MEDI3726

Several next-generation ADC programmes, including PSMA- and B7-H3-directed agents such as MEDI3726 and DS-7300, have reported early antitumour activity signals. At the same time, the global development landscape remains fragmented across targets, payload classes, endpoints, and sponsor types. This study therefore aimed to map the contemporary landscape of ADC clinical trials for prostatic neoplasms, clarify current development patterns, identify translational opportunities and gaps, and provide an integrated overview to support future clinical development.

Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 (dual PSMA/STEAP1-targeted), and DXC008 (dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, the B7-H3-targeted ADC ifinatamab deruxtecan has initiated an international multicenter phase Ⅲ clinical trial (NCT06925737) for mCRPC in May 2025. This review summarizes recent advances in ADCs targeting key antigens in mCRPC (including PSMA, B7-H3, STEAP1, TROP2, SLC44A4, and others) and explores combination strategies, offering insights to inform the clinical management of this highly lethal disease.