Emerging Evidence for Sequencing and Combining PSMA-Based Therapies in Prostate Cancer - Beyond the Abstract
Our review synthesises recent evidence across the expanding PSMA-targeted therapeutic portfolio, including radioligand therapies, antibody–drug conjugates (ADCs), bispecific T-cell engagers, and CAR-T approaches, and explores how these modalities may be optimally integrated into clinical pathways. Notably, PSMA expression is dynamic and influenced by disease biology, tumour heterogeneity, and prior systemic therapies, suggesting that purposeful sequencing, such as introducing RLT earlier in the disease course or pairing it with agents that upregulate PSMA expression, may enhance therapeutic efficacy.
Beyond sequencing, combination strategies incorporating androgen-receptor–targeted agents, PARP inhibitors, CDK4/6 inhibitors, immunotherapy, docetaxel, or stereotactic radiotherapy are gaining momentum, with early-phase data indicating encouraging safety and biological activity; however, a definitive survival benefit remains to be demonstrated. These innovations are now extending beyond metastatic castration-resistant disease into high-risk localised, oligometastatic, and metastatic hormone-sensitive settings, raising new considerations around patient selection, long-term toxicity, re-challenge opportunities, and the economic and logistical feasibility of broader implementation.
As the field advances, collaborative trial designs, robust biomarkers, and standardised PSMA-PET metrics will be essential. Ultimately, the PSMA landscape is evolving from isolated single-agent therapies to a more integrated, biologically informed treatment framework—one that holds significant promise, provided it is guided by careful multidisciplinary collaboration and thoughtful translation into clinical practice.
Written by: Sola Adeleke, School of Biomedical Engineering and Imaging Sciences (BMEIS), King's College London, London, UK
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