vobramitamab duocarmazine (MGC018)

P1, N=31, Completed, MacroGenics | Active, not recruiting --> Completed

Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC. B7-H3, PSMA, and STEAP1 targeted ADC therapies combining genotoxic payloads with Bcl-xL inhibitors induce p53-dependant apoptotic cell death in mCRPC, providing a clinically viable strategy for the treatment of advanced prostate cancer.

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.

P1, N=32, Active, not recruiting, MacroGenics | N=278 --> 32

P2, N=9, Active, not recruiting, Georgetown University | N=17 --> 9 | Recruiting --> Active, not recruiting

P1, N=278, Active, not recruiting, MacroGenics | Trial completion date: Jun 2025 --> Oct 2025 | Trial primary completion date: Apr 2025 --> Jul 2025

P2, N=192, Completed, MacroGenics | Active, not recruiting --> Completed

P1, N=278, Active, not recruiting, MacroGenics | Recruiting --> Active, not recruiting | Trial completion date: Mar 2026 --> Jun 2025

P2, N=192, Active, not recruiting, MacroGenics | Trial primary completion date: Feb 2025 --> Jul 2024

P2, N=192, Active, not recruiting, MacroGenics | N=382 --> 192 | Trial completion date: May 2027 --> Feb 2025 | Trial primary completion date: May 2027 --> Feb 2025

P2, N=17, Recruiting, Georgetown University | Not yet recruiting --> Recruiting

P2, N=382, Active, not recruiting, MacroGenics | N=100 --> 382 | Trial completion date: Dec 2026 --> May 2027 | Trial primary completion date: Dec 2026 --> May 2027