Prostate Cancer, Part 2: PSMA and Beyond

Prostate-specific membrane antigen (PSMA) has fundamentally reshaped prostate cancer imaging and therapy, delivering an unprecedented combination of high lesion conspicuity, broad clinical applicability, and direct theranostic linkage between molecular imaging and radionuclide treatment. Building on the broader non-PSMA radioligand landscape reviewed in part 1, this companion article focuses on PSMA biology, the mechanistic basis for PSMA radiopharmaceutical performance, and emerging molecular strategies that address heterogeneity, treatment resistance, and access constraints. This article summarizes contemporary PSMA PET agents and PSMA-directed radioligand therapy, highlighting how chelator chemistry, linker design, and accessory binding sites influence pharmacokinetics, affinity, internalization, and suitability for imaging versus therapy. β-emitting therapy with ¹⁷⁷Lu-PSMA-617 is supported by high-level evidence and regulatory approvals, demonstrating improved progression-free and overall survival in metastatic castration-resistant prostate cancer. In parallel, α-emitting strategies such as ²²⁵Ac-PSMA exploit high linear energy transfer and short path length to treat micrometastatic and radioresistant disease, including post-β-therapy progression, but are constrained by toxicity risk, daughter redistribution, complex dosimetry, and limited radionuclide supply. Emerging radionuclides and ligand-engineering approaches are discussed as routes to improve tumor retention, enable true theranostic pairing, and expand global feasibility. The next wave of strategies that broaden molecular coverage beyond PSMA alone, including gastrin-releasing peptide receptor- and fibroblast activation protein-targeted agents and dual-target heterodimers, designed to address inter- and intrapatient heterogeneity and PSMA-insufficient disease, are also outlined. These advances shift prostate cancer theranostics from a single-target paradigm toward a more nuanced ecosystem requiring rational selection, sequencing, and personalization of radioligand choice across the disease continuum.