(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. John Shen discussing results from APEX-01, a first-in-human phase 1/2 study of ARX517, an anti-PSMA antibody-drug conjugate, in patients with metastatic castration-resistant prostate cancer (mCRPC). Previous PSMA-targeted antibody drug conjugates demonstrated early clinical efficacy, but drug development was discontinued due to intolerable toxicities, resulting from premature release and off-target delivery of the cytotoxic payload. ARX517 is a novel antibody-drug conjugate composed of a fully humanized anti-PSMA monoclonal antibody conjugated to amberstatin-269, a potent tubulin inhibitor:
ARX517 was designed to reduce off-target antibody-drug conjugate instability-related toxicity issues observed in earlier anti-PSMA antibody-drug conjugates by using site-specific synthetic amino acids and stable oxime conjugation chemistry to minimize premature payload release in the human circulation.
The APEX-01 trial used an i3+3 dose escalation design, with eligible patients having ≥ 2 FDA-approved treatments for mCRPC with progression by Prostate Cancer Working Group criteria:
Key objectives include safety, pharmacokinetic, and clinical efficacy. Baseline PSMA PET expression was not required for eligibility but was evaluated as a biomarker.
As of the data cutoff of September 5, 2023, 65 patients received ARX517 every 3 weeks at escalating doses. Patients had a median of 4 prior lines of therapy, 100% received ≥ 1 androgen pathway inhibitor, 66% received taxane, and 17% received PSMA-targeted radionuclide therapy:
Grade 1/2 treatment-related adverse events were dry mouth (28%), fatigue (20%), and diarrhea (15%). There were 6 (9%) patients that had grade 3 adverse events. No dose limiting toxicities, treatment-related serious adverse events, or ≥ grade 4 adverse events were reported. The following figure shows PSA reductions with increasing ARX517 dose:
Overall, 52% (12/23) of patients experienced ≥50% PSA reduction at putative therapeutic doses (≥ 2.0 mg/kg):
Reductions of ≥ 50% in ctDNA occurred in 81% (17/21) of patients in cohorts 6-8:
RECIST v1.1 target lesion reduction was observed in 56% (5/9) of patients in cohorts 4-8:
Dr. Shen concluded his presentation by discussing results from APEX-01, a first-in-human phase 1/2 study of ARX517 in patients with mCRPC by emphasizing that ARX517 monotherapy achieved a favorable safety profile and demonstrated early efficacy, with deep PSA and ctDNA reductions, and confirmed RECIST v1.1 tumor response in men with mCRPC who progressed on multiple FDA-approved treatments.
Presented by: John Shen, MD, UCLA, Los Angeles, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.