade ejaculation was preserved in 90.8% of cases. On average, 21 (7-42) lymph nodes were dissected. 5 patients exhibited teratomatous elements in the primary orchiectomy specimens and 4 patients demonstrated teratomatous elements in the resected lymph nodes. The mean number of positive lymph nodes was 2 (1-3), with an average size of 1.3 (0.3-3.0) cm. Ten patients (20.4%) showed a pN0 stage. Six patients (12.2%) developed a recurrence and were cured by salvage chemotherapy. Conclusions: Primary RPLND for marker negative clinical stage II/ABnonseminomatous germ cell tumors results in a high cure rate without additional chemotherapy and it is associated with a low rate of complications if performed in experienced hands. Additionally, nsRPLND can safe unnecessary cytotoxic systemic therapy in 20% of patients. Furthermore, 8.1% of patients with teratoma containing lymph nodes would not have been cured by chemotherapy. Primary nsRPLND should be included in the management of marker negative CS IIA/B NSGCT.

Spatial transcriptomic analysis of tumor tissue from patients with metastatic urothelial carcinoma (mUC) receiving ipilimumab (IPI) plus nivolumab (Nivo) combined with sacituzumab govitecan (SG).

863 Background: We previously reported that the combination of IPI-NIVO plus SG shows high efficacy with 83.3% objective response rate (ORR) and durable responses as first-line treatment for cisplatin-ineligible mUC patients in a Phase I/II trial. However, two grade 5 immune-mediated myocarditis events attributed to IPI-NIVO occurred, leading to early trial termination after accruing 25 patients. Given the high ORR, we performed correlative analysis to identify a predictive biomarker for response. Methods: For Nanostring GeoMx DSP spatial transcriptomics, 19 baseline tumor samples were evaluable. Patients were categorized as responders (CR+ PR, n=15) and non-responders (SD+ PD, n=4). The raw Nanostring GeoMx probeQC count data was quality-controlled for both segment and gene levels using GeomxTools package in R version 4.3. The segments with flags such as ‘Low Percent Aligned Reads’, ‘Low Percent Stitched Reads’, ‘Low Surface Area’, ‘Low Nuclei Count’, ‘Low Negative Mean’, and ‘Low gene detection rate’ were excluded from further analysis. In total, 35 and 24 segments were left for responder and non-responder groups, respectively. Genes with raw count smaller than the ROI-specific limitation of quantification (LOQ) and low detection rate among segments were excluded from downstream analysis. Totally, 8230 genes were left for 59 segments for further analysis. The differential expression between groups was done using a linear mixed-effect model. Results: 90 and 136 genes were significantly up- and down-regulated in responder group and non-responder group (P value < 0.05 for both). The top upregulated genes in responders included: IGHG2, IGKC, ACKR2, KRT80 and SCD, while those upregulated in non-responders included: S100A2, AKR1C3, MYCN, MAGEA3, and OBSCN (P value < 0.05) . Gene set enrichment analysis (GSEA) revealed gene signatures from B cell-mediated immunity pathway significantly enriched in the responder group (FDR = 0.02), while gene signatures from PRC2_EZH2_UP.V1_DN related to polycomb-mediated transcription reprogramming and promoting tumorigenesis were significantly enriched in the non-responder group (FDR = 0.0017). Trop2 and Topoisomerase 1 genes were upregulated in responders but not statistically significant. Conclusions: Spatial transcriptomics analysis suggests that upregulated B cell-mediated immunity pathways may predict response to combination IPI-NIVO + SG in patients with mUC. The PRC2-EZH2 pathway may represent a potential resistance mechanism and therapeutic target. Transcriptomic evaluation of the therapeutic targets of the antibody and the payload in antibody-drug conjugates warrant further study as predictive biomarkers. Further analyses to identify biomarkers for severe immune events may help optimally select patients for the best therapeutic index. Clinical trial information: NCT04863885 .