The Past, Present, and Future of PSMA-Targeted Therapies in Prostate Cancer

Abstract

Prostate-specific membrane antigen (PSMA) is a well-characterized cell-surface antigen with 100- to 1000-fold increased expression in prostate cancer relative to normal prostate tissue, establishing it as a compelling therapeutic target in metastatic castration-resistant prostate cancer (mCRPC). Decades of clinical investigation across radioligand therapy, antibody-drug conjugates (ADCs), chimeric antigen receptor T-cell (CAR-T) therapy, and bispecific T-cell engagers (BiTEs) have validated PSMA as a clinically actionable target. However, across these modalities, antigen expression heterogeneity, the immunosuppressive tumor microenvironment, and construct-level limitations have consistently emerged as the primary determinants of therapeutic outcome. The approval of ¹⁷⁷Lu-PSMA-617 (lutetium-177 vipivotide tetraxetan; Pluvicto) established proof-of-concept for PSMA-directed therapy in mCRPC, yet a substantial proportion of patients derive limited or no durable benefit, and early immunotherapeutic platforms encountered recurring challenges including cytokine release syndrome, immunogenicity, and insufficient T-cell persistence. Next-generation bispecific constructs incorporating tumor-conditional activation via molecular masking, exemplified by VIR-5500, have demonstrated markedly improved tolerability and encouraging anti-tumor activity in Phase 1 evaluation. This review traces the clinical and biological insights that have guided successive generations of PSMA-targeted therapeutic design and discusses the combination strategies and molecular profiling tools that will be essential for extending durable benefit across the broader mCRPC population.