Dr. Tagawa on the Evolution of ADCs in mCRPC

Scott Tagawa, MD, MS, FACP, professor, medicine and urology, medical director, Genitourinary Oncology Research Program, Weill Cornell Medical College, attending physician, New York Presbyterian Hospital, discusses the evolution of antibody-drug conjugates (ADCs) in metastatic castration-resistant prostate cancer (mCRPC), as well as potential future targets for ADC development in this space.

One of the first ADCs developed in mCRPC targeted prostate-specific membrane antigen (PMSA), Tagawa begins. This ADC failed to gain approval due to heightened toxicity arising from problems with its first-generation linker, Tagawa says. However, PSMA continues to be a focus for drug development efforts, with 2 approved diagnostics validating its viability as a target, he emphasizes. Meanwhile, linker technology and other aspects of ADC design have substantially improved in recent years alongside the identification of actionable targets for drug development, Tagawa says.

Accordingly, the number of approved ADCs may soon increase in prostate cancer, Tagawa continues. Targets currently being investigated include PSMA, the cell surface immunomodulatory glycoprotein B7-H3, and the inhibitory Notch pathway ligand Delta-like 3 (DLL3), he lists. Notably, the DLL3-targeted experimental ADC rovalpituzumab tesirine (SC16LD6.5) has shown efficacy in a phase 1/2 basket study (NCT02709889), although there are some toxicity concerns, Tagawa adds.

Several other markers have been identified as potential targets for future investigation in mCRPC, including the cell membrane protein STEAP1, prostate stem-cell antigen (PSCA), and hk2, Tagawa says.

Importantly, initial administration of therapies targeting these markers, such as small-molecule inhibitors or Lutetium-177 (177Lu)–PSMA-617 (Pluvicto), should not necessarily preclude the administration of ADCs designed against the same target, Tagawa notes. This is because loss of the target is not the main mechanism of drug resistance for most of these agents, he concludes.

Disclosures: Dr Tagawa reports received institutional research support from Sanofi, Medivation, Astellas, Janssen, Amgen, Progenics, Dendreon, Lilly, Genentech, Newlink, BMS, Inovio, AstraZeneca, Immunomedics, Aveo, Rexahn, Atlab, Boehringer Ingelheim, Millennium, Bayer, Merck, Abbvie, Karyopharm, Endocyte, Clovis, Seattle Genetics, Novartis, Gilead, POINT Biopharma, Ambrx; he worked as a paid consultant for Sanofi, Medivation, Astellas, Dendreon, Janssen, Genentech, Bayer, Endocyte, Eisai, Immunomedics, Karyopharm, Abbvie, Tolmar, Seattle Genetics, Amgen, Clovis, QED, Pfizer, AAA/Novartis, Clarity, Genomic Health, POINT Biopharma, Blue Earth, AIkido Pharma, Telix Pharma, Convergent Therapeutics, EMD Serono, Myovant, Merck, Daiichi Sankyo; he was an unpaid consultant for Atlab Pharma, Phosplatin Therapeutics, Amgen, Ambrx; he has a patent filed with Immunomedics / Gilead / Weill Cornell for Biomarkers for sacituzumab govitecan therapy.