Smith, Norm D.

Abstract Purpose: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer. To guide therapeutic development and treatment strategies, we examined prostate tumors and evaluated expression, molecular features, and overall survival (OS), accounting for tissue site, hormone sensitivity status, and race. Experimental Design: A total of 8,157 prostate cancer samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC), or neuroendocrine prostate cancer (NEPC). Expression quartiles were B7-H3–high (>75th percentile) or B7-H3–low (<25th percentile). The OS was evaluated using Kaplan–Meier and Cox proportional hazards models. Results: B7-H3 expression was broadly maintained but varied by tumor site, hormone sensitivity status, and race. High expression aligned with AR-associated transcription factors (HOXB13 and FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, and TMPRSS2:ERG fusions), and actionable surface antigens (TROP2 and NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, and ASCL1) and NEPC-associated surface antigens (DLL3 and CEACAM5). High B7-H3 expression in primary tumors and HSPCs portended adverse OS [hazard ratio (HR), 1.342 and 1.30; confidence interval (CI), 1.19–1.512 and 1.15–1.46; q < 0.0001] although it was favorable in metastatic tumors (HR, 0.823; CI, 0.719–0.942; q = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with the poorest survival in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49–9.29; q = 0.012). Conclusions: Maintained B7-H3 expression in various prostate cancer settings supports its viability as a target. The associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody–drug conjugates suggest potential dual-targeting strategies. See related article by Sharma et al., p. 3365

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.

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.

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy ( ORC ) vs robot‐assisted RC ( RARC ), pelvic lymph node dissection ( PLND ) and urinary diversion for oncological outcomes, complications and health‐related quality of life ( HRQL ) measures with a primary endpoint of 2‐year progression‐free survival ( PFS ). RAZOR is a multi‐institutional, randomized, non‐inferior, phase III trial that will enrol at least 320 patients with T 1– T 4, N 0– N 1, M 0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics ( CRAB ) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T 1– T 4, N 0– N 1, M 0 patients with bladder cancer to ORC vs RARC , PLND and urinary diversion. RAZOR is a multi‐institutional, non‐inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2‐year PFS . Full data from the RAZOR trial are not expected until 2016–2017.