Lutetium-177 [177Lu]Lu-PSMA-I&T plus radium-223 in patients with metastatic castration-resistant prostate cancer (AlphaBet): an interim analysis of the investigator-initiated, single-centre, single-arm, phase 1/2 trial
Mené sur 36 patients atteints d'un cancer de la prostate résistant à la castration et présentant des métastases osseuses (âge médian : 72,5 ans ; durée médiane de suivi : 13,3 mois), cet essai de phase I/II détermine la dose maximale tolérée du [177Lu]Lu-PSMA-I&T en combinaison avec du radium 223 (Ra223, un émetteur de particules alpha ciblant les os)
Background: Lutetium-177 [177Lu]Lu-PSMA-I&T (177Lu-PSMA-I&T) and the bone-seeking
α-emitter radium-223 (223Ra) are established life-extending therapies for patients with metastatic castration-resistant prostate cancer; however, resistance and progression are inevitable. We aimed to evaluate the safety and preliminary antitumour activity of 177Lu-PSMA-I&T combined with 223Ra in this patient group.
Methods
:
We conducted an investigator-initiated, single-centre, single-arm, phase 1/2 trial (AlphaBet) at the Peter MacCallum Cancer Centre in Melbourne, Australia. Adults (aged
≥18 years) with a diagnosis of progressive, metastatic castration-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0–2, at least two visible bone metastases not treated with radiotherapy, previous exposure to an androgen receptor pathway inhibitor, prostate-specific membrane antigen (PSMA)-positive disease (defined by maximum standardised uptake value ≥20 at a site of disease), and no discordant sites (ie, avid on 2-[18F]fluoro-2-deoxy-D-glucose-PET–CT with minimal PSMA expression and no uptake on bone scintigraphy) were eligible for inclusion. Phase 1 dose-escalation assessed two dose levels of 223Ra (27·5 kBq/kg and 55·0 kBq/kg) combined with 7·4 GBq 177Lu-PSMA-I&T, administered intravenously every 6 weeks for up to six cycles. Phase 2 dose expansion continued with the recommended phase 2 dose. Co-primary endpoints were the maximum tolerated or administered dose and the recommended phase 2 dose (phase 1), and the PSA response rate (phase 2), analysed in all patients treated at the maximum tolerated or administered dose in either phase. Safety was assessed in all patients who received at least one dose of either protocol treatment in phase 1 or 2. Herein, we report the results of an interim analysis, which was added to the protocol following an amendment on May 30, 2024. This trial is registered at ClinicalTrials.gov (NCT05383079) and follow-up is ongoing.
Findings: Between Nov 3, 2022, and Nov 5, 2024, 37 patients were enrolled, of whom 36 (97%; median age 72·5 years [IQR 67·0–78·0]) were included in the safety analysis and 33 (89%) were included in the preliminary activity analysis. No dose-limiting toxicities were observed. The recommended phase 2 dose of 223Ra was 55·0 KBq/kg combined with 7·4 GBq 177Lu-PSMA-I&T, administered every 6 weeks. With a median follow-up of 13·3 months (IQR 8·7–17·1), 11 (31%) patients completed all six cycles of both treatments. 18 (50%) patients discontinued treatment early, primarily due to unequivocal disease progression (11 [61%]) or adverse events (three [17%]). A reduction in PSA of at least 50% was observed in 18 (55%; 95% CI 36–72) patients. Grade 3 or higher treatment-related adverse events occurred in five (14%) of 36 patients, including anaemia (four [11%]) and neutropenia (three [8%]), with no treatment-related deaths. Non-clinically significant grade 3 lymphopenia occurred in ten (28%) patients.
Interpretation: The combination of 177Lu-PSMA-I&T and 223Ra 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.
The Lancet Oncology , résumé, 2025