Dr Shen on the Utility of ARX517 in mCRPC

John Shen, MD, medical oncologist, University of California Los Angeles Health Encino Cancer Care, discusses the utility of the prostate-specific membrane antigen (PSMA)–directed antibody-drug conjugate (ADC) ARX517 in patients with metastatic castration-resistant prostate cancer (mCRPC), highlighting early outcomes with this agent.

ARX517 is an ADC designed to target PSMA, Shen begins. The phase 1/2 APEX-01 trial (NCT04662580) marked the initiation of the first-in-human study evaluating ARX517 in patients with refractory mCRPC, he explains. Early data from this trial demonstrated both the efficacy and safety of ARX517 in a patient population that had undergone extensive prior treatments, Shen explains. Notably, substantial reductions in prostate-specific antigen (PSA) levels were observed with increasing doses of ARX517, even in patients who had previously received PSMA-targeted radionuclide therapies, he notes. 

This study highlights that at putative therapeutic doses of 2 mg/kg or higher, 52% of patients achieved a PSA reduction of 50%, he expands. These early efficacy results, particularly in terms of PSA reduction, are promising, Shen elucidates.

A key finding emphasized across this study and others evaluating ARX517 is the stable conjugation of the ADC, indicating minimal free-floating payload, according to Shen. This characteristic of ARX517 contrasts with earlier versions of PSMA-targeting ADCs, which exhibited a less favorable toxicity profile, he continues. ARX517 demonstrates a cleaner toxicity profile, marking a significant advancement in this class of drugs, Shen concludes.

ARX517 aims to resolve the stability issues associated with other PSMA-targeted ADCs. These issues often result in severe toxicities caused by the premature release and unintended delivery of the cytotoxic payload. To enhance stability, the developers of ARX517 integrated several features into the drug, including a non-cell permeable payload, a noncleavable PEG linker, and a unique oxime conjugation chemistry facilitated by a genetically encoded and biosynthetically integrated synthetic amino acid. Notably, in July 2023, the FDA granted fast track designation to ARX517 for the treatment of patients with mCRPC who have experienced disease progression on an androgen receptor pathway inhibitor.