Koshkin, Vadim S.

Abstract Purpose: Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of [177Lu]Lu-FAP-2286 (177Lu-FAP-2286) in heavily pretreated patients with advanced solid tumors and identified the recommended phase II dosage (RP2D). Patients and Methods: LuMIERE is a prospective, open-label, nonrandomized, phase I/II, multicenter study. Phase I followed a Bayesian optimal interval design evaluating four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq). Patients were selected by positive [68Ga]Ga-FAP-2286 (68Ga-FAP-2286, also known as [68Ga]Ga-HKG301) PET/CT imaging on all target lesions [maximum standardized uptake value (SUVmax) ≥1.5× SUVmean of mediastinal blood pool]. 177Lu-FAP-2286 was administered intravenously every 6 weeks for ≤6 cycles. The primary endpoint was dosage-limiting toxicities (DLT) and treatment-emergent adverse events (TEAE). Results: Of 35 patients imaged with 68Ga-FAP-2286, 27 received 177Lu-FAP-2286 (3.70 GBq, n = 3; 5.55 GBq, n = 6; 7.40 GBq, n = 7; 9.25 GBq, n = 11). Two DLTs were observed: one patient who received 5.55 GBq of 177Lu-FAP-2286 experienced grade 4 lymphopenia, and one patient who received 9.25 GBq experienced grade 3 hemoptysis; these were the only treatment-related grade ≥3 TEAEs. All-cause grade ≥3 TEAEs were reported for 11 patients (40.7%). The RP2D for 177Lu-FAP-2286 monotherapy was determined to be 9.25 GBq. Preliminary Response Evaluation Criteria in Solid Tumors efficacy findings demonstrated a partial response in 1 patient and stable disease in 10 patients (maintained for at least two assessments in 6 patients). Conclusions: 177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II.

4584 Background: EVP is the preferred frontline regimen in pts with aUC. Despite initial response to treatment, many pts treated with EVP ultimately have progression. We hypothesized that recurrence patterns would differ between pts with and without baseline liver metastases. Methods: UNITE is a multi-institutional retrospective database capturing clinical and treatment characteristics of pts with aUC receiving systemic therapies. We queried this database to identify pts who achieved an observed response (OR) to EVP. Pts were grouped by initial metastatic sites using a non-mutually exclusive approach. Descriptive statistics were used to summarize observed response rates (ORR) and recurrence patterns at time of progression. Progression-free survival (PFS) from start of EVP was estimated using the Kaplan-Meier method. The effect of liver metastases on PFS was assessed via multivariable Cox regression. Median-follow up time was estimated using the reverse Kaplan-Meier method. Statistical analyses were conducted in RStudio. Results: We identified 464 pts treated with EVP (median age 72; 74% male, 80% White). Best ORR in pts with baseline liver metastases (n=77) were complete response 9%, partial response 35%, stable disease 18%, and progressive disease 21%, compared with 18%, 37%, 27%, and 18%, respectively, in pts without baseline liver metastases (n=325). The estimated median follow-up time was 52 weeks (95% CI 48-62). Among pts with initial OR to EVP, those with baseline liver metastases showed a non-significant trend toward shorter PFS (HR 1.35; 95% CI 0.67–2.75; p=0.40) versus those without baseline liver metastases. Among pts with initial OR to EVP and subsequent progression the distribution of sites of recurrences at progression for those with (n = 10) and without (n = 40) baseline liver metastases were: liver (50% vs. 10%), lymph nodes (60% vs. 55%), lungs (50% vs. 38%), bone (20% vs 20%), and primary tumor (20% vs 25%). EVP responders with baseline liver metastases had a numerically higher rate of site-specific metastasis resolution at progression versus those with lymph node or lung metastases (Table). Conclusions: Our analysis suggests that liver metastases may be associated with shorter PFS among EVP responders, though these pts frequently do not retain liver metastases at time of progression. Study limitations include retrospective analysis, investigator-assessed response, small sample size, selection and confounding biases. Patterns of recurrence following EVP merits further evaluation. Metastatic Site Pts with Site-Specific Baseline Metastases (n) Pts with Resolution of Site-Specific Metastases at Progression, n (%) Pts without Baseline Metastases at Site (n) Pts who Remained Free of Site-Specific Metastases at Progression, n (%) Liver 10 5 (50%) 40 36 (90%) Lymph Nodes 37 12 (32%) 13 10 (77%) Lungs 26 8 (31%) 24 22 (92%)

4565 Background: EVP is the preferred 1 st -line regimen for patients (pts) with aUC. EV-related toxicities are often managed with dose adjustments, such as reductions and holds. Analysis of EV monotherapy trials showed consistent survival outcomes despite dose adjustments. We hypothesized that on-treatment EV dose adjustments would not impact survival in these pts. Methods: Pts with aUC treated with EVP in the multisite UNITE study were analyzed. Early dose reductions (DR) and holds were defined as occurring < 9 weeks from EVP start, with the remainder classified as late. Pts with DR at treatment start were excluded. Survival endpoints were progression-free survival (PFS) and overall survival (OS) from EVP start, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (≥ 75 vs < 75), ECOG performance status (0-1 vs 2-3), Hgb level (< 10 vs ≥ 10) and liver metastases (present vs not). A time-dependent covariate was used to reduce immortal time bias. Complementary MVA landmark analyses were performed, aligned to the total number of treatment cycles received, with six analyses from cycles 2 to 7. Results: 360 pts from 17 sites were included (median age 70; 78% Caucasian; 76% male; 27% upper tract primary; 35% histology subtype component; 17% with liver metastasis; 78% frontline); median follow-up was 11.7 months (95% CI [10.79, 13.08]). Median number of cycles was 6 in pts with DR and 3 with no DR. Early DRs (100 pts [28%]) and holds (18 pts [5%]) were most commonly due to rash (28% of all early DRs and holds). Late DR (75 pts [21%]) and holds (50 pts [14%]) were most commonly due to neuropathy (52% of all late DRs and holds). Pts with early or late DR had longer PFS and OS vs those who did not (Table); however, there was no significant PFS or OS difference with dose hold vs no hold (PFS HR 0.65, 95%CI (0.40, 1.05), p = 0.08; OS HR 0.70, 95%CI (0.39, 1.27), p=0.24). In landmark analyses, about 50% of pts had DR; no significant difference in PFS or OS was observed at most landmarks, except for longer OS in the DR cohort at cycle 4 (HR 0.53, 95% CI (0.29, 0.98), p = 0.042) and cycle 5 (HR 0.43, 95% CI (0.19, 0.99), p = 0.048). Conclusions: In this real-world retrospective analysis, EVP efficacy was maintained despite DR and dose holds. Survival difference noted in the time-dependent analyses were not consistently reproduced in landmark analyses, suggesting exposure-related selection bias rather than causal effect. Prospective studies are warranted to validate these hypothesis-generating findings. Association of EV DR with PFS/OS (time-dependent analyses). Early DR Late DR DR vs no DR outcomes UVAHR (95% CI), p MVAHR (95% CI), p UVAHR (95% CI), p MVAHR (95% CI), p PFS 0.50 (0.35, 0.72), <.001 0.56 (0.38, 0.84), 0.005 0.32 (0.21, 0.49), <.001 0.36 (0.23, 0.57), <.001 OS 0.51 (0.32, 0.79), 0.003 0.57 (0.35, 0.92), 0.022 0.26 (0.15, 0.45), <.001 0.31 (0.17, 0.55), <.001

4562 Background: Approximately 50-80% of patients (pts) with la/mUC have tumors with HER2 protein expression. As HER2-directed therapies enter development, a robust understanding of HER2 prevalence and real-world outcomes with standard-of-care (SOC) therapies across HER2 expression subgroups is needed. SGNDV-003 (NCT05902494) is a global retrospective chart review study in which HER2 status was assessed via central lab testing and outcomes were analyzed by HER2 status in pts with la/mUC. Methods: SGNDV-003, conducted 6/2023-7/2025, included pts with la/mUC who received ≥1 prior treatment (tx) (incl. 1 line of platinum-based chemotherapy [chemo]). HER2 status was centrally tested using a UC-specific investigational immunohistochemistry [IHC] and in situ hybridization (ISH) assays. HER2 status was defined as: HER2-positive (IHC3+ or IHC2+/ISH+), HER2-low (IHC2+/ISH- or IHC1+), HER2-expressing (IHC3+, 2+, 1+), and HER2-zero (IHC0). Index line of therapy (LOT) was defined as the first LOT received after platinum-based chemo. Outcomes included real-world objective response rate (rwORR) (per RECIST 1.1 or physician-assessed response) to index LOT, real-world progression-free survival (rwPFS), and overall survival (OS) from start of index LOT. Data was analyzed via descriptive statistics. Results: A total of 353 pts with la/mUC and available HER2 status were analyzed (male, 76%; median age, 70 years). 70% of pts were HER2 expressing (19% HER2-positive, 51% HER2-low); 30% were HER2-zero. Disease characteristics were well balanced by HER2 status. Index LOT tx and real-world outcomes are shown in the Table. Immuno-oncology therapies (IO) and enfortumab vedotin (EV) were the most common index LOTs. For IO, rwORRs were 21% for HER2-expressing and 17% for HER2-zero. For EV mono, rwORRs were 36% (HER2-expressing) and 38% (HER2-zero), respectively. Conclusions: This global study provides a robust estimate of HER2 distribution in la/mUC based on standardized central lab testing, showing high prevalence of HER2 expression. Real-world outcomes with current SOC therapies were broadly consistent across HER2 subgroups, establishing an important benchmark for the clinical development of HER2-directed therapies in this setting. HER2-positive (n=67) HER2-low (n=181) HER2-expressing (n=248) HER2-zero (n=105) Total (n=353) Real-world Outcomes rwORR, n (%)[95% CI] 17 (25.4)[15.5, 37.5] 50 (27.6)[21.3, 34.7] 67 (27.0)[21.6, 33.0] 22 (21.0)[13.6, 30.0] 89 (25.2)[20.8, 30.1] Median rwPFS (95% CI), mo 2.8(2.0, 4.1) 3.7(2.7, 5.1) 3.0(2.7, 4.5) 2.6(2.1, 3.4) 2.9 (2.6, 3.5) Median OS(95% CI), mo 12.2(9.3, 16.5) 11.5(9.5, 13.5) 11.9(10.3, 13.4) 7.7(5.9, 9.9) 10.8(9.1, 12.3) Index LOT, n% IO EV monoChemoOther tx 37 (55)17 (25)10 (15)3 (5) 94 (52)51 (28)24 (13)14 (8) 131 (53)68 (27)34 (14)17 (7) 65 (62)21 (20)12 (11)7 (7) 196 (56)89 (25)46 (13)24 (7)

794 Background: HER2 protein, encoded by ERBB2 gene, is the target of emerging therapies for patients (pts) with advanced urothelial carcinoma (aUC). High HER2 IHC expression (IHC 3+) is present in ~15% of pts with aUC, while >50% of pts have HER2 IHC 1+/2+/3+ expression. EVP is the preferred 1 st line regimen for pts with aUC, but the impact of HER2 status on EVP outcomes is unclear. Methods: We identified pts from the UNITE study with tumor samples tested for HER2 by IHC and another cohort with next-generation sequencing (NGS) data available. Outcomes were compared by HER2 IHC status (HER2 IHC 0/1+ vs 2+/3+) and separately based on ERBB2 status (alteration vs wild-type). X 2 test was used to compare observed response rate (ORR) and logistic regression was used to compare disease control rate (DCR). Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) from EVP start were evaluated using log-rank test and Cox proportional hazards models. Multivariate analysis (MVA) included age, sex, race, ECOG PS, neutrophil:lymphocyte ratio, albumin, hemoglobin, primary tumor site, tumor histology, prior lines of treatment, and metastatic sites as covariates. Results: Among 521 pts treated with EVP from 16 sites, 112 had HER2 IHC data and 313 had NGS. Median age was 71, 74% were men, 84% Caucasian, 82% had ECOG PS 0-1, 65% pure urothelial histology, and 73% received frontline EVP. HER2 IHC distribution (n=112) was 27%/21%/37%/15% for 0/1+/2+/3+, respectively. ERBB2 alterations were present in 14% (44/313). Baseline characteristics were similar in HER2 0/1+ and 2+/3+ pts, except more primary bladder tumors in 2+/3+ pts (83% vs 63%, p=0.01). For the overall cohort (n=521), with a median follow up of 7.3 mos from EVP start, ORR was 54%, DCR 81%, median DOR (mDOR) 8.5 mos, median PFS (mPFS) 8.5 mos, and median OS (mOS) 19.8 mos. Pt outcomes by HER2 IHC status are shown (Table). In univariate analysis (UVA), pts with HER2 IHC 0/1+ had longer mOS compared to HER2 IHC 2+/3+, but this was not significant in MVA (HR: 0.5; CI: 0.2–1.3, p=0.17). No significant differences were observed in other outcomes. Evaluating clinical outcomes by ERRB2 status, no significant differences were seen for ERBB2 -altered vs wild-type pts. Conclusions: In this retrospective study, no significant differences were seen in EVP treatment outcomes based on HER2 IHC status or ERBB2 status. These findings are hypothesis-generating and require validation in larger and prospective cohorts. HER2 0/1+ (n=54)* HER2 2+/3+ (n=58) OR (95%CI, p) HR UVA (95%CI, p) HR MVA (95%CI, p) ORR 49% (23/47) 55% (27/49) 1.3 (0.6-2.9, p=0.5) - - DCR 79% (37/47) 88% (43/49) 1.9 (0.7-6.2, p=0.2) - - mDOR 11.7 mos 10.4 mos - 1.3 (0.7-2.4, p=0.4) 1.2 (0.4-3.3, p=0.8) mPFS 5.9 mos 7.1 mos - 0.8 (0.5-1.4, p=0.5) 1.1 (0.5-2.5, p=0.9) mOS 42.4 mos 18.7 mos - 2.3 (1.1-4.5, p=0.02) 2.0 (0.8-5.4, p=0.2) *HER2 0/1+ used as reference.

696 Background: EVP is the preferred 1st-line therapy for patients (pts) with aUC. Upfront EV dose reductions may be utilized to enhance tolerance and minimize treatment-related toxicities when intolerance is anticipated. Prior studies of EV monotherapy suggest that starting dose 1.25 mg/kg resulted in exposure that maximized chance of response. We hypothesize that upfront EV dose reductions would not compromise EVP efficacy. Methods: Pts with aUC treated with EVP in the multi-site UNITE database were analyzed. Upfront dose reduction was defined as starting dose < 1.25 mg/kg. Correlation between clinical features and EV dose reduction were assessed using Fisher’s Exact test. Endpoints include progression-free survival (PFS) and overall survival (OS) from EVP initiation, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (< 75 vs ≥ 75), ECOG performance status (PS) (0-1 vs 2-3), hemoglobin level (< 10 vs ≥ 10), and liver metastases (present vs absent), chosen in accordance with Bellmunt criteria. Correlation with investigator-assessed observed response rate (ORR) was determined using logistic regressions. All tests were 2-sided with p < 0.05 considered significant. Results: A total of 456 pts across 17 sites were included (median age 72; 77% Caucasian; 75% male; 26% upper tract primary; 66% pure UC; 77% ECOG PS 0-1; 17% with liver metastasis; 89% 1 st line EVP). Upfront dose reduction occurred in 96 pts (21%); 76 pts (79%) started at 1.0 mg/kg and 20 pts (21%) at 0.75 mg/kg. Upfront dose reduction was significantly associated with age ≥ 75 (p = 0.002), ECOG PS 2/3 (p = 0.04), and hemoglobin < 10 (p = 0.01) but not with liver metastasis (p = 0.9). Lower starting EV dose correlated with shorter median PFS (5 vs 6 months) and OS (9 vs 10 months), and lower ORR (28% vs. 60%) when compared to full dose (Table). In MVA adjusting for prognostic factors for PFS and OS, these associations were no longer statistically significant. Conclusions: In this real-world analysis, upfront EV dose reductions were most frequently used in pts with factors associated with frailty and poor prognosis, e.g. older age and ECOG PS 2/3, and were associated with lower ORR. When adjusted for these factors, upfront EV dose reductions were not associated with shorter PFS/OS though a trend towards inferior outcomes persisted. These differences in outcomes may reflect baseline risk factors rather than dose intensity; however, prospective investigation is required to validate our hypothesis-generating results. Association of upfront EV dose reduction with outcomes. Outcome (Upfront dose reduction vs no upfront dose reduction) Univariable analysis Multivariable analysis PFS: HR (95% CI), p 1.50 (1.11 – 2.02), 0.008 1.33 (0.95-1.86), 0.09 OS: HR (95% CI), p 1.56 (1.11-2.20), 0.01 1.41 (0.96-2.06), 0.08 ORR: OR (95% CI), p 0.35 (0.21-0.60), 0.0001 0.38 (0.21-0.67), 0.0009

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 combination of enfortumab vedotin and pembrolizumab (EVP) has recently revolutionized care for patients with previously untreated locally advanced and metastatic urothelial carcinoma. However, predictive biomarkers of response, the optimal duration of EVP for patients who respond well to therapy, and the role of circulating tumor DNA to monitor treatment response have not yet been fully elucidated. In this molecular tumor board, we summarize 6 patients from 4 different academic institutions with unresectable or oligometastatic urothelial carcinoma who achieved long-term remission on surveillance after a short duration of EVP treatment that resulted in complete response on follow-up imaging followed by consolidative radical cystectomy. We discuss potential predictive biomarkers for patients with exceptional response to EVP. These findings highlight the need to determine an optimal duration of EVP to maximize efficacy while minimizing adverse events. We aim to further define and explore the value of local therapy with consolidative cystectomy in the setting of unresectable, locally advanced, oligometastatic disease, or those with metastatic disease who achieve complete response of disease outside of the bladder. Identifying this subset of patients who may be candidates for this type of multidisciplinary management may result in durable treatment-free remission.

5060 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) in men with BRCA-mutated chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) vs a control arm of physician’s choice of therapy (docetaxel or androgen-receptor pathway inhibitor [ARPI] therapy: abiraterone acetate or enzalutamide) in the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study. Herein, we conducted an analysis to determine the impact of germline vs somatic mutation status on the efficacy of rucaparib. Methods: Patients were randomized 2:1 to receive rucaparib 600 mg BID or physician’s choice of docetaxel or ARPI following progression while on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Color Health did genetic testing. Treatment-emergent adverse events (TEAEs) were reported for the BRCA subgroup. Results: In the rucaparib arm, 201/270 patients had BRCA mutations, and in the physician’s choice arm, 101/135 patients had BRCA mutations. Of patients with BRCA mutations: in the rucaparib arm, 80/201 (40%) were germline and 116/201 (58%) were somatic with 5/201 (2%) BRCA mutation status unknown, while in the physician’s choice arm, 39/101 (39%) were germline and 48/101 (48%) were somatic with 14/101 (14%) BRCA mutation status unknown. rPFS was significantly improved with rucaparib treatment vs physician’s choice in both the germline and somatic mutation groups (germline: HR, 0.52 [95% CI, 0.32–0.84]; somatic: HR, 0.38 [95% CI, 0.25–0.59]). Incidence rates of TEAEs were similar overall between patients with germline and somatic BRCA mutations in both arms. Conclusions: Rucaparib improves progression-free survival for patients with mCRPC with either germline or somatic BRCA mutations with a manageable safety profile. These data support the use of rucaparib as a beneficial treatment option for patients with BRCA-mutated mCRPC with germline or somatic mutations. Clinical trial information: NCT02975934 .