255AC-J591 Shows Preliminary Efficacy, Safety Among Patients with Metastatic Castration-Resistant Prostate Cancer

According to a phase I trial, a single dose of ²⁵⁵AC-J591 was safe, and showed preliminary efficacy among patients with castration-resistant prostate cancer.

Scott Tagawa, MD, Weilll Cornell Medicine, New York, New York, and coauthors wrote, ²⁵⁵AC-J591 is an “anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.” J591 has been previously evaluated in metastatic castration-resistant prostate cancer therapy. Dr Tagawa et al hypothesized “radiolabeling the PSMA-targeting [monoclonal antibody] J591 with 225Ac would provide good antitumor activity against a broader range of prostate cancer metastases with acceptable tolerability.”

This open-label, phase 1 dose-escalation study enrolled 32 patients with metastatic castration-resistant prostate cancer who had already received treatment with ≥1 androgen receptor pathway inhibitor, and had either previously been treated with taxane chemotherapy, or had refused, or had been deemed ineligible. There was no selection done for PSMA. Patients were treated with a single dose of ²⁵⁵AC-J591 at 1 of 7 predetermined doses level ranging from 13.3 KBq/kg to 93.3 KBq/kg. Dose level was determined based on predicted organ dosimetry from previous experience with ⁸⁹Zr-J591, ¹⁷⁷Lu-J591, and ¹¹¹In-J591. Of all 32 patients, 22 were enrolled in the accelerated dose-escalation design and 10 to the dose expansion cohort.

The primary end point of this study was the percentage of patients who experienced a dose-limiting toxicity, defined as grade ≥3 nonhematologic adverse events attributable to treatment or severe grade 4 hematologic adverse events, within 8 weeks of treatment. Additional end points included determination of the recommended phase 2 dose, PSA response, and radiographic response.

There was 1 patient who experienced a dose-limiting toxicity during escalation, at 80 KBq/kg. There were no patients at the highest dose level who experienced any dose-limiting toxicities. Therefore, 93.3 KBq/kg was determined as the recommended phase 2 dose and was used in the expansion cohort.

PSA declines and circulating tumor cell control were observed with 46.9% of patients experiencing at least 50% PSA decline at any time, and 59.1% experiencing a protocol-defined circulating tumor cell count response. There were 34.4% of patients who had a confirmed PSA response. Of 11 patients with measurable disease at baseline and follow-up imaging results, 2 had partial response, 7 had stable disease, 2 had progression of disease.

Dr Tagawa et al concluded, “this is the first-in-human phase 1 dose-escalation trial of a single dose of ²⁵⁵AC-J591 in 32 patients with pretreated progressive [metastatic castration-resistant prostate cancer] demonstrated safety and preliminary efficacy signals.”

Associate editor for Journal of Clinical Oncology, Michael A Carducci, MD, Johns Hopkins University, Baltimore, Maryland, added, “this early phase study of an alpha-emitting PSMA targeted monoclonal antibody is highly encouraging given its novelty and activity in heavily pretreated metastatic castration-resistant prostate cancer patients, including those with prior lutecium-based therapy.”

Source:

Tagawa S, Thomas C, Sartor AO, et al. Prostate-specific membrane antigen-targeting alpha emitter via antibody delivery for metastatic castration-resistant prostate cancer: A phase I dose-escalation study of ²⁵⁵AC-J591. J Clin Oncol. Published online November 3, 2023. doi:10.1200/JCO.23.00573