Abstract 1159: Preclinical characterization of a novel STEAP1 antibody-drug conjugate ADRX-0405 for the treatment of mCRPC

Abstract Prostate cancer remains a leading cause of mortality in men. Despite significant advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), there remains a need for more durable treatment options with improved quality of life. STEAP1 (Six-Transmembrane Epithelial Antigen of the Prostate 1) is a validated tumor-associated antigen, highly expressed in various solid tumors, including prostate cancer, with restricted expression in normal tissues. Most noteworthy, STEAP1 expression is sustained in metastatic sites and expressed even in PSMA-negative patients, thus potentially providing an opportunity of a targeted therapeutic approach to the majority of patients with mCRPC. ADRX-0405 is a novel STEAP1-targeting antibody-drug conjugate (ADC), consisting of a humanized IgG1 antibody conjugated to a topoisomerase inhibitor via a novel and stable cleavable linker at a drug-to-antibody ratio of 8 (DAR8). ADRX-0405 specifically binds STEAP1, induces H2AX phosphorylation and PARP cleavage in line with its payload mechanism of action, resulting in nanomolar and target-dependent cytotoxicity in tumor cells. In addition, ADRX-0405 exhibits a potent bystander activity, which translates to robust in vivo efficacy in xenograft models of prostate cancer with both high and low target expression. In a mouse clinical trial of patient-derived xenografts with varying STEAP1 expression levels, ADRX-0405 achieved an overall response rate (ORR) of 83%. Detailed PD characterization study of ADRX-0405 confirms its mechanism of action as a DNA topoisomerase inhibitor, inducing apoptosis through increased levels of cleaved caspase-3 and pH2AX. Notably, ADRX-0405 treatment also leads to upregulation of PD-L1 expression as a result of immunogenic cell death. DNA damage inducers such as topoisomerase inhibitors are known to synergize with DNA damage repair inhibitors such as PARP inhibitors. ADRX-0405 exhibited a strong synergistic effect on tumor growth when combined with PARP inhibitors, thus providing a compelling rationale for clinical combination opportunities. A payload distribution study in tumor-bearing mice demonstrated improved delivery of the payload to tumors over normal tissues and plasma driven by its excellent stability and PK profile. Compared to a STEAP1 antibody conjugated to deruxtecan, the estimated safety margin as determined by the ratio of free payload in tumor over normal tissues was improved by 2-3-fold. Consequently, ADRX-0405 was well tolerated in non-human primates repeat-dose toxicology evaluation. Strikingly, no toxicity was detected in the lungs, which is a known safety liability for the topoisomerase inhibitor payload class. In summary, the preclinical efficacy and safety profile of ADRX-0405 strongly supports its clinical evaluation in mCRPC. A phase 1a/b study with ADRX-0405 is initiated. Citation Format: Maria Shahmoradgoli, Andrew M. Hau, Oscar Betancourt, Felipe Acosta, Sam Janssen, Paul Datta, Anna Y. Wang, Peter P. Challita, Kris Zhang, Mario M- Kuo, Albert Goldson, Erin Nye, Alexis Mahloch, Maojun Guo, Alex Chu-Kung, Dong Jun Lee, Hui Li, Sabine Rottmann, Pia M. Challita-Eid. Preclinical characterization of a novel STEAP1 antibody-drug conjugate ADRX-0405 for the treatment of mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1159.