Reimers, Melissa A.

5004 Background: Patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated continuously with testosterone suppression (TS) plus an androgen receptor pathway inhibitor (ARPI) can experience cumulative toxicity. We conducted this single-arm phase 2 trial (NCT05241860) to test the hypothesis that pts who achieve favorable response to TS + ARPI can have prolonged treatment-free interval with testosterone recovery after treatment interruption (TI). Here we report on the primary endpoint. Methods: Eligible pts had mHSPC by conventional imaging with prostate-specific antigen (PSA) ≥ 5 ng/ml and testosterone ≥ 150 ng/dl prior to starting TS+ARPI, with PSA < 0.2 ng/ml and testosterone < 50 ng/dl at the time of enrollment after having received TS for 540-750 days and ARPI for ≥ 360 days. Prior local therapy, radiation to metastases and docetaxel were permitted. After enrollment, pts discontinued TS and ARPI and were followed with PSA and testosterone levels every 3 months (mo), CT/MRI and bone scan at least every 6 mo, and FACT-P questionnaire for patient-reported outcomes (PROs) every 6 mo. Treatment was resumed for PSA ≥ 5 ng/ml, radiographic change (progressive disease [PD] per RECIST 1.1 on CT/MRI or unconfirmed PD per PCWG3 on bone scan), or prostate cancer-related symptoms. The primary endpoint was proportion of men remaining treatment-free 18 mo after TI with eugonadal testosterone ( > 150 ng/dl). Target enrollment was 75 pts to differentiate 18-mo treatment-free rates of 0.30 (H 0 ) and 0.45 (H a ). Results: Of 79 pts enrolled between 07/2022 and 03/2024, 78 were eligible and underwent TI. Among these 78, median PSA prior to starting TS+ARPI was 19 (range 5-6759), 27 (35%) had high volume disease, 31 (40%) never received local therapy, and 55 (71%) did not receive radiation to metastases. By 18 mo after TI, 67% (52/78) recovered testosterone and 58% (45/78) remained treatment-free; 41% (32/78) remained treatment-free with testosterone recovery (80% CI 33.5-48.9%, one-sided p 0.0249). At median follow-up of 21.2 mo, 35% (27/78) resumed initial TS+ARPI after meeting re-initiation criteria (of whom 1 required treatment switch for PD 9 mo later); 5% (4/78) resumed prior to meeting criteria; 9% (7/78) pursued alternative therapy instead of resuming TS+ARPI per protocol; 5% (4/78) withdrew; 1 died of myocardial infarction prior to resuming treatment. 4 pts died, 1 of prostate cancer. Conclusions: The primary objective was achieved with 41% of favorable responders to TS+ARPI remaining treatment-free with testosterone recovery at 18 mo after TI. Analyses of biomarkers and PROs are in progress, and pts will be followed for long-term outcomes. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org, Veracyte Inc. Clinical trial information: NCT05241860 .

4514 Background: Maintenance avelumab is a standard of care in patients (pts) with la/mUC who do not progress after first-line PBC. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM, active in multiple solid tumors. We hypothesized that an avelumab (Av)-CABO combination would improve outcomes in pts with mUC with an acceptable safety profile compared to avelumab maintenance alone. Methods: MAIN-CAV (NCT05092958) is a phase III randomized, multicenter, international trial for la/mUC pts who did not progress after 4-6 cycles of any PBC (gemcitabine-cisplatin, gemcitabine-carboplatin, MVAC, ddMVAC). Pts were randomized 1:1 to Av 800 mg IV every 2 weeks alone or with CABO 40 mg daily for ≤2 years. Stratification factors were response to first-line PBC (complete response [CR] vs partial response [PR] vs stable disease [SD]) and visceral metastases. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), safety and quality of life. The target accrual was 654 pts; the trial closed early after enrollment of 68 pts following adoption of enfortumab vedotin plus pembrolizumab as the new preferred first-line standard in the US. Results: From 3/2022 to 3/2024, 68 pts were randomized (Av n = 33; CABO-Av n = 35). Median OS was 24.8 months (mo) with Av and 23.0 mo with Avb-CABO (Hazard ratio 1.41; 95% CI 0.66–3.01; p = 0.186). Median PFS was 4.6 mo with Av vs 6.0 mo with Av-CABO (p = 0.343). Objective response rate among pts with PR or SD after first-line PBC was 20.8% with Av vs 11.5% with Av-CABO (p = 0.424). Grade ≥3 treatment-related adverse events occurred in 24.2% pts on the Av arm vs 39.4% of pts on the Av-CABO arm and CABO dose reductions occurred in 63% of pts. Conclusions: Addition of CABO to Av did not improve OS or PFS compared with Av alone in this underpowered, prematurely closed phase III trial; safety was consistent with known profiles. U10CA180821,U10CA180882; U24CA196171, U10CA180863. (CCTG);U10CA180888 (SWOG); https://acknowledgments.alliancefound.org. Clinical trial information: NCT05092958 .

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

4183 Background: High grade neuroendocrine neoplasms (HG-NENs) are treated with platinum doublets mirroring guidelines for small cell lung cancer (SCLC) but recurrences are common and salvage options are limited in efficacy. Cabozantinib (CABO), an inhibitor of VEGFR, MET, and TAM kinases (TYRO3, AXL, and MER) was approved by the FDA for treatment of well differentiated (WD) NENs of both pancreatic and extrapancreatic origins based on the CABINET study (Chan, NEJM 2025). However, its efficacy in the whole spectrum of HG-NEN patients including poorly differentiated disease (PDD) has not been prospectively explored. Methods: This was a single institution, Phase II study of CABO in patients with HG-NENs who had progressed on at least one prior treatment. Key inclusion/exclusion criteria were NENs of any origin except SCLC, high grade by Ki-67 of > 20% or histology consensus, ECOG of < = 1, appropriate hematological parameters and no history of bleeding or active cardiac disease. CABO was given orally starting at 60 mg po daily in 3-week cycles. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). A Simon optimal 2-stage design tested the null hypothesis that the true ORR is < = 1% at the type I error rate of 5%, resulting in projected enrollment of up to 32 total patients. Toxicities were graded according to CTCAE v5.0 and response was evaluated according to RECIST v1. Results: All patients have been accrued, with 4/32 patients still on treatment. Median age at diagnosis was 62 years and male to female ratio was 1.46. Origin of tumor was GI in 68.8% of the cases, the rest being thoracic (6.3%), prostate (6.3%) cervical (6.3%) head/neck (3.1%) and unknown (9.4%). Median Ki-67 was 55%, 11 patients had Ki-67 > 70%. Histology was WD-HG in 40% of patients and PDD in 60%. Two patients had mixed PDD/other components (MiNEN). Median PFS in evaluable patients was 4.01 months [95% CI 1.61 to 9.30] and mOS was 9.89 mo [95% CI 6.73 to 18.96]. Three patients so far (9.3%) have had partial response as best response (PDD-colon, WD-pancreas and PDD-cervical) while 19/32 (59.4%) patients have had stable disease as best response so far (disease control rate 68.8%). Five (15.6%) patients have received more than 10 treatment cycles. The three longest treated patients had WD-pancreas (23 and 17 cycles) and PDD-unknown (12 cycles). One patient had eventual resection of a metastatic site and is currently without evidence of disease. Three patients withdrew from the trial because of toxicities (shortness of breath, GI bleeding, thromboembolism). Twenty-six patients have expired. Conclusions: CABO monotherapy showed efficacy in some HG-NEN patients with not just WD but also the very aggressive PDD histology. No new side effects to the ones previously described for this agent were noted. Supported by Exelixis and a Siteman investment program grant. Clinical trial information: NCT04412629 .

Abstract Introduction: Urine cell-free DNA (cfDNA) is a promising ultra-noninvasive analyte for genitourinary cancers (GU) cancers. In this study, we investigated urine cfDNA fragmentomic features and evaluated their ability to predict the tumor tissue of origin. Methods: A total of 204 GU cancer patients and 34 healthy adults were enrolled in this prospective study. Preoperative urine was collected from 89 bladder cancer (BC) patients (64% muscle-invasive) undergoing cystectomy, 65 renal cell carcinoma (RCC) patients undergoing nephrectomy and 50 metastatic prostate cancer (mPC) patients. Urine cfDNA was isolated and sequenced at 5x genome-wide coverage on a NovaSeq S4 flow cell. To identify malignant tissue of origin, we analyzed somatic copy number alterations (CNAs), genome-wide fragment length ratios, and 4-mer end motifs. CNAs and tumor fraction (TFx) were quantified using ichorCNA in 1-Mb windows, while chromosome arm-level fragment count z-scores and fragment length ratios were calculated in 5-Mb bins across the genome. Relative frequencies of all 256 possible 4-mer end motifs were calculated for each sample. Individual logistic regression models were developed based on each fragmentomic feature using leave-one-out cross validation (LOOCV). Outputs from these models were combined into multi-feature XGBoost models. Cohort-specific end-motif enrichments were identified using Kruskal-Wallis tests with FDR correction. Motifs were then hierarchically clustered based on their cohort-wise median frequencies to define groups of motifs with shared fragmentation patterns. Results: Across urine cfDNA in the GU cohort, BC showed the highest mean TFx at 10.0%, followed by mPC at 3.6% and RCC at 2.7%. A machine learning model based on 4-mer end motifs achieved a mean ROC AUC of 0.933 with classification accuracies of 63% for healthy, 87% for BC, 72% for mPC, and 83% for RCC. This model outperformed models based on ichorCNA (AUC = 0.767), chromosome arm fragment-count z-scores (AUC = 0.827), and fragment length ratios (AUC = 0.674). Combining end motifs with other fragmentomic features did not improve prediction accuracy. Multi-feature models incorporating end motifs with ichorCNA, chromosome arm-level z-scores, or fragment-length ratios yielded mean AUCs between 0.908-0.924, lower than the end-motif only model. Kruskal-Wallis tests identified 179 of 256 end motifs (79%) as significantly different across healthy, BC, mPC, and RCC. Hierarchical clustering of cohort-level median motifs revealed distinct end motif patterns: Motifs beginning with CT were enriched in RCC; AAAA was strongly enriched in BC; and motifs beginning with CA, AC, and AG were enriched in mPC. Conclusion: Urine cfDNA 4-mer end motifs capture GU cancer-specific biological patterns that enable accurate tissue-of-origin prediction, underscoring their promise as a diagnostic tool. Citation Format: Jessica Linford, Pradeep S. Chauhan, Irfan Alahi, Yohan Kim, Arpit Panda, Nathan Colon, Ryan Mueller, Faridi Qaium, Eric H. Kim, Melissa A. Reimers, Zachary L. Smith, Woodson W. Smelser, Fabrice Lucien-Matteoni, Aadel A. Chaudhuri. Urine cfDNA 4-mer end-motif signatures outperform other fragmentomic features for tissue-of-origin classification in genitourinary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2590.

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

TPS5130 Background: Patients with prostate cancer and deleterious HRRa have poorer prognosis but derive benefit from poly (ADP-ribose) polymerase (PARP) inhibition. However, prevalence of HRRa and response to PARP inhibition are less well defined in racial/ethnic minorities. We designed the HARMONY trial to evaluate the efficacy of N/AA/P in HL and NHB patients with mHSPC and deleterious HRRa. Methods: This multicenter, open label, phase II study is open through the Hoosier Cancer Research Network in the United States. The trial enrolls patients who self-identify as HL or NHB and have mHSPC with HRRa including BRCA 1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L. Eligible patients will have hormone sensitive, treatment naïve or minimally treated prostate cancer (i.e., bicalutamide ≤ 45 days, androgen deprivation therapy [ADT] ± AA plus P ≤ 45 days allowed). Prostate cancer variants, other therapy in mHSPC setting, or symptomatic brain metastases are exclusionary. Enrolled patients will receive 24 weeks (w) of ADT plus N/AA dual action tablet (DAT) plus P, followed by an adaptive approach based on prostate specific antigen (PSA) response. Subjects in Arm A (PSA > 4.0 ng/mL at 24 w) can continue ADT/N/AA/P for max 2 years or stop N and escalate therapy to ADT/AA/P plus 6 cycles of docetaxel followed by standard of care (SOC) therapy. Subjects in Arm B (PSA ≤ 4.0 ng/mL at 24 w) will continue ADT/N/AA/P for a total of 12 months. At 12 months in Arm B, subjects with PSA ≥ 0.2 ng/mL will continue ADT/N/AA/P for max 2 years, and subjects achieving PSA < 0.2 ng/mL have the option to continue ADT/N/AA/P for max 2 years or discontinue all therapy with the option to start SOC treatment at disease progression. PSA decline to < 0.2 ng/mL at 24w (primary endpoint) will be evaluated for each racial/ethnicity group against a historic rate of 50%. Thirty patients per racial/ethnic cohort will give 80% power at 0.1 significance to determine noninferiority with a no-inferiority margin of 0.185. Estimating 5% drop out, 64 patients will be enrolled (n=32 HL and n=32 NHB). Key secondary/exploratory endpoints include PSA reduction ≥ 90%, overall response rate, PSA/radiographic progression free survival, overall survival, time to subsequent anti-cancer therapy, quality of life and safety. Key genomic correlatives will be evaluated. ClinicalTrials.gov: NCT06392841. Study support of drug and funding: Janssen Scientific Affairs LLC. Clinical trial information: NCT06392841 .

4545 Background: The treatment landscape of front-line nccRCC has evolved with recent trials demonstrating the efficacy of combination systemic therapy. However, the efficacy of treatment after combination therapy is unknown. This study evaluates the efficacy of VEGF-based regimens in nccRCC patients (pts) previously treated with combination regimens. Methods: ORACLE is a real-world, multi-center, retrospective database that includes nccRCC patients that received combination systemic therapies (IO+IO, IO+VEGF and VEGF+ mTOR) in any line. Subsequent treatments were categorized as VEGF only regimens (cabozantinib vs other VEGF), IO+ VEGF and VEGF+ mTOR. The primary endpoint was objective response rate (ORR) assessed by investigator review using RECIST 1.1. Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving complete or partial responses or stable disease, time to treatment progression (TTP), calculated from the date of VEGF-based initiation to progression or last follow-up using the Kaplan-Meier method. Differences between groups were estimated with the log-rank test, and categorical outcomes were compared with the chi-square test. Results: 105 pts who received VEGF – based regimens after combination therapy were included in the analysis. Baseline characteristics: median age: 59years, 71 % male, 58% white, 25% black, 87% ECOG 0-2. IMDC-risk categories included:21% favorable, 59% intermediate and 20% poor risk. Histology included papillary (40%), unclassified (32%), chromophobe (16%) and other rare subtypes (12%). Prior combination therapies included IO+IO: 62%, IO+ VEGF: 34% and VEGF+ mTORi:4%. 70% pts received combination therapy in the first line setting while the remainder received combination therapy in a second or later line. Outcomes with subsequent treatments are described in Table1. IMDC risk score correlated with TTP. Conclusions: Modest antitumor activity was observed with VEGF- based approaches in combination therapy refractory nccRCC. Optimal management of nccRCC remains an unmet need. Outcomes of nccRCC patients by treatment and histologic type. Outcomes per Treatment n ORR (%) DCR (%) mTTP (mo.) Cabozantinib 56 18 47 3.6 VEGF/mTOR 19 16 42 9.3 IO+VEGF 17 29 47 5.6 Other VEGF 13 15 46 5.5 Outcomes per Histology Papillary 42 19 43 6.5 Unclassified 33 21 42 6.1 Chromophobe 17 29 59 8.9 Other * 13 0 46 NR

Abstract Introduction: We previously developed a urine liquid biopsy assay to measure urine tumor DNA (utDNA) levels in bladder cancer (BC) patients. Here, we extended this approach significantly by layering in cell-free DNA fragmentomic and cell-free RNA analysis, and extending the method to the full spectrum of genitourinary (GU) cancers, to enable both GU cancer detection and tumor tissue of origin prediction. Methods: A total of 155 GU cancer patients and 34 healthy adults were enrolled in this prospective study. Preoperative urine was collected from 94 bladder cancer (BC) patients, including 65 with muscle-invasive disease, all undergoing cystectomy. Additionally, urine samples were collected from 18 renal cell carcinoma (RCC) patients undergoing nephrectomy and 42 metastatic prostate cancer (mPC) patients. Urine cfDNA and cfRNA were isolated and sequenced, with cfRNA sequenced to 100 million reads per sample on an Illumina NovaSeq X and cfDNA sequenced at 5x genome-wide coverage on a Novoseq S4 flow cell. To identify malignant tissue of origin, we analyzed somatic copy number alterations (CNAs), genome-wide fragment length ratios, and 4-mer end motifs. Tumor fraction (TFx) was estimated using ichorCNA, while DELFI was employed for fragment length ratios in 5 megabase bins across the genome and chromosome arm-level z-scores. Individual logistic regression models were developed based on each fragmentomic feature, and validated using a training and held-out testing approach. Outputs from these models were combined into a single comprehensive model, also trained and held-out tested using the same approach. Urine cfRNA transcript isoform abundance was quantified using Salmon and normalized to Transcripts Per Million (TPM) to account for sequencing depth variations. Results: Bladder cancer (BC) showed the highest mean tumor fraction (TFx, 10.5%), followed by RCC (3.8%) and mPC (3.4%). Among 94 BC patients, 42% achieved a pCR, while 58% had residual disease and did not. Patients without pCR had significantly higher urine TFx compared to those with pCR (14.7% vs. 4.7%, p=0.0008). A machine learning model based on genome-wide fragment length ratios achieved an ROC AUC of 0.74, while models using genome-wide CNAs and end motifs achieved AUCs of 0.81 and 0.88, respectively. Combining all features into a single model yielded an AUC of 0.92, with classification accuracies of 89% for bladder cancer, 80% for RCC, and 60% for prostate cancer. Additionally, urine cfRNA analysis using the top 1, 000 coding transcripts achieved an AUC of 0.95, with classification accuracies of 100% for mPC, 87% for BC, and 78% for RCC. Conclusion: Fragmentomic features from urine cfDNA and transcriptomic features from urine cfRNA demonstrate strong potential for predicting tumor tissue-of-origin in GU cancers, underscoring the promise of non-invasive diagnosis across the spectrum of GU malignancies through urine liquid biopsy. Citation Format: Pradeep Singh Chauhan, Irfan Alahi, Jessica Linford, Arpit Panda, Nathan Colon, Ryan Mueller, Faridi Qaium, Peter K. Harris, John Sheng, Eric H. Kim, Melissa A. Reimers, Zachary L. Smith, Woodson W. Smelser, Aadel A. Chaudhuri. Predicting genitourinary cancer tissue-of-origin using urine cell-free DNA fragmentomics and cell-free RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3258.

TPS5118 Background: Novel androgen receptor pathway inhibitors (ARPIs) improve overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in conjunction with testosterone suppression (TS) relative to TS alone. However, the duration of treatment required to derive clinical benefit is unclear, as is whether continuous treatment is requisite for optimal cancer outcomes. Favorable PSA declines have been associated with prolonged OS in clinical trials testing TS + ARPIs. We thus designed this single-arm Phase 2 trial to test the hypothesis that pts who achieve exceptional response to upfront TS + ARPI can suspend treatment, allowing for T recovery and improvement in quality of life while maintaining favorable clinical outcomes. Methods: Eligible pts had mHSPC by conventional imaging with PSA ≥ 5 ng/ml and T ≥ 150 ng/dl (or not known to have been hypogonadal) prior to starting treatment, have been receiving TS for 540-750 days and ARPI for ≥ 360 days, and have achieved PSA < 0.2 ng/ml (stable or falling for 3 consecutive measurements) with castrate T <50 ng/dl at the time of enrollment. Intermittent ADT for biochemical recurrence prior to mHSPC diagnosis, prior local therapy, prior radiation to metastatic sites, and up to 6 cycles of docetaxel in mHSPC are permitted. Pts who underwent surgical castration, received ARPI prior to mHSPC diagnosis, or are receiving experimental treatment for mHSPC or participating in a clinical trial that does not allow for TS or ARPI interruption are excluded. After enrollment, pts discontinue both TS and ARPI and are followed with PSA and T levels every 3 months, conventional CT/MRI and bone scan at least every 6 months, and FACT-P questionnaire for patient-reported outcomes every 6 months. Treatment re-initiation triggers are PSA increase to ≥ 5 ng/ml, radiographic change (progressive disease per modified RECIST 1.1 on CT/MRI or unconfirmed progressive disease per PCWG3 on bone scan), or symptoms attributable to prostate cancer. Subsequent management is per physician discretion. The primary endpoint is remaining treatment-free with eugonadal T (> 150 mg/dl) 18 months after the start of treatment interruption, with 75 pts to be enrolled to differentiate 18-month treatment free rates of 0.30 (null hypothesis) and 0.45 (alternative hypothesis). Secondary endpoints include time to eugonadal T, duration off treatment, and changes in patient-reported outcomes. Exploratory endpoints include radiographic progression-free survival, time to next treatment, OS, and correlation of tissue- and blood-based biomarkers with clinical endpoints. The study was activated in July 2022 and accrual is ongoing throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org , Veracyte Inc. Clinical trial information: NCT05241860 .