Citations

5022 Background: Racial disparities are evident in PCa, with Black men experiencing a higher incidence and worse survival compared to NHW patients (pts). The molecular alterations that distinguish these groups remain incompletely characterized. Herein, we investigate the clinical-genomic features that potentially contribute to the differences in outcomes between Black and NHW pts with PCa. Methods: Comprehensive next-generation sequencing of DNA (592-gene panel/whole exome) and RNA (whole transcriptome) was performed at Caris Life Sciences on PCa tissue samples (n = 5,412), collected from 2015 to 2023. Transcriptomic signatures – Androgen Receptor (AR), Neuroendocrine PCa (NEPC) scores – were calculated. Real-world overall survival (OS) data was obtained from insurance claims and was analyzed using Kaplan-Meier estimation. Results: Overall, 1,078 pts with PCa identified as Black, while 4,334 were NHW. Black pts were younger at biopsy collection than NHW pts (median age 66 vs 71 years, P < 0.001). The proportion of metastatic samples was higher in Black pts compared to NHW pts (43% vs 38%, P < 0.01). The prevalence of castrated PCa specimens was similar between Black and NHW pts (26.0% vs 25.4%, P = 0.72). Among non-castrated PCa tumors, tumors from NHW pts had more frequent alterations in TP53 , PTEN , PIK3CA , and CHEK2 , while tumors from Black pts had more SPOP and CTNNB1 mutations. In the castrate setting, TP53 and PTEN alterations were more frequent in tissue samples from NHW pts, while CDK12 and SPOP mutations were more frequent in tumors from Black pts. TMPRSS2 fusions were more prevalent in the NHW cohort across both castrated and non-castrated tumors. Tumors from Black pts had higher FOLH1 / PSMA and STEAP1 expression, elevated AR scores, but lower CD276 / B7H3 expression and NEPC scores. In the overall cohort, Black pts demonstrated a shorter median OS from diagnosis compared to NHW pts (86 vs 94 mos, P = 0.03). Black pts had a significantly longer time on treatment with enzalutamide in both the non-castrate (HR 0.82, P= 0.04) and castrate subgroups (HR 0.77, P= 0.03). Among pts with homologous recombination repair (HRR) deficiency-harboring tumors, PARP inhibitors provided a numerically longer survival benefit in Black pts than in NHW pts (21 vs 13 mos, P = 0.09). Conclusions: This multi-institutional study reveals distinct molecular profiles between Black and NHW pts with PCa. Despite having molecular features associated with better prognosis, Black men demonstrated worse survival outcomes, pointing to multifaceted determinants of disease outcomes. Notably, Black pts had improved outcomes on enzalutamide and showed potential benefit from PARP inhibitors in the presence of HRR mutations. These findings highlight genomic differences in diverse PCa populations and suggest therapeutic opportunities to address outcome disparities.

5013 Background: There is no established role for the use of docetaxel with ADT and RT for HRLPC, with mixed results seen in prior RCTs. Prior work from ICECaP (Ravi et al, Eur Urol 2024) has shown that patients (pts) with very high-risk disease (i.e. 2 or 3 risk factors [RFs]: Gleason ≥8, PSA >20, ≥cT3 and/or cN1) have the poorest outcomes with RT+ADT for HRLPC, with 5-year metastasis-free survival (MFS) of ≤80%. We aimed to perform an IPD meta-analysis of the role of docetaxel with ADT+RT for HRLPC and specifically evaluate whether patients with very high-risk disease benefit from the addition of docetaxel. Methods: IPD from RCTs involving pts with HRLPC treated with RT+ADT +/- docetaxel collated by ICECaP were analyzed. “High-risk” disease was defined as presence of 1 RF and “very high-risk” disease as 2-3 RFs and/or cN1 disease. The primary outcomes of interest were MFS and overall survival (OS). Hazard ratios (HR) for MFS and OS were estimated using Cox regression, stratified by year of randomization and adjusted for age at randomization and ECOG performance status. 5-year MFS and OS rates were estimated using the Kaplan-Meier method. Subgroup analyses were performed according to the severity of disease (high- and very high-risk), and p-values for interaction were tested using the likelihood ratio test. Results: 1690 pts treated on 4 RCTs (GETUG-12, DFCI 05-043, STAMPEDE, RTOG-0521) between 2002-2015 were eligible. Median age was 65, median PSA was 23 (IQR 10-48); 154 (9%) pts had cN1 disease and 1444 (85%) received long-term ADT with RT. Median follow-up was 10 years (range: <1-15). Overall, the addition of docetaxel to RT+ADT was not associated with a significant benefit in MFS (HR=0.89 [0.76-1.05], p=0.160) or OS (HR=0.88 [0.74-1.05], p=0.167). Though there was some evidence for favoring docetaxel in pts with very high-risk disease (n=1054; MFS HR=0.86 [0.71-1.05]; OS HR=0.85 [0.68-1.07]) compared to high-risk disease (n=636; MFS HR=0.97 [0.74-1.27]; OS HR=0.95 [0.71-1.28]), there was no evidence of a significant difference in treatment effect by risk group (p-interaction >0.1). 5- and 10-yr MFS and OS in pts with high- and very high-risk disease, stratified by receipt of docetaxel, are shown in the Table. Conclusions: Some HRLPC pts with very high-risk disease may benefit from the addition of docetaxel to RT+ADT. Biomarker evaluation within this group may identify those who are candidates for treatment intensification with docetaxel with RT+ADT (+/- androgen receptor pathway inhibitors) in HRLPC. % (95% CI) High risk Very high-risk RT+ADT RT+ADT+docetaxel RT+ADT RT+ADT+docetaxel 5yr MFS 87 (82-90) 90 (86-93) 74 (71-78) 80 (76-83) 5yr OS 90 (86-93) 93 (90-96) 84 (80-86) 89 (86-92) 10yr MFS 67 (61-72) 71 (65-76) 51 (46-55) 55 (49-60) 10yr OS 74 (69-79) 77 (72-82) 62 (57-67) 67 (62-72)

e16001 Background: Esophageal carcinoma ranks among the top 10 malignancies in the world, contributing to high morbidity and mortality. With radiotherapy being one of the most administered treatment options, different variations of administration have evolved. Two such variations include intensity-modulated radiotherapy and 3D conformational radiotherapy. These modalities have been investigated for their efficacy and rate of adverse events. However, conclusions from the trials conducted have been variable. In this systematic review and meta-analysis, we aim to collate these findings to assess the exposure of cancerous cells and rates of adverse events following IMRT or 3D-CRT. Methods: A comprehensive literature search was conducted across three databases for all articles published from inception till September 2024. All primary studies evaluating the comparative efficacy of IMRT vs 3D-CRT were included. Outcomes assessed include dose volume histograms (DVHs) at heart and lung, Dmax at the spinal cord, and irradiation toxicity. Data analysis was conducted in RevMan 5.4 using a random-effects model. Results: A total of twenty records were included in the study, with a sample size of 3090 patients. Radiation dosage, estimated as DVHs, was equal across both regimens at heart (MD: 2.67; 95%CI: –0.15 to 5.48; P = 0.06), except at 40 Gy of radiation, where a lower DVH was noted among patients being administered IMRT (MD: 6.64; 95%CI: 0.25 to 13.03; P = 0.04). At the lung, a higher DVH was noted, especially for doses of 20 Gy or above, on using IMRT. Similarly, a lower dosage in the spinal cord was noted in the IMRT group (MD: 2.87; 95%CI: 1.04 to 4.70; P = .002). Consequently, a lower risk of esophagitis was noted among the IMRT group (OR: 1.54; 95%CI: 1.14 to 2.07; p = 0.009]). While considering patient outcomes, the odds of survival were higher in the IMRT group at 3 years post-treatment (OR: 0.53; 95%CI: 0.31 to 0.92; P = 0.02). Conclusions: IMRT was superior to 3D-CRT in terms of volume of tissue irradiated and lower spinal toxicity. A higher chance of survival was noted in the IMRT group. Further trials are needed to strengthen these findings. Outcome Mean Difference (MD) 95% confidence interval (CI) P value Mean dosage at lung 1.14 0.6, 1.68 <0.0001 Mean dosage at heart 2.67 -0.15, 5.48 0.06 Radiation esophagitis Odds ratio, OR: 1.38 1.09, 1.76 0.009 Radiation pneumonitis OR:1.37 0.62, 3.01 0.43 3-year OS OR: 0.69 0.56, 0.84 0.0003 5-year OS OR: 0.53 0.31, 0.92 0.02 Maximum dosage at spinal cord 2.87 1.04, 4.7 0.0002

5069 Background: Ra-223 improves the overall survival in patients with mCRPC to the bone. We assessed the safety of standard-of-care Ra-223 in combination with peposertib, a DNA-dependent protein kinase inhibitor, with or without avelumab, an anti-PD-L1 antibody. Methods: Patients with mCRPC and two or more skeletal metastases identified by bone scintigraphy with or without lymph node metastases up to 3 cm in size, but no visceral metastases, were eligible. Progression after progression after at least one androgen receptor pathway inhibitor or taxane was required. Phase 1 consisted of a two-step sequential safety lead-in using a 3+3 design. Step 1 combined 6 standard cycles of Ra-223 (55 kBq/kg), with increasing doses of peposertib: 50, 100, and 200 mg PO bid on days 3-26 of each cycle. Step 2 combined Ra-223 with the maximum tolerated dose of peposertib and added standard avelumab 800 mg IV every 14 days, starting at cycle 2 of Ra-223. Results: A total of 9 patients participated in Step 1, where the maximum tolerated peposertib dose of 200 mg PO bid with Ra-223 was deemed tolerable. A total of 6 patients participated in Step 2 and the combination of Ra-223, peposertib at 200 mg PO bid, and standard avelumab was deemed tolerable. Of the 15 patients in Phase 1, none experienced grade 4 or higher treatment-related toxicities, while 7 experienced grade 3 toxicities, including neutropenia (1), anemia (1), cardiac chest pain (1), fall (1), maculopapular rash (2), and lymphopenia (2). The median (Q1, Q3) PSA velocity from the beginning to the end of treatment was lower for Step 2 versus Step 1: 2.1 (-0.1, 4.6) versus 23.5 (18.6, 77.1) ng/mL/month (p = 0.0067). OS and PFS were calculated with the limitation that the Phase 1 was non-randomized. Median OS was not reached for Step 2, as only 1 of 6 patients had died, versus 15.2 months for Step 1, where 8 out of 9 patients had died (p = 0.0537). The patient who died in Step 2 discontinued therapy prematurely after 3 cycles due to progression and survived 15.2 months (the 5 alive completed all 6 cycles). The median radiographic PFS was 7 months for Step 2 versus 12.7 months for Step 1 (p = 0.8910). Conclusions: The combination of Ra-223 and peposertib, with or without avelumab was well tolerated. The triplet combination showed the most promising results at this early evaluation. We continue to accrue in the randomized Phase II portion of the trial. Clinical trial information: NCT04071236 .

1530 Background: Regular breast cancer screening reduces mortality. The American College of Radiology (ACR) recommends annual screening mammography for asymptomatic, average risk 1) transgender and gender diverse (TGD) men (individuals assigned female sex at birth but identify as men) age 40+ and with residual breast tissue and 2) TGD women (individuals assigned male sex at birth but identify as women) age 40+ and on gender-affirming hormone therapy for 5+ years. This nationwide study investigated screening mammography in TGD individuals. Methods: Four cohorts were identified with complex algorithms of medical and pharmacy data in the OptumLabs Data Warehouse, a longitudinal, administrative insurance claims database that includes patients with commercial insurance and Medicare Advantage: 1) TGD men, 2) TGD women, 3) individuals with gender dysphoria not meeting other TGD criteria (NMOT), and 4) cisgender women -- all of whom met ACR screening criteria. The primary endpoint was the percentage of individuals with high adherence, defined as completing >75% of recommended screenings; comparisons were made across the cohorts (Chi-square test). Multivariable logistic regression was used to compare adherence between TGD men and cisgender women with adjustment for demographics and with 1:4 matching (on race/ethnicity, age group, year of healthcare plan enrollment, and duration of follow-up). Results: 10,478 TGD individuals (3,778 TGD men; 1,294 TGD women; and 5,406 with gender dysphoria NMOT) and 6,218,369 cisgender women were identified. For TGD men, TGD women, individuals with gender dysphoria NMOT, and cisgender women, high adherence was observed in 41.1% (95% confidence interval (CI): 39.5, 42.6%); 7.4% (95% CI: 6.0, 8.8%); 11.9% (95% CI: 11.0, 12.7%); and 38.3% (95% CI: 38.3, 38.4%), respectively, p < 0.0001. No screening ever in these same populations was observed in 23.6% (95% CI: 22.2, 24.9%); 81.3% (95% CI: 79.2, 83.4%), 72.8% (95% CI: 71.6, 74%), and 35.9% (95% CI: 35.8, 35.9%), respectively, p < 0.0001. When TGD men were matched and compared to 15,112 cisgender women, a differential association was observed between gender and high adherence by age group (p < 0.0001); compared to cisgender women, the likelihood of high adherence in TGD men ages 40-49 (n = 2,472), 50-59 (n = 852), 60-69 (n = 320), and 70+ (n = 134) were as follows: odds ratios (OR‘s): 1.38 (95% CI: 1.28, 1.50), p < 0.0001; 1.57 (95% CI: 1.35, 1.81), p < 0.0001; 0.812 (95% CI: 0.619, 1.065), p = 0.1316; and 1.277 (95% CI 0.835, 1.951), p = 0.2595, respectively. Conclusions: This study found that TGD men manifest relatively high adherence to screening mammography, whereas TGD women and individuals with gender dysphoria NMOT manifest low adherence. Future research should focus on improving breast cancer screening in these underserved populations.

1510 Background: The National Comprehensive Cancer Network (NCCN) Harmonized Guidelines for Sub-Saharan Africa (SSA) have emerged as leading cancer treatment guidelines in SSA. The NCCN-SSA guidelines, derived by adapting NCCN guidelines for the SSA context, offer standardized recommendations to guide cancer care and shape policy in SSA. This study examines the evidence cited in support of the NCCN-SSA guidelines, with a focus on population characteristics and generalizability to SSA. Methods: Two reviewers independently examined the NCCN-SSA guidelines for the eight most common cancers in SSA to identify all studies cited in support of treatment/management recommendations. Study selection discrepancies were resolved by discussion. Full-text articles were reviewed and data on age, sex, race, and recruitment geography were abstracted. Descriptive analyses were performed using R statistical software. Results: Overall, 4,589 citations were reviewed, and 2,938 (64.0%) studies with individual-level data were included, representing >10.4 million study participants. Of the 2,061 studies reporting geographic information (70%), 50 (2.4%) recruited in SSA; of these, 39 (83.0%) recruited from South Africa. Three studies (0.2%) recruited exclusively in SSA. Most studies (95.3%) recruited exclusively from high or upper-middle income countries. Only 29.2% of studies with race data included >10% Black study participants. Conclusions: Most studies cited in the NCCN-SSA guidelines were conducted in high-income countries outside SSA. A small minority of all study participants were Black. Our findings underscore potential limitations in the generalizability of the NCCN-SSA guidelines to SSA and highlight a pressing need to generate and incorporate context-specific data to guide care and inform policy. WHO region of recruitment, race, and country-level income of studies included in NCCN-SSA guidelines. Cancer type # (%) studies reporting geography # (%) studies by recruitment region*: Americas # (%) studies by recruitment region*: Europe # (%) studies by recruitment region*: Sub-Sah. Africa % participants, White % participants, Black % participants, Other race # (%) studies representing only HMIC (per World Bank) Overall 2061(70%) 1177 (57%) 921 (45%) 50 (2%) 79% 9% 11% 1964(95%) B-cell 325(57%) 173 (53%) 178 (55%) 5(2%) 82% 7% 10% 307(94%) Breast 206(44%) 123 (60%) 124 (60%) 12 (6%) 80% 9% 11% 179(87%) Cervical 163(90%) 100 (61 %) 44(27%) 3(2%) 64% 14% 22% 158(97%) Colorectal 584(82%) 278 (48%) 292 (50%) 11 (2%) 80% 10% 10% 571 (98%) Hepato-cellular 183(74%) 80(44%) 68(37%) 0(0%) 69% 9% 22% 169(92 %) Kaposi sarcoma 51(80%) 25 (49%) 19(37%) 5(10%) 38% 51% 10% 44(86%) Ovarian 115(56%) 76 (66%) 35 (30%) 0(0%) 83% 4% 13% 115(100%) Prostate 434(88 %) 322 (74 %) 161 (37%) 14 (3%) 79% 9% 12% 421(97%) HMIC = high and upper-middle income countries. *Percent of studies includes as the denominator only the number of studies with reported geographies.

e18596 Background: The International Consensus (ICC), but not the 5 th edition of the WHO classification (WHO5), distinguishes mature from immature mast cell leukemia (MCL) and systemic mastocytosis (SM) associated with myeloid neoplasm (SM-AMN) from SM associated with myeloid or lymphoid neoplasm (SM-AHN). The objectives of the current study were i) to assess prognostic input from disease classification by ICC vs. WHO5, and ii) to compare the predictive performance of the Mayo Alliance Prognostic scoring (MAPS) with other prognostic models and its prognostic interaction with the ICC-based morphologic classification. Methods: Study patients met diagnostic criteria per ICC/WHO5. MAPS risk variables included i) age >60 years, ii) hemoglobin below sex-adjusted lower limit of normal, iii) platelets <150 × 10⁹/L, iv) alkaline phosphatase above upper limit of normal, and v) advanced, including MCL, SM-AMN, and aggressive (ASM) vs. indolent/smoldering (ISM/SSM) SM. ICC-defined MCL includes only MCL-immature whereas WHO-defined MCL includes both MCL-immature and MCL-mature. WHO-defined SM-AHN includes SM-AMN and SM associated with lymphoid neoplasm (SM-ALN). Results: 910 Mayo Clinic patients with SM were diagnosed between 1968 and 2024 (median age 56 years). ICC categories were ISM/SSM (N=552), ASM (N=115), SM-AMN (N=235), and MCL (N=8). At median follow-up of 4 years, 345 (38%) deaths and 35 (3.8%) leukemic transformations were documented. Overall survival (OS) predictive performance at 5 years was superior with ICC (AUC 0.85), compared to WHO5 (AUC 0.83); median survival was 24.3 years in ISM/SSM, 5.8 years for ASM, 2.0 years for SM-AMN, 2.3 years for SM-AHN, 1.8 years for MCL-mature and 0.08 years for MCL-immature; the difference in OS was significant between MCL-immature and SM-AMN (p<0.01) but not between MCL-mature and SM-AHN (p=0.3). Similarly, OS was similar between MCL-mature and ASM (p=0.8) and between SM-ALN and ASM (p=0.08) but different between MCL-immature and ASM (p<0.01), SM-AMN and ASM (p<0.01), and MCL-mature and MCL-immature (p<0.01). Predictive performance at 5 years was superior with MAPS (AUC 0.91) and MAPS-molecular (AUC 0.91), compared to the mutation-adjusted risk score (MARS; AUC 0.82). Median OS estimates were not reached, 24.2, 11.7, 5.7, 2.6, and 0.7 years, in the presence of 0, 1, 2, 3, 4, or 5 of the forementioned MAPS risk factors. Among informative cases, ASXL1 mutation was the only genetic risk factor with MAPS-independent prognostic relevance. Prognostic inter-independence between ICC and MAPS was confirmed by multivariable analysis. Conclusions: The current study confirms the superior performance of MAPS, in regard to survival prediction, with little additional contribution from mutations. SM sub-classification by the ICC is prognostically independent of MAPS and more valuable than classification by WHO5.

e18590 Background: TP53 mutations ( TP53 MUT ) are known to be associated with adverse prognosis in acute myeloid leukemia (AML) and multihit TP53 MUT in myelodysplastic syndromes (MDS). The prognostic relevance of multihit TP53 MUT in myeloproliferative neoplasms (MPN) was recently highlighted. The current study illustrates survival comparisons in multihit TP53- mutated MPN vs. AML and analysis of associated risk factors. Methods: A Mayo Clinic enterprise-wide database search identified 61 MPN and 81 AML cases with multihit TP53 MUT . Conventional statistical methods were used for analyses. Results: 142 patients with multihit TP53 MUT were included: i) chronic phase MPN (MPN-CP; N=19), ii) accelerated phase MPN (MPN-AP; N=14), iii) blast phase MPN (MPN-BP; N=28) and iv) AML, not including MPN-BP (N=81). Concomitant ASXL1 MUT , EZH2 MUT , IDH1 MUT and IDH2 MUT were more common in MPN-BP, compared to AML. At a median follow up of 0.6 years, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from time of TP53 MUT detection was similar between MPN-BP (median 4.6 months) and MPN-AP (5.6 months; p=0.5). OS in MPN-BP/AP (median 4.8 months) was inferior to that of AML (median 7.4 months; p=0.04) while that of MPN-CP (median 11.6 months) was similar to AML (0.07) but superior to that of MPN-BP/AP (p<0.01). Age-adjusted multivariable analysis (MVA) confirmed the independent prognostic significance of undergoing ASCT (HR 0.4, p=0.03), MPN-CP or achieving response to pre-transplant therapy (HR 0.2, p<0.01), and concurrent TET2 MUT or DNMT3A MUT (HR 2.7, p<0.01) on OS. Based on these risk factors, a 3-tiered risk model was constructed: low (no risk factors; N=18; median OS 23.8 months); intermediate (1 risk factor; N=44; median 11.1 months); and high (2 or more risk factors; N=80; median 4 months; p<0.01). Comparative analysis of risk factors among distinct diseases confirmed the prognostic significance of ASCT (HR 0.3, p=0.03), achieving response to pre-transplant therapy (0.4, p<0.01) and concurrent TET2 MUT or DNMT3A MUT (HR 5.0, p<0.01) in AML. In MPN AP/BP, OS was influenced by having received chemotherapy vs. supportive care (HR 0.1; p<0.01) and achieving response to pre-transplant therapy (0.2, p<0.01). No significant risk factors for OS were identified in MPN-CP. In MVA, ASCT did not appear to influence OS in MPN AP/BP (p=0.7) and MPN-CP (p=0.4) but the number of informative cases was too low to make definitive conclusions. Conclusions: The current study highlights the equally detrimental impact of multihit TP53 MUT in securing long-term survival in MPN and AML. Short-term survival was positively influenced by ASCT, at least in AML, and disease stage or remission status at time of mutation detection and ASCT, respectively.

5076 Background: C and Lu are both life-prolonging therapies for pts with mCRPC after progression on androgen receptor pathway inhibitor (ARPI) and docetaxel (D). Herein, our objective was to assess the comparative effectiveness of C vs. Lu in pts with mCRPC with prior progression on D and ARPI in real-world pts in the USA. Methods: A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract pt-level data. Eligibility: pts with mCRPC who progressed on D and ARPI and received for the first-time single-agent C or Lu. Pts who received alternative Lu or C in a later line of therapy (LOT) were excluded. Endpoints: real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS). These were summarized via Kaplan-Meier survival estimates with a 95% confidence interval (CI) and compared in the context of propensity score (PS) matching weighted analysis using the Cox proportional hazard model. PS model included the following covariates: age, race-ethnicity, socioeconomic status, treatment year, Gleason score, ECOG performance status, log2PSA, alkaline phosphatase, hemoglobin, creatinine, LOT, insurance, and practice type. All the covariates achieved balance after PS matching weighting. Results: Among 24,105 pts with metastatic prostate cancer in the dataset, 1,445 met the eligibility criteria and were included (1,227 treated with C, 218 treated with Lu). In C cohort: median age was 73 (IQR 67 – 78), 66.9% had Gleason score ≥ 8, and median LOT was 4 (IQR 3-4). In Lu cohort: median age was 75 (IQR 67.25 – 80), 68.1% had Gleason score ≥ 8, and median LOT was 4 (IQR 3-5). In PS matching weighting analysis, there was evidence that pts receiving Lu had a significantly improved rwTTNT (median 8.3 months [mo], 95% CI 6.3 – 9.8) compared to those receiving C (median 4.7 mo, 95% CI 4.2 – 5.4) (HR 0.49, 95% CI 0.37 – 0.63, p < 0.001), which persisted after adjusting for covariates (HR 0.43, 95% CI 0.32 – 0.57, p < 0.001). Additionally, there was evidence that rwOS was longer in pts receiving Lu (median 10.3, 95% CI 8.9 – 12.8) compared to those receiving C (median 8.8 mo, 95% CI 6.6 – 10.8) (HR 0.69, 95% CI 0.51 – 0.92, p = 0.01). This improvement in rwOS with Lu compared to C persisted after adjusting for covariates (HR 0.61, 95% CI 0.44 – 0.84, p < 0.001). Conclusions: This is the largest real-world data to date assessing the comparative effectiveness of Lu vs. C, and it showed significantly longer rwTTNT and rwOS with Lu compared to C in pts with mCRPC pretreated with ARPI and D. Limitations: retrospective nature, selection bias, missingness, lack of randomization, etc. and residual confounding in real-world datasets. Upon external validation, these findings could guide treatment selection in the clinic and design of clinical trials.

5073 Background: B7-H3 ( CD276 ) is an immunomodulatory protein overexpressed in prostate cancer (PC), representing a promising therapeutic target. However, expression of B7-H3 across PC disease states (hormone sensitive [HSPC], castration resistant [CRPC], neuroendocrine [NEPC]) and across races is poorly understood. We analyzed PC samples from a large clinico-genomic database to comprehensively characterize B7-H3 expression and elucidate its therapeutic potential in PC patients. Methods: We analyzed 7,682 PC samples with paired DNA/RNA profiling from Caris Life Sciences. Using CD276 mRNA expression measured by transcripts per million (TPM), samples were stratified into B7-H3-high (>75% centile) or low (<25% centile) groups. Annotations of HSPCs and CRPCs were based on time of biopsy collection relative to first use of androgen deprivation therapies. NEPC was defined histologically (Epstein, AJSP 2014). Transcriptomic alterations were compared using Mann-Whitney U tests. Overall survival (OS) was obtained from insurance claims data and assessed by Kaplan-Meier and Cox proportional hazards analyses. Results: B7-H3 was expressed at similar levels across specimen sites (prostate, lymph node, bone, liver, lung). HSPCs and CRPCs had similar levels of B7-H3 expression, but was reduced in NEPCs (TPM = 5.07, 4.96, 4.48; q<0.0001). While B7-H3-high was associated with worse OS in HSPCs (HR 1.32, 95CI 1.14-1.53, p=0.0002), it was associated with better OS in CRPC (HR 0.82, 95CI 0.69-0.97, p=0.018). B7-H3 expression was comparable in white, African American (AA), and Asian patients. However, Asian patients with high B7-H3 had worse outcomes (HR 4.08, 95CI 2.10-7.93, p<0.0001) while AA patients had improved outcomes (HR 0.74, 95CI 0.57-0.97, p=0.027). In co-expression analyses, B7-H3 was positively correlated with AR transcriptional co-factors ( HOXB13 , FOXA1 ) (R=0.59, 0.47; q<0.0001) but had weaker correlations with lineage plastic factors ( EZH2 , SOX2 , ASCL1 ) (R=0.26, 0.11, -0.02). Further, B7-H3-high correlated with high AR-score and low-NEPC. Given emergent bi-specific therapeutics in PC, we examined co-expression of B7-H3 with other cell surface targets. TROP2 ( TACSTD2 ) and NECTIN-4 ( PVRL4 ) exhibited the greatest correlation with B7-H3 (R=0.42, 0.40; q<0.0001); whereas PD-L1 ( CD274 ), CTLA4 , DLL3 , and CEACAM5 had weaker correlations (R=0.18, 0.08, 0.14, 0.09). Conclusions: High B7-H3 expression worsens prognosis in HSPC but improved prognosis in CRPC. Outcomes differed by race, with B7-H3-high Asian patients exhibiting worse OS while AA patients had better OS. The positive correlation between B7-H3 and AR co-factors suggests that B7-H3 is AR-regulated, at least in CRPC. Lastly, bi-specific approaches may be valuable against B7-H3-high tumors, with co-targeting of TROP2 and/or NECTIN-4.