(UroToday.com) At the 2025 PSMA and Beyond annual meeting, Dr. John Lee discussed the landscape surrounding antibody drug development (ADC) in prostate cancer.
His talk started with a history of ADC program in advance prostate cancer, and it’s a disappointing one. Multiple trials with negative results utilizing different agents.
However, he notes there are still compounds which gives him cautious hope. He highlights ongoing trials with two promising agents. ARX-517 with an auristatin payload, showing robust response in phase 1 trial. FOR46 (targeting CD 46), is a fully humanized ADC with MMAE payload. Phase 1 data shows promise.1
Dr. Lee pivots to the work behind understanding WHY have ADCs failed in the past. A notable feature is antigen heterogeneity. PSMA expression appears volatile. He presented data obtained from University of Washington’s rapid autopsy program that showed a significant variation in PSMA expression, whilst STEAP-1 is more consistently presented in tumor cells.2
Moving past the first generation of ADCs, Dr. Lee updates us on innovations in next generation of ADC’s. New targets are being identified with new payloads being mounted. Of particular interest is the advances that allow dual payloads and dual targets (such as PSMA and STEAP 1, of the currently known targets) in order to enhance drug delivery.
He notes preclinical effort to nominate payload duos that may show synergy with work done in his lab showing promise for a variety of combinations.
Similarly, work is also being done to expand the known targets in advanced prostate cancer. All with hope of building an ADC with more varied clinical applications.
Presented by: John Lee, MD, University of California, Los Angeles
Written by: Helen Moon, MD, Hematologist and Oncologist at the Kaiser Permanente Riverside Medical Center, Principal Investigator with the Cancer Clinical Trials Access Program, Southern California Permanente Medical Group, during the 2025 PSMA and Beyond Annual Meeting, Los Angeles, CA, Fri, Mar 28 – Sat, Mar 29, 2025.
References:
- Aggarwal RR, Vuky J, VanderWeele D, Rettig M, Heath EI, Quigley D, Huang J, Chumber A, Cheung A, Foye A, Leung S, Abbey J, Dorr A, Nasoff M, Hunter J, Wang S, Flavell RR, Fong L, Liu B, Small EJ. Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2025 Mar 26:JCO2401989. doi: 10.1200/JCO-24-01989. Epub ahead of print. PMID: 40138611.
- Ajkunic A, Sayar E, Roudier MP, Patel RA, Coleman IM, De Sarkar N, Hanratty B, Adil M, Zhao J, Zaidi S, True LD, Sperger JM, Cheng HH, Yu EY, Montgomery RB, Hawley JE, Ha G, Lee JK, Harmon SA, Corey E, Lang JM, Sawyers CL, Morrissey C, Schweizer MT, Gulati R, Nelson PS, Haffner MC. ASSESSMENT OF CELL SURFACE TARGETS IN METASTATIC PROSTATE CANCER: EXPRESSION LANDSCAPE AND MOLECULAR CORRELATES. Res Sq [Preprint]. 2023 Dec 19:rs.3.rs-3745991. doi: 10.21203/rs.3.rs-3745991/v1. Update in: NPJ Precis Oncol. 2024 May 17;8(1):104. doi: 10.1038/s41698-024-00599-6. PMID: 38196594; PMCID: PMC10775381.