Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Nov;26(11):1479-1488.
doi: 10.1016/S1470-2045(25)00559-5. Epub 2025 Oct 18.

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

Louise Kostos  1 , James P Buteau  2 , Jing Xie  3 , Anthony Cardin  2 , Tim Akhurst  4 , Ramin Alipour  2 , Lewis Au  1 , Joanna Chan  5 , Kwang Y Chin  6 , Brittany Emmerson  7 , Luc Furic  8 , Quinn Garcia  9 , Anthony J Hamilton  1 , Mohammad B Haskali  10 , Price A Jackson  2 , Raghava K Kashyap  2 , Grace Kong  2 , Lisa MacFarlane  2 , Declan G Murphy  11 , Belinda S Parker  12 , Aravind S Ravi Kumar  2 , Javad Saghebi  2 , Yang Wang  1 , Ben Tran  1 , Arun A Azad  1 , Michael S Hofman  13
Affiliations
Clinical Trial

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

Louise Kostos et al. Lancet Oncol. 2025 Nov.

Abstract

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.

Funding: Prostate Cancer Foundation, Bayer, and National Health and Medical Research Council.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests LK reports PhD support through an Australian Government Research Training Program Scholarship; receipt of honoraria for speaker duties from AstraZeneca, Bayer, and Astellas; and receipt of fees from Bayer for participation in an advisory board. JPB reports support from a Prostate Cancer Foundation Young Investigator Award and PhD support through an Australian Government Research Training Program Scholarship. LA has received speaker fees from Bristol-Myers Squibb, MSD, Eisai, AstraZeneca, and Ipsen; travel support from Roche Genentech; consulting fees from Eisai; and honoraria for participation in advisory boards from Bristol-Myers Squibb and MSD. LA is also supported by the Peter MacCallum Cancer Foundation Discovery Partner Fellowship. JC has received honoraria from Bristol-Myers Squibb. BE has received honoraria from University of Western Ontario; and financial support from the Australasian Association of Nuclear Medicine Specialists. DGM has received personal fees for consulting activities from Astellas, Bayer, Johnson & Johnson, Mundipharma, Cipla, Device Technologies, and Novartis. BT reports receipt of institutional research support from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Genentech, Ipsen, Janssen, MSD, Pfizer, and Movember; consulting fees or having served on an advisory board for Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, IQVIA, Janssen, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Tolmar; and receipt of honorarium from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Tolmar. AAA reports consulting or serving in an advisory role for Astellas Pharma, Novartis, Janssen, Sanofi, AstraZeneca, Pfizer, Bristol-Myers Squibb, Tolmar, Telix Pharmaceuticals, MSD, Bayer, Ipsen, Merck Serono, Amgen, Noxopharma, Aculeus Therapeutics, and Daiichi Sankyo; participating in a speakers bureau for Astellas Pharma, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol-Myers Squibb, and Merck Serono; receipt of travel funding from Astellas Pharma, Sanofi, Merck Serono, Amgen, Janssen, Tolmar, Pfizer, Bayer, and Hinova Pharmaceuticals; receipt of honoraria from Janssen, Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol-Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, MSD, Noxopharm, Aculeus Therapeutics, and Daiichi Sankyo; and receipt of institutional research funding from Astellas Pharma, Merck Serono, Novartis, Pfizer, Bristol-Myers Squibb, Sanofi, AstraZeneca, GlaxoSmithKline, Aptevo Therapeutics, MedImmune, Bionomics, Synthorx, Astellas Pharma, Ipsen, Merck Serono, Lilly, Gilead Sciences, Exelixis, MSD, and Hinova Pharmaceuticals. MSH reports receipt of research support or advisory board consulting fees to Peter MacCallum Cancer Centre from AdvanCell, Australia Nuclear Science and Technology Organisation, Bayer, Isotopia, and Novartis; and personal consulting fees for lectures or participation in advisory boards from Janssen, MSD, and Sanofi. All other authors declare no competing interests.

Publication types

MeSH terms

Associated data