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.

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John Shen, MD, discusses the utility of ARX517 in patients with metastatic castration-resistant prostate cancer.

John Shen, MD, medical oncologist, University of California Los Angeles Health Encino Cancer Care, discusses unique features associated with the use of the prostate-specific membrane antigen (PSMA)–directed antibody-drug conjugate (ADC) ARX517 in patients with metastatic castration-resistant prostate cancer (mCRPC) and highlights early efficacy and safety findings with this agent.

The ongoing, first-in-human phase 1/2 APEX-01 trial (NCT04662580) is investigating the safety and preliminary efficacy of ARX517 monotherapy in PSMA-unselected patients with mCRPC whose disease has progressed on at least two prior lines of FDA-approved treatments, with at least one being a second-generation androgen receptor pathway inhibitor, and who have met at least one of the following three criteria: PSA progression defined by a minimum of 2 rising PSA values, radiographic progression by RECIST v1.1 criteria, and/or disease progression by the presence of new bone lesions.

Across all 8 cohorts in APEX-01 (n = 65), grade 3 treatment-related adverse effects (TRAEs) were observed in 6 patients. These TRAEs included lymphocyte count decrease (n = 3), transient platelet count decrease (n = 2), and asymptomatic left ventricular dysfunction (n = 1). No treatment-related grade 3 or higher serious adverse effects occurred.

The tolerability of ARX517 is largely due to the ADC’s stable conjugation, Shen says. Previous research efforts targeting PSMA using other ADCs have been limited, and those ADCs did not progress further in clinical development because of their associated toxicities, Shen notes. Notably, the early findings from the APEX-01 trial show no such toxicity concerns associated with ARX517. Dose-escalation portions of this trial are ongoing to glean additional data regarding the safety profile of this agent, Shen explains.

Additionally, across all patients who received at least 2.0 mg/kg of the study drug, 61% achieved a prostate-specific antigen (PSA) response of 30% or greater, 52% achieved a PSA response of 50% or greater, and 26% achieved a PSA response of 90% or greater.

Although the PSA reductions of more than 50% and more than 90% are encouraging, investigators aim to determine the duration of these responses, particularly in heavily pretreated patients, according to Shen. The trial recently enrolled an additional 40 patients, and the data with these patients will be presented in the future, Shen concludes.

John Shen, MD, discusses unique features associated with the use of the prostate-specific membrane antigen–directed antibody-drug conjugate ARX517 in patients with metastatic castration-resistant prostate cancer and highlights early efficacy and safety findings with this agent.

John Shen, MD

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