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5005 Background: Androgen receptor pathway inhibitors (ARPIs) may have distinct central nervous system (CNS) penetration and differential effects on cognition or quality of life (QOL). AFT-47, “ARACOG” is a prospective, randomized open-label phase 2 trial comparing objective and patient-reported cognitive and QOL outcomes between patients with metastatic hormone sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) treated with darolutamide (DAR) or enzalutamide (ENZ). Methods: Between 8/17/2021 and 3/11/2025, 111 pts were enrolled and randomized 1:1 to treatment with ENZ or DAR. CANTAB, a validated computer-based platform evaluating 5 cognitive domains (PALFAM-memory recall, SWM- spatial working memory, SSP-short-term visual memory, working memory, RVP-rapid visual processing, and OTSMCC- executive function), was performed at baseline, 12, 24, and 48 weeks. Crossover (Xover) was allowed at 12 or 24 weeks for significant pre-specified decline in cognitive testing or patient reported outcome measures (PROMs), or for CNS-associated adverse events, including falls. The primary endpoint was the percent change in the maximally changed cognitive domain (MCCD) from baseline to 24 weeks and was compared between groups with the Wilcoxon rank sum statistic. Patients crossing over prior to 24 weeks were evaluated at the time of Xover and analyzed with their randomized arm. Secondary endpoints included comparison of Xover rates. Results: Among 111 pts, 55 received DAR and 56 received ENZ; median age was 71, 83% White. 95 pts (48 DAR, 47 ENZ) were evaluable for the primary endpoint. Baseline CANTAB was similar between groups. Median cognitive change in MCCD between baseline and 24 weeks was -15.8% and -36.1% for the DAR and ENZ pts, respectively (p = 0.009) (Table). Individual cognitive domains suggest possible learning effect (increased scores) for DAR and are stable or show mild decline for ENZ treated patients at 24 weeks. 32 DAR (58%) and 33 ENZ (59%) participants were eligible for Xover by 24 weeks, and 23 pts crossed over by 24 weeks. All Xover was pts randomized to ENZ (crossed to DAR), with the most common causes being decline in objective (N = 14) or subjective (N = 11) cognitive testing. Conclusions: In this US randomized trial comparing DAR to ENZ, the primary endpoint of differential cognitive effects was met. ENZ showed significantly greater cognitive score decline than DAR at 24 weeks in the MCCD after treatment initiation. Learning effect was seen with DAR but not ENZ. Longer term follow-up of cognitive change and PROM analyses are ongoing. Clinical trial information: NCT04335682 . Percent change in maximally changed cognitive domain by treatment. DAR (N=48) ENZ (N=47) Wilcoxon Rank Sum Test Result CANTAB domain PALFAM SWM Degree of change -15.8 (-38.8, -2.6) -36.1 (-59.3, -16.7) P=0.009

4500 Background: BM occur in ~30% of RCC pts and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in advanced prostate cancer. A pilot study of radium-223 with VEGF tyrosine kinase inhibitors (TKI) in RCC with BM showed safety and early efficacy (McKay, CCR, 2018). Cabozantinib is a TKI that showed efficacy in BM. RADICAL (NCT04071223) was designed to investigate cabozantinib ± radium-223 in RCC with BM. Methods: This open label multicenter study enrolled RCC pts with ≥1 symptomatic BM not previously irradiated and Karnofsky performance status ≥60%. Prior therapies were allowed; non-clear cell population was limited to 20%. Randomization was 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, baseline opioid use, and IMDC risk. In Arm A, cabozantinib was 40 mg daily cycle 1, 60 mg thereafter if tolerated; radium-223 was 1.49 microcurie/kg IV every 28 days for 6 doses. In Arm B, cabozantinib was 60 mg daily. The primary endpoint was SSE-free survival (SSE-FS). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study was designed with 85% power to detect improvement in 6-month SSE-FS from 65% to 78% (one-sided α=0.05), with planned interim futility analysis at 50% of expected events. Results: From 12/2019 to 9/2025, 90 pts were enrolled and evaluable for the interim analysis. Median age was 63 years; 74.4% male, 90.0% White, 83.3% clear cell histology. 11.1% were treatment naïve, 80.0% received OTT, 51.1% had baseline opioid use. IMDC risk was 16.7% favorable, 68.9% intermediate, 14.4% poor. Median cabozantinib dose was 31.4 mg (Arm A) and 40.0 mg (Arm B); median radium-223 cycles was 6. Median follow-up was 13.1 (range 0.1-49.4) months with 50 events, 17 SSEs (Arm A: 10; Arm B: 7) and 33 deaths (Arm A: 13; Arm B: 20). Outcomes are in Table. 71 pts were evaluable for response. ORR was 22.2% (Arm A), 22.9% (Arm B). Any grade treatment-related adverse events were 97.7% (Arm A), 93.2% (Arm B); grade ≥3 were 65.9% (Arm A), 56.8% (Arm B). The trial closed after interim analysis as SSE-FS did not meet the prespecified futility boundary (HR≤1). Conclusions: Radium-223 did not improve the primary endpoint of SSE-FS when added to cabozantinib but a numerical prolongation in OS was observed. Combination treatment was safe. Alternative radiotherapeutics warrant investigation in RCC. Clinical trial information: NCT04071223 . Interim efficacy analysis. Arm Median(95% CI) HR (95% CI) Stratified SSE-FS A 17.9 (15.0-NE) 1.24 (0.62-2.48) B 17.6 (10.9-NE) Unstratified SSE-FS A 17.9 (15.0-NE) 0.90 (0.51-1.59) B 17.6 (10.9-NE) OS A 32.2 (17.9-NE) 0.77 (0.42-1.41) B 21.3 (12.3-NE) Stratified PFS A 11.0 (5.8-17.4) 1.39 (0.72-2.66) B 11.2 (9.0-18.5)

4219 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a notoriously difficult-to-treat malignancy, with limited therapy options for patients with advanced disease. While KRAS mutations are the dominant oncogenic driver in PDAC, next-generation sequencing has enabled the identification of rare, targetable alterations such as the BRAF V600E mutation, which occurs in approximately 2-3% of cases. BRAF mutant cell lines are responsive to MEK and RAF inhibitors. This study evaluates the efficacy of the combination of encorafenib and binimetinib as ≥ 2nd line therapy in this specific molecular subgroup of pancreatic cancer patients. Methods: This study used a planned two-stage design. Seven patients were pre-registered; one did not meet eligibility criteria and was excluded. Six patients were enrolled in Stage 1, which required an objective response (OR) in 40% of patients to proceed to Stage 2. Stage 2 was planned to enroll an additional 16 patients, contingent on meeting this efficacy threshold. Enrolled patients received treatment in 28-day cycles until disease progression or for a maximum of 36 cycles. Patients self-administered encorafenib (450 mg orally once daily) and binimetinib (45 mg orally twice daily) starting on Day 1 of each cycle. Objective responses were assessed using RECIST version 1.1 over 24 weeks. Results: The median number of cycles was 8. The objective response rate at 24 weeks was 33.33%. The overall objective response rate was 50%. The median time to response for progression-free survival, overall survival, duration of response, and time to response was 7.1, 15.0, 9.9, and 3.9 months respectively, with 95% CI in all categories. 50% of patients experienced at least one Grade ≥3 adverse event, including anemia, thromboembolic events, and acute kidney injury. Conclusions: The six BRAF-V600E-mutated PDAC patients in our cohort demonstrated meaningful antitumor activity with a manageable safety profile after treatment with encorafenib and binimetinib. Although the study was prematurely terminated due to limited accrual, observed objective responses and survival outcomes suggest that dual RAF/MEK inhibition may represent a feasible therapeutic strategy in this rare molecular subgroup. Larger studies are warranted to further define the efficacy and safety of this treatment combination in BRAF-V600E-mutated pancreatic cancer. Clinical trial information: NCI-2020-02972 .

4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .

3626 Background: For patients (pts) with dMMR stage III colon cancer, the addition of atezolizumab (atezo) to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) significantly improved disease-free survival in ATOMIC (NCT02912559). Here we present HRQOL data. Methods: Pts with surgically resected stage III dMMR colon cancer were randomized (1:1) to receive mFOLFOX6 + atezo (840 mg IV q2 weeks) for 12 cycles (6 months [mo]) followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 for 12 cycles. HRQOL was an exploratory endpoint measured using the FACT-C (includes FACT-G), FACT/GOG-NTX, EQ5D-5L, and PRO-CTCAE. Optional participation was by paper surveys at trial registration, prior to treatment cycles 4 and 7, and at 6, 12, and 36 mo after registration. Mean changes from baseline (BL) were compared between treatment arms using general linear mixed models (negative mean changes indicate worsening). At 6 mo, a two-sided 95% confidence interval excluding a difference of 1.9 points (FACT/GOG-NTX) and 6 points (FACT-C Trial Outcome Index [TOI]) favoring the mFOLFOX6 arm would indicate non-inferiority of the addition of atezo. Rates of side effect bother (FACT-G item GP5) and pt-reported adverse events (AEs) by PRO-CTCAE (composite scores, baseline adjusted) were compared using Fisher’s exact tests. Results: Of 712 randomized pts, 581 (285 atezo+mFOLFOX6; 296 mFOLFOX6) consented to participate in the survey. Pts completed 2398/3021 (79%) of expected surveys across all time points (1218/1489 [82%] atezo+mFOLFOX6; 1180/1532 [77%] mFOLFOX6). The difference in mean changes from BL between arms indicated non-inferiority of the addition of atezo at 6 mo (table); differences remained small at 12 and 36 mo. No significant differences in mean changes from BL between arms were found at 6, 12, or 36 mo for any scale. At 6 mo, 16% vs 20% of pts in each arm reported at least “quite a bit” of side effect bother (p=0.34), favoring atezo. Across cycles, atezo was associated with higher rates of pt-reported itchy skin (62% vs 48%), cough (53% vs 43%), and shortness of breath (51% vs 41%) [all p<0.05]. Conclusions: Addition of atezo to mFOLFOX6 slightly increases pt-reported AEs, but its effect on HRQOL is minimal and not clinically meaningful. Results support tolerability of atezo+mFOLFOX6 as standard of care adjuvant treatment for pts with dMMR stage III colon cancer. Support: UG1CA189823, U10CA180821, U10CA180882; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 . Scale Mo Mean change from BL – atezo+mFOLFOX6 Mean change from BL – mFOLFOX6 Diff (95% CI) FACT/GOG-NTX 6 -10.0 -10.6 0.6 (-0.8, 2.1) 12 -8.0 -9.4 1.4 (-0.2, 2.9) 36 -7.2 -6.9 -0.4 (-2.1, 1.4) FACT-C TOI 6 -4.1 -2.5 -1.6 (-3.7, 0.6) 12 2.1 1.8 0.3 (-1.9, 2.6) 36 0.7 1.8 -1.1 (-3.7, 1.5)

3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .

3014 Background: Macrocyclic next-generation tyrosine kinase inhibitors (TKIs) have transformed outcomes in ALK- and ROS1-positive NSCLC; such creatively designed medicines are similarly needed to improve outcomes in EGFR-mutant NSCLC. Using a novel, mutant-selective macrocyclic structure, BH-30643 was designed for super-potency against driver EGFRm, largely sparing wildtype (WT) EGFR, and with unique invulnerability to resistance from C797S with or without T790M. Here we report emerging first-in-human dose-escalation data from the SOLARA trial (NCT06706076). Methods: Phase 1 dose escalation used a BOIN design with backfill at potentially efficacious doses. Expansion cohorts targeted populations of interest. Patients (pts) had advanced NSCLC with EGFR and/or HER2 mutations detected on local testing (tissue or plasma). Measurable disease was required; asymptomatic untreated brain metastases (BM) were permitted. Objectives included safety, PK, and RECIST response rate (ORR). Plasma NGS was performed at baseline and on treatment. Results: As of 01/05/2026, 72 pts enrolled into dose escalation and backfill across 7 dose levels at a total daily dose of 20mg -160mg, median age 62, 44% Asian, 65% with history of BM, median of 3 prior lines of treatment (range 1-12). EGFR mutations included classical (38 pts), exon20ins (14 pts) and other/atypical (18 pts) or HER2 mutations (2 pts). Plasma exposures at doses of 40mg BID and above achieved > 10x coverage over target EC90 and exceeded exposure levels of most contemporary EGFR TKIs. Common TRAE ( > 10%) were WT EGFR-associated, including diarrhea (38%), rash (28%), fatigue (15%), stomatitis (13%), and were predominantly grade 1. Bilirubin elevation was seen in 26 pts (36%) related to off-target UGT1A1 inhibition (Gilbert’s-like). Grade 3 TRAE were seen in 15 pts (18%), most commonly bilirubin (8/15); DLTs included bilirubin increase and mucositis, occurring at doses ≥ 60mg BID. No pneumonitis was observed. Responses were observed across diverse EGFRm subsets, including in CNS. Including expansion pts, 28 pts enrolled with C797S on their most recent informative molecular testing (6 with concurrent MET+ or KRAS+), with 23 still on therapy. Of 17 with on-treatment scans, partial responses (confirmed or ongoing) were seen in 10 (59%); ORR was comparable with (50%) or without (66%) T790M. Of 9 pts with baseline C797S detected in ctDNA (3 with T790M), 7 had > 99% reduction of C797S VAF on treatment. Conclusions: Leveraging a novel macrocyclic scaffold, BH-30643 is the first TKI monotherapy to demonstrate clinical responses against C797S both with or without T790M. High plasma exposures combined with super-potency, CNS activity, and favorable safety offers potential for deep and durable EGFR inhibition. Enrollment into backfill and expansion cohorts is ongoing to better characterize activity in both TKI-naïve and resistant pts. Clinical trial information: NCT06706076 .

2646 Background: Immune checkpoint inhibitors (ICIs) have transformed the management of many advanced cancers but identifying patients who are likely or unlikely to benefit from ICI treatment remains a critical challenge. Biomarkers, such as PD-L1, mismatch repair deficiency, and tumor mutational burden, capture only static, unidimensional features of the complex tumor microenvironment, and therefore inadequately predict response to immunotherapy in patients. In contrast, live tumor fragments (LTFs) preserve the full complexity of the tumor microenvironment and enable functional ex vivo assessments of ICI activity. Previous efforts have had limited clinical applicability because they required larger resection specimens often collected at a single academic center. Here, the predictive capability of an ex vivo platform using core needle and forceps biopsies from multiple clinical sites was assessed and compared to approved biomarkers. Methods: Patients with eligible solid tumors (where ICI has an indication, including renal, non-small cell lung, bladder, colorectal, and triple-negative breast cancer, and others) were enrolled in ongoing, prospective observational trials (NCT05478538, NCT05520099, NCT06349642). Biopsies were cut into LTFs, encapsulated in hydrogel, and treated sequentially with IgG antibody followed by ICI (αPD-[L]1 with or without αCTLA-4). Cytokine production was assessed by a multiplexed bead-based immunoassay at multiple time points during ex vivo treatment. Using receiver operating characteristic and precision recall analyses, we identified 9 predictive cytokines (including IFN-γ, granzyme B, and CXCL9/10), which were used to develop the Elephas score (ELP-score) to assess cytokine response to ex vivo ICI treatment. Results: Of 167 eligible patient specimens, 85% (n = 142) passed quality control metrics and 130 were used for model development. Hierarchical clustering of cytokine production revealed that 27% (n = 35) of patient specimens exhibited a cytokine response to ICI. In a validation set of 20 tumors, collected from patients who were subsequently treated with ICI, ELP-score positivity correctly identified 9 of 11 patients (82%) who had an objective response (PR/CR) to ICI, including 2 patients who were negative for FDA-approved standard-of-care ICI biomarkers. Furthermore, 5 of 5 patients (100%) with clinical progressive disease were correctly characterized as ELP-score negative. Conclusions: Using routine biopsy specimens, the ex vivo live tumor platform accurately identifies patients with clinical response to ICI therapy, including those incorrectly identified by conventional biomarkers. Ongoing efforts will test these findings in an additional validation set. If confirmed, the ex vivo LTF platform could enable the identification of patients likely to benefit from ICI therapy. Clinical trial information: NCT05478538 , NCT05520099 , NCT06349642 .

12010 Background: BWEL (Alliance A011401; NCT02750826) is a Phase III trial that randomizes patients (pts) with stage II-III breast cancer and body mass index (BMI) ≥27 kg/m 2 1:1 to a 24-month (mo) lifestyle-based WLI + health education (HE) or HE alone. Here we report prespecified secondary outcomes of the impact of the WLI on patient-reported QOL and symptoms. Methods: The first 540 BWEL pts (randomized between 9/2016 and 7/2017) were included in this substudy that collected PROMIS 29 Profile 2.0 and Global Health scores at enrollment, 6 and 24 mos. Adjusting for baseline scores, mean physical function (predefined substudy primary outcome), global physical and mental health, fatigue and other scores were compared at 6 and 24 mos using analysis of covariance (ANCOVA). P-values <0.05 were considered significant. Positive differences in positive attributes (e.g., physical function) and negative differences in negative attributes (e.g., anxiety) represented better outcomes in the WLI arm. Results: At baseline, median BMI was 32.9 kg/m 2 (26.5 – 69.1), median age was 53 (25 - 78) years; 83.9% of pts were non-Hispanic White, 10.7% were Black and 5.9% were Hispanic. At 6 mos, the WLI (vs HE) arm had significantly better physical function (ANCOVA-based mean difference between arms 1.9 [95% CI 0.8, 3.0]; p<0.001), global physical health (2.0 [95% CI 0.9, 3.0]; p<0.001), global mental health (1.30 [95% CI 0.2, 2.4], p=0.03), social roles and activities (2.3 [95% CI 1.1, 3.6]; p<0.001), and fatigue (-1.7 [95% CI -3.1, -0.4], p=0.01) (Table). Improvements were generally maintained at 24 mos. Similar findings were seen in analyses using longitudinal mixed modeling. Conclusions: The BWEL WLI demonstrated QOL benefits for patients with breast cancer, resulting in significantly better physical function, global physical and mental health, and symptoms. Future analyses will evaluate which populations experienced the most benefit, as well as the relationships among QOL, symptoms, and weight loss. Support: U10CA180821, U10CA180882, UG1CA189823; U10CA180820; U10CA180868; U10CA180863, CCS 707213; U10CA180888; UG1CA189858; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02750826 . Analysis of covariance-adjusted least squares means values at 6-mos adjusted for baseline scores. QOL/Symptom Attributes HE WLI Between arm difference (95% CI)* P value Physical Function 47.1 49.0 1.9 (0.8, 3.0) <0.001 Global Physical Health 46.2 48.1 2.0 (0.9, 3.0) <0.001 Global Mental Health 48.6 49.9 1.3 (0.2, 2.4) 0.03 Social Roles and Activities 52.7 55.0 2.3 (1.1, 3.6) <0.001 Anxiety 50.2 50.0 -0.2 (-1.6, 1.2) 0.77 Depression 47.5 47.5 -0.0 (11.2, 1.2) 0.96 Fatigue 50.6 48.9 -1.7 (-3.1, -0.4) 0.01 Sleep Disturbance 51.0 51.1 0.1 (-0.6, 0.8) 0.80 Pain Interference 51.3 50.3 -1.0 (-2.4, 0.4) 0.15 *Positive differences in positive attributes and negative differences in negative attributes favor WLI arm.

10610 Background: The role for genetic testing (GT) for prostate cancer (PCa) patients (pts) has expanded to find pts with germline pathogenic variants (PV) for therapeutic opportunities given FDA-approvals for PARP inhibitors in metastatic PCa as well as understanding familial cancer risk and opportunities for tailored screening and risk reduction. The PROMISE Registry (NCT04995198) was set up as a genetic registry to partner with PCa pts for rapid access to a new standard of care given insurance coverage and clinical implementation were initially major barriers. A second goal is to characterize disease features and treatment outcomes to inform management and provide updates about novel therapeutic clinical trials, both of which remain important to rare genetic variant carriers. Methods: PROMISE is a US decentralized prospective PCa genetic registry initiated in 2021 with initial phase to enroll and provide clinical-grade germline genetic testing (30 gene cancer-specific panel) to 5,000 PCa pts to identify ~500 PCa pts with variants of interest (pathogenic variants, PV, and variants of uncertain significance, VUS) in DNA repair genes for long-term clinical follow-up of 15 years (LTFU). Here, we report the initial phase testing results and identification of the LTFU cohort. Study design and enrollment strategy have been reported separately. Results: Between 2021-2026, 7,275 pts with any stage PCa across 50 US states self-consented to PROMISE, of which 5,674 (78%) of pts completed genetic testing, indicating feasibility of patient-directed, decentralized enrollment. We have identified 495 (8.7%) pts for LTFU. Baseline data is reported for n=367 (Table 1, will be updated at time of presentation). The most frequently observed PV/LPV variants being in CHEK2 (25%) , BRCA2 (23%) , ATM (12%) , and BRCA1 (4.6%). At the time of PCa diagnosis, the majority of LTFU pts had non-metastatic disease, with 47% of pts with Gleason>7, median PSA of 5 ng/mL, and median time from diagnosis to PROMISE GT of 25 months. Conclusions: PROMISE is a nationwide decentralized PCa genetic registry that has completed initial goal to recruit 5,000 PCa pts to offer germline genetic testing and recruit a cohort of 500 for LTFU. Data about diagnosis characteristics are reported, and analysis of ongoing disease course, treatment response/outcomes and overall survival is being collected. Clinical trial information: NCT04995198 . Long-term follow-up participant demographics. Characteristic Overall, N = 367 Age at Diagnosis (yrs) 63 (57, 69) Race N = 361 (6, nr) Asian, American Indian or Alaska Native, Multiracial, Other 22 (6.0%) Black or African American 22 (6.0%) White 317 (86%) Disease State at Diagnosis N = 348 (19, nr) Metastatic 46 (13%) Non-metastatic 302 (87%) Time from Diagnosis to PROMISE GT (months) 25 (4, 82) Gleason Score N = 280 (87, nr) </= 7 148 (53%) >7 132 (47%) PSA At Diagnosis (ng/mL) 5 (0, 10) (88, nr) Subjects with baseline data entered. nr=not reported. Median (Q1, Q3); n (%).