In an interim analysis of an Australian single-center phase I/II trial (AlphaBet) reported in The Lancet Oncology, Kostos et al found that the combination of lutetium Lu-177–labeled PSMA–I&T (LuPSMA-I&T) and the bone-seeking alpha-emitter radium Ra-223 dichloride (Ra-223) was active in patients with metastatic castration-resistant prostate cancer with bone metastasis.
Study Details
In the investigator-initiated study, 37 patients were enrolled at Peter MacCallum Cancer Centre, Melbourne, between November 2022 and November 2024; 36 were included in the safety analysis and 33 were in the preliminary activity analysis. No dose-limiting toxicities were observed in phase I. In the phase II extension, patients received Ra-223 at 55.0 kBq/kg (selected phase II dose) plus LuPSMA-I&T at 7.4 GBq every 6 weeks for up to six cycles. Prostate-specific antigen (PSA) response was a primary outcome measure.
Key Findings
With a median follow-up of 13.3 months (interquartile range = 8.7–17.1 months), 11 patients (31%) completed all six cycles of both treatments. A total of 18 (50%) discontinued treatment early, with causes including disease progression in 11 and adverse events in 3.
Reduction in PSA of at least 50% was observed in 18 patients (55%, 95% confidence interval [CI] = 36%–72%). Reduction of at least 90% was observed in 6 (18%, 95% CI = 7%–35%).
Among 10 patients with measurable disease per RECIST, 5 (50%) had an objective response, including complete response in 2. In a post hoc analysis of best response using Prostate Cancer Clinical Trials Working Group 3 criteria, 27 patients (82%) exhibited no bone progression.
Median PSA progression-free survival was 5.3 months (95% CI = 4.0–9.0 months), median radiographic progression-free survival was 10.0 months (95% CI = 6.7–13.5 months).
Grade 3 or higher treatment-related adverse events occurred in 39% of patients, including nonclinically significant grade 3 lymphopenia (28%), anemia (11%), and neutropenia (8%). No treatment-related deaths were reported.
The investigators concluded: “The combination of [LuPSMA-I&T] and [Ra-223] is safe and feasible in patients with metastatic castration-resistant prostate cancer and bone metastases. These findings warrant further evaluation of combined α-emitting and β-emitting approaches.”
Michael S. Hofman, MBBS, of Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Prostate Cancer Foundation, Bayer, and National Health and Medical Research Council. For full disclosures of all study authors, visit thelancet.com.
