University of Colorado Cancer Center

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

Our previous preclinical studies demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and naproxen significantly inhibited prostate tumorigenesis in a TMPRSS2-ERG fusion-driven model compared to non-fusion models. Since TMPRSS2-ERG fusion-positive tumors display heightened inflammatory signaling and substantial immune infiltration, we hypothesized that the differential efficacy of NSAIDs may arise from their ability to remodel the tumor immune microenvironment. Accordingly, in the present study, we systematically profiled innate and adaptive immune-cell populations: F4/80⁺ macrophages, mast cells, neutrophils, CD3⁺ T cells, CD8⁺ cytotoxic T cells, FoxP3⁺ regulatory T cells, CD20⁺ B cells, IgKC⁺ plasma cells, and Granzyme B⁺ effector cells in highly infiltrated dorso-lateral prostate regions of TMPRSS2-ERG fusion-driven and non-fusion PCa models, with and without NSAID intervention. Our analyses revealed pronounced macrophage infiltration in TMPRSS2-ERG. Ptenflox/flox and Hi-Myc+/ - model, which was further augmented by NSAIDs. Importantly, NSAID intervention shifted macrophage polarization toward an M1-like, pro-inflammatory state, contrasting with the M2-dominant phenotype characteristic of untreated tumors. NSAID treatment reduced mast cell density within the stromal compartment, suggesting suppression of mast cell-mediated tumor-promoting signals. In the fusion model, infiltration of total T cells and CD8⁺ cytotoxic T cells decreased following NSAID exposure, whereas FoxP3⁺ Tregs remained largely unaffected. Both models showed increased B-cell infiltration independent of NSAID efficacy, and no clear correlation was observed between plasma-cell presence and treatment response. Collectively, our findings offer new insight into NSAID-mediated immunomodulation in TMPRSS2-ERG fusion-driven PCa; however, further in-depth immune subtyping and spatial mapping could fully delineate the immunological mechanisms driving NSAID responsiveness.

New advanced bladder diagnoses usually occur in the 8th or 9th decade of life. Most data on bladder cancer care has been garnered from a younger population. Older adults with cancer are more likely to have comorbid conditions, undetected vulnerabilities, and priorities that value function in comparison to younger adults with cancer. However, functional assessments and value elicitation are not consistently employed at the outset of care planning in this unique population. We proposed the use of an intervention bundle, or framework, to guide early care planning for older adults with advanced bladder cancer to address the delivery of goal-concordant care. We followed a modified Delphi process to determine the components of the framework. We undertook an initial literature review and then convened a transdisciplinary group of professionals with internationally recognized expertise in urologic oncology (medical and surgical), clinical trial design, geriatric oncology, palliative care, exercise physiology, or cancer rehab. This panel participated in surveys and meetings to determine representative measures for the (1) functional assessment, (2) chemotherapy toxicity estimate, and (3) guided goals of care discussion components of the framework. The group recommended the short physical performance battery to measure functional status, the Cancer and Aging Research Group chemotherapy toxicity calculator to estimate chemotherapy risks, and the Serious Illness Conversation Guide to elicit patient values and priorities. This consensus building process utilized evidence-based measures backed by expert consensus to contribute to a pragmatic framework to guide care planning in older adults with advanced bladder cancer.

This study identifies oxidative metabolism as a critical driver of selection for TET2 -deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.

726 Background: Older patients with incurable genitourinary (GU) cancers are at high risk for receiving care that does not align with their goals. This study assessed the feasibility and acceptability of a treatment planning framework including validated geriatric, oncologic, and palliative approaches at initial assessment to better align and improve care. Methods: This single-arm pilot study evaluated the feasibility and acceptability of the ABC123 framework for aligning cancer treatment with older adults’ goals. Originally designed for an advanced bladder cancer (ABC) population, the framework integrates 1. geriatrics (geriatric functional assessment), 2. oncology (chemotherapy toxicity), and 3. palliative care (goals-of-care discussions) delivered by an advanced practice provider. The intervention occurred within 2 weeks of the initial oncology visit and patients followed up (FU) at 1, 3, and 6 months. We enrolled patients aged ≥ 65. The primary outcome was feasibility (recruitment and retention). Secondary outcomes included patient-oncologist care alignment, acceptability, goal-concordant care (Ottawa Decision Scales and Advanced Illness Coordinating Care Survey [AICCS]), and quality of life. Results: The study was feasible with 50% of those approached consented (n = 34). Although expected attrition occurred, 16 completed the 1 mo FU and 12 completed 3 mo FU measures. The study expanded beyond bladder cancer and 9 patients had a GU cancer. At 1 mo FU, 75% patient-oncologist goals of treatment were most aligned, with 17% less aligned, and 8% least aligned (Table 1). At baseline, the mean AICCS score was 3.8, increasing to 4.4 at 3 mo (p = 0.02). No significant differences were observed for Ottawa Self-Efficacy (89.9 vs. 88.1, p = 0.49), Decision Conflict (26.7 vs. 19.6, p = 0.25), Informed subscale (29.0 vs. 23.1, p = 0.44), Value Clarity subscale (27.2 vs. 19.9, p = 0.42), or FACT-G (2.8 vs. 3.0, p = 0.89). Items were coded so a more positive outcome is indicated by a higher score except Decisional Conflict and its subscales. No differences in demographics or cancer/co-morbidities were noted between those who completed 3 mo outcomes and those who did not. Conclusions: This pilot study demonstrated the feasibility of enrollment and follow-up in older patients with incurable cancer, with staff and patients noting acceptability of the design including delivery of a primary goals of care discussion by an advanced practice provider. Excellent patient-oncologist care alignment was noted, and most patient-reported outcomes trended to improvement. A larger randomized study was planned based on this pilot experience. Goal of treatment assignment. 1-Month Oncologist Perspective PatientPerspective Supportive Life prolonging Rehabilitative Curative Supportive 0 2* 0 0 Life prolonging 0 9** 0 0 Rehabilitative 0 0 0 0 Curative 1# 0 0 0 Most aligned=**; Less aligned=*; Least aligned=#.

168 Background: In the phase 3 TALAPRO-2 study, talazoparib (TALA) + enzalutamide (ENZA) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) vs placebo (PBO) + ENZA as first-line treatment (tx) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) unselected (cohort 1) and selected for homologous recombination repair gene alterations (HRRm cohort). Here, we report post-hoc analyses of PSA kinetics from the final OS analysis cutoff date. Methods: Pts were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg or PBO once daily. The primary endpoint was rPFS; OS, a key secondary endpoint. We performed post hoc analyses of PSA flare (defined as a rise in PSA above baseline followed by a return to baseline or lower within 12 months), PSA response ≥50% (PSA50), PSA response ≥90% (PSA90), undetectable PSA (defined as PSA <0.2 ng/mL), and duration of PSA response. OS and rPFS were analyzed in PSA50 responders. Results: At data cutoff (Sep 3, 2024), PSA flare was observed in 2–3% of pts in both tx arms of the unselected and HRRm cohorts (Table). The median time for PSA to decline back to or below baseline after a rise above baseline was 57 days in both tx arms in the unselected cohort, and 60 and 117 days with TALA + ENZA and PBO + ENZA, respectively, in the HRRm cohort (Table). A greater proportion of pts taking TALA + ENZA achieved PSA50, PSA90, and undetectable PSA compared with PBO + ENZA in both cohorts (Table). In both cohorts, pts in the TALA + ENZA arm also had a longer median duration of PSA50 response, PSA90 response, and undetectable PSA vs PBO + ENZA (Table). In the unselected cohort, rPFS and OS directionally favored TALA + ENZA vs PBO + ENZA in PSA50 responders (rPFS HR: 0.72 [95% CI 0.57, 0.89], median 39.8 vs 27.6 months; OS HR: 0.90 [0.72, 1.13], median 53.3 vs 47.3 months). Similarly, in the HRRm cohort, rPFS and OS favored TALA + ENZA in PSA50 responders (rPFS HR: 0.51 [0.38, 0.70], median 36.1 vs 18.3 months; OS HR: 0.62 [0.44, 0.86], median not reached vs 38.2 months). Conclusions: In both cohorts, a greater proportion of pts in the TALA + ENZA arm achieved PSA responses with longer durations vs PBO + ENZA. Also, PSA flare was unusual (2–3%) and resolved in ~60 days (both cohorts) with TALA + ENZA vs ~60 days (unselected) and ~120 days (HRRm) with PBO + ENZA. In both cohorts, OS and rPFS numerically favored TALA + ENZA vs PBO + ENZA in PSA50 responders. Analyses of PSA responses for specific genes (e.g. BRCA2 ) are underway. Clinical trial information: NCT03395197 . Unselected Cohort HRRm Cohort TALA + ENZA (n=402) PBO + ENZA (n=403) TALA + ENZA (n=200) PBO + ENZA (n=199) PSA flare, n (%) 12 (3) 11 (3) 5 (2) 5 (3) Median time for PSA decline back to or below baseline, days 57 57 60 117 PSA50, n (%) 335 (83) 285 (71) 173 (86) 126 (63) Median duration, days 430 284 420 225 PSA90, n (%) 253 (63) 182 (45) 139 (70) 80 (40) Median duration, days 480 419 589 308 Undetectable PSA, n (%) 159 (40) 107 (27) 87 (44) 44 (22) Median duration, days 644 539 650 365

821 Background: Nectin-4 targeting antibody drug conjugate (ADC) enfortumab vedotin (EV), in combination with pembrolizumab, is the first-line treatment for patients with metastatic or locally advanced urothelial cancer (UC). However, optimal treatment strategies for non-responders remain an unmet clinical need. We analyzed tumor transcriptomes to identify ADC target expression profiles which may inform treatment selection for these patients. Methods: We conducted a literature search to identify ADC targets approved or under investigation for UC. Molecular targets of interest included Nectin-4 ( NECTIN4 ), Her2 ( ERBB2 ), Trop-2 ( TACSTD2 ), DLL3, B7-H3 ( CD276 ), FGFR3, and PDL1 ( CD274 ). We interrogated The Cancer Genome Atlas (TCGA) dataset, comprising tumors from 434 patients with UC and 19 normal bladder tissue samples. Hierarchical clustering was used to identify recurrent ADC target expression profiles. To validate our findings, we repeated the analysis on an independent cohort of 478 patients with UC from the Oncology Research Information Exchange Network (ORIEN) using R version 4.5.1. Results: Two mutually exclusive patterns of ADC target expression were identified in the TCGA dataset. Cluster 1 (70.2%, n = 318) was characterized by overexpression of ERBB2 , FGFR3 , NECTIN4 and TACSTD2 . Cluster 2 (29.8%, n = 135) was characterized by overexpression of DLL3 , CD276 , and CD274 . The two clusters of ADC targets demonstrated a significant negative correlation (Spearman rho = -0.40, p < 0.0001). Normal bladder tissue did not cluster according to ADC gene expression profiles. In the ORIEN dataset, a similar pattern was observed: where the seven target genes were separated into two clusters. One cluster showed overexpression of FGFR3 , NECTIN4 , and TACSTD2 , while the other showed overexpression of DLL3 , CD276 , CD274 and ERBB2 . The enrichment scores of the two clusters were also negatively correlated (Spearman rho = -0.79, p < 0.0001) in the ORIEN dataset. Notably, ERBB2 clustered with the second group in ORIEN, suggesting biological variability. Conclusions: Through interrogation of TCGA data and validation in an independent ORIEN cohort, we identified two mutually exclusive ADC target expression profiles in UC. Tumors lacking overexpression of NECTIN4 , TACSTD2 , or FGFR3 were enriched for DLL3 , CD276 and CD274 expression, suggesting alternative ADC targets for non-responders to current therapies. The differential ERBB2 clustering highlights potential biological variability of this target. These findings warrant prospective proteomic validation and may inform rational treatment selection beyond EV.

SummaryPatient navigation comprises person-centred activities focused on addressing barriers and facilitating timely access to health care. Despite demonstrated effectiveness, the scope of patient navigation remains unclear. To clarify the scope of patient navigation and support global implementation, the Global Initiative to Advance Cancer Navigation for Better Outcomes (GINO) aimed to develop a practice framework for patient navigation in cancer care. Phase 1 involved reviewing patient navigation literature and identifying key areas of practice. Phase 2 involved a modified Delphi process with international experts in navigation (July to December 2024) to establish consensus on practices to include in the framework. Patient navigation experts across regions and disciplines were invited. Two rounds of online surveys were conducted where participants rated the importance of each practice on a scale from 1 (“Not important”) to 5 (“Critically important”). Practices rated ≥4 by ≥ 75% of participants in Round 2 met consensus criteria. The remaining items were discussed in a consensus meeting. Eighty-one experts from 29 countries (n = 45, 56% high-income, n = 36, 44% low-middle-income) participated in Round 1. Of these, 60 also participated in Round 2, including healthcare practitioners (n = 30, 50%), navigators (n = 16, 27%), researchers (n = 24, 40%), and advocates (n = 10, 17%). After Round 2, 27/35 (77%) practices reached consensus for inclusion. After the consensus meeting, two items were reworded, and 32 items were included in the final framework. We reached consensus among international experts on the contents of the GINO practice framework for patient navigation in cancer care. By describing the scope of patient navigation, the framework can support the development and implementation of patient navigation programs globally.

Abstract Background: The incidence of central nervous system (CNS) metastases varies with BC subtype, but there is limited data about clinical and molecular predictors of CNS vs non-CNS recurrence risk after neoadjuvant chemotherapy (NACT). Here we present patterns of distant recurrence among patients (pts) in the I-SPY2 trial. Methods: This analysis included 2023 pts with molecularly high-risk stage II and III BC who enrolled in the I-SPY2 trial from 2010-2022 with event-free survival (EFS) data (as of 6/22/25). We analyzed type of recurrence (local vs distant) and site(s) of initial distant recurrence (CNS-only, both CNS- and non-CNS, or non-CNS only). We used a competing risk (Fine-Gray) model to estimate cumulative incidence of site-specific relapse at five years and assessed associations with clinical/molecular subtype, clinical staging (cT, cN), and response to NACT by Residual Cancer Burden (RCB) class. Results: Among 2023 evaluable pts, at a median follow up of 4.7 yrs there were 361 EFS events, most of which were distant recurrences (n=259, 72%). Of the pts with distant recurrences, most had initial non-CNS events (180/259, 69%), 36 pts had initial simultaneous CNS- and non-CNS events (36/259, 14%), and 43 pts had initial CNS-only events (43/259, 17%). Table 1 summarizes the cumulative incidence of initial CNS- and/or non-CNS recurrences at 5 years by clinical/molecular features. Rates of CNS-only recurrence were low and similar across clinical and response predictive subtypes (p=0.47 and =0.19 respectively). Risk of distant recurrence increased in pts with larger tumors and node positive disease at both CNS- and non-CNS sites (see Table 1). Rates of initial non-CNS recurrence increased with the amount of residual disease at surgery, with lowest rates in pts with RCB-0 and highest rates in pts with RCB-III (p<0.01). In contrast, the rate of CNS-only recurrence was low but remained similar across the four RCB classes (p=0.67). Because of this, 39% (18/46) of pts with RCB-0/I disease had initial CNS-only recurrence, whereas only 12% (24/204) of pts with RCB-II/III disease had initial CNS-only recurrence. Most CNS recurrences, isolated or not (64/79, 81%), occurred within the first three years after surgery. Conclusions: In pts with molecularly high-risk stage II and III BC who underwent NACT, the incidence of initial CNS-only metastases was low, but the rate was consistent across the four RCB classes, supporting that the CNS is a sanctuary site. Initial CNS-only recurrence accounted for 39% of EFS events for pts with RCB-0/I vs 12% for pts with RCB-II/III. CNS recurrence risk was similar across high-risk BC subtypes, but higher in pts with larger tumors and node positive disease. These results support future research to identify biomarkers that predict CNS recurrence risk and to incorporate CNS-penetrant therapies into early-stage treatment for CNS high-risk pts. Citation Format: L. Huppert, C. Yau, D. Idossa, A. Kahn, F. M. Howard, E. Shagisultanova, A. Zimmer, E. Stringor-Reasor, J. Perlmutter, D. Yee, R. Nanda, N. Hylton, W. F. Symmans, R. Shatsky, C. Isaacs, L. Van't Veer, H. S. Rugo, P. R. Pohlmann, A. DeMichele, L. Pusztai, L. Esserman. Site(s) of Distant Recurrence after Neoadjuvant Therapy for Patients With High-Risk Early-Stage Breast Cancer (BC): Analysis of Data from the I-SPY2 Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD13-01.