Abstract 727: Association of baseline tumor and peripheral biomarker features with efficacy in metastatic castration-resistant prostate cancer patients treated with xaluritamig

Abstract Xaluritamig, a novel STEAP1 x CD3 XmAb® 2+1 T-cell engager, is showing initial safety and efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the association of baseline tumor and peripheral biomarker characteristics with efficacy in the first-in-human dose exploration trial. We examined STEAP1 target expression by immunohistochemistry in fresh and archival tumor biopsies, peripheral immune populations by multiparameter flow cytometry, and tumor somatic mutations via circulating tumor DNA (ctDNA) in plasma. STEAP1 was broadly expressed in mCRPC subjects with greater than 95% of tumor biopsies containing at least 1% STEAP1-positive tumor cells. STEAP1 expression was similar at various metastatic sites examined in the patient cohort and was not impacted by the number or types of prior therapies. Additionally, STEAP1 expression levels were not correlated with PSMA expression. Neither STEAP1 IHC intensity nor the percentage of STEAP1-positive tumor cells correlated with response to xaluritamig. Baseline peripheral immune cell populations and blood chemistry features may potentially associate with response. Patients who achieved a PSA50 response had lower neutrophil counts, neutrophil-to-lymphocyte ratio, and C-reactive protein than non-responding patients. The association between xaluritamig response and baseline tumor T cell infiltration is being assessed. Baseline somatic tumor mutations were determined by analysis of ctDNA. The distribution of somatic tumor mutations was consistent with published mCRPC mutational frequencies, with deleterious alterations in TP53, AR, PTEN and RB1 observed most frequently. Xaluritamig efficacy was observed in patients whose tumors carried these common mCRPC alterations, as well as in patients with detectable TMPRSS2:ERG fusions Taken together, these data suggest that xaluritamig has anti-tumor activity in a broad mCRPC patient population and provide support for enrolling patients with mCRPC in a Phase 3 study of xaluritamig (NCT06691984) regardless of STEAP1 expression levels or tumor mutational status. Citation Format: Benjamin E. Decato, Zhao Yang, Isabelita Vengco, Katherine Paweletz, Amrita Pati, Anita Reddy, Tara O'Donohue, Sheryl Treichel, Kristen M. Smith. Association of baseline tumor and peripheral biomarker features with efficacy in metastatic castration-resistant prostate cancer patients treated with xaluritamig [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 727.