Narayan, Vivek

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

5077 Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]