Antibody-drug conjugates(ADCs) are promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer(mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, conferred sensitivity and were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive(ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 wild-type ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 non-expressors governed response. Importantly, wild-type TP53 predicted non-responsiveness (7/8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.
The Journal of clinical investigation. 2023 Sep 19 [Epub ahead of print]
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T Ku, Aian Neil Alilin, Eva Corey, Martine P Roudier, Lawrence D True, Ruth F Dumpit, Ilsa Coleman, John K Lee, Peter S Nelson, Brian J Capaldo, Aida Mariani, Clare E Hoover, Ilya S Senatorov, Michael Beshiri, Adam G Sowalsky, Elaine M Hurt, Kathleen Kelly
Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, NCI, NIH, Bethesda, United States of America., Center for Cancer Research, NCI, NIH, Bethesda, United States of America., Department of Urology, University of Washington, Seattle, United States of America., University of Washington, Seattle, United States of America., Division of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, United States of America., AstraZeneca, AstraZeneca, Gaithersburg, United States of America.