Clinical Trial

. 2025 Aug;31(8):2722-2736.

doi: 10.1038/s41591-025-03704-9. Epub 2025 May 27.

Lutetium-177-PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial

Edmond M Kwan^#^{1

2

3}, Sarah W S Ng^#¹, Sofie H Tolmeijer¹, Louise Emmett^{4

5

6}, Shahneen Sandhu^{7

8}, James P Buteau^{7

8}, Amir Iravani^{7

8

9

10}, Anthony M Joshua^{5

6

11}, Roslyn J Francis^{12

13}, Vinod Subhash¹⁴, Sze-Ting Lee^{15

16

17

18}, Andrew M Scott^{15

16

17

18}, Andrew J Martin^{19

20}, Martin R Stockler^{20

21}, Gráinne Donnellan¹, Matti Annala²², Cameron Herberts¹, Ian D Davis^{23

24}, Michael S Hofman^{25

26}, Arun A Azad^{27

28}, Alexander W Wyatt^{29

30}; TheraP Investigators and the ANZUP Cancer Trials Group

Collaborators, Affiliations

Collaborators

TheraP Investigators and the ANZUP Cancer Trials Group:
Tim Akhurst, Ramin Alipour, Dale L Bailey, Patricia Banks, Alexis Beaulieu, Louise Campbell, Wei Chua, Megan Crumbaker, Nattakorn Dhiantravan, Kate Ford, Craig Gedye, Jeffrey C Goh, Alex D Guminski, Anis Hamid, Mohammad B Haskali, Rodney J Hicks, Edward Hsiao, Terry Hung, Ian D Kirkwood, Grace Kong, Ailsa Langford, Nicola Lawrence, Jeremy Lewin, Peter Lin, Michael McCarthy, Margaret M McJannett, William McDonald, Kate Moodie, Declan G Murphy, Siobhan Ng, Andrew Nguyen, David A Pattison, David Pook, Izabella Pokorski, Shakher Ramdave, Nisha Rana, Aravind S Ravi Kumar, Andrew D Redfern, Paul Roach, Peter Roselt, Natalie K Rutherford, Javad Saghebi, Geoffrey Schembri, Lavinia Spain, Shalini Subramaniam, Thean Hsiang Tan, Sue Ping Thang, Paul Thomas, Ben Tran, John A Violet, Roslyn Wallace, Andrew Weickhardt, Scott G Williams, Sonia Yip, Alison Y Zhang

Affiliations

¹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
² Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
³ Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
⁴ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia.
⁵ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
⁶ Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
⁷ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
⁹ Division of Nuclear Medicine, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA.
¹⁰ Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹¹ Department of Medical Oncology, Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
¹² Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
¹³ Medical School, University of Western Australia, Perth, Western Australia, Australia.
¹⁴ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.
¹⁵ Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia.
¹⁷ School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
¹⁸ Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
¹⁹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
²⁰ Centre for Clinical Research, University of Queensland, Brisbane, Queensland, Australia.
²¹ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
²² Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.
²³ Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia. ian.davis@monash.edu.
²⁴ Cancer Services, Eastern Health, Melbourne, Victoria, Australia. ian.davis@monash.edu.
²⁵ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. michael.hofman@petermac.org.
²⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. michael.hofman@petermac.org.
²⁷ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. arun.azad@petermac.org.
²⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. arun.azad@petermac.org.
²⁹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. alexander.wyatt@ubc.ca.
³⁰ Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada. alexander.wyatt@ubc.ca.

^# Contributed equally.

PMID: 40425844
DOI: 10.1038/s41591-025-03704-9

Clinical Trial

Lutetium-177-PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial

Edmond M Kwan et al. Nat Med. 2025 Aug.

. 2025 Aug;31(8):2722-2736.

doi: 10.1038/s41591-025-03704-9. Epub 2025 May 27.

Authors

Collaborators

TheraP Investigators and the ANZUP Cancer Trials Group:
Tim Akhurst, Ramin Alipour, Dale L Bailey, Patricia Banks, Alexis Beaulieu, Louise Campbell, Wei Chua, Megan Crumbaker, Nattakorn Dhiantravan, Kate Ford, Craig Gedye, Jeffrey C Goh, Alex D Guminski, Anis Hamid, Mohammad B Haskali, Rodney J Hicks, Edward Hsiao, Terry Hung, Ian D Kirkwood, Grace Kong, Ailsa Langford, Nicola Lawrence, Jeremy Lewin, Peter Lin, Michael McCarthy, Margaret M McJannett, William McDonald, Kate Moodie, Declan G Murphy, Siobhan Ng, Andrew Nguyen, David A Pattison, David Pook, Izabella Pokorski, Shakher Ramdave, Nisha Rana, Aravind S Ravi Kumar, Andrew D Redfern, Paul Roach, Peter Roselt, Natalie K Rutherford, Javad Saghebi, Geoffrey Schembri, Lavinia Spain, Shalini Subramaniam, Thean Hsiang Tan, Sue Ping Thang, Paul Thomas, Ben Tran, John A Violet, Roslyn Wallace, Andrew Weickhardt, Scott G Williams, Sonia Yip, Alison Y Zhang

Affiliations

¹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
² Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
³ Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
⁴ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia.
⁵ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
⁶ Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
⁷ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
⁹ Division of Nuclear Medicine, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA.
¹⁰ Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹¹ Department of Medical Oncology, Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
¹² Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
¹³ Medical School, University of Western Australia, Perth, Western Australia, Australia.
¹⁴ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.
¹⁵ Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia.
¹⁷ School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
¹⁸ Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
¹⁹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
²⁰ Centre for Clinical Research, University of Queensland, Brisbane, Queensland, Australia.
²¹ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
²² Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.
²³ Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia. ian.davis@monash.edu.
²⁴ Cancer Services, Eastern Health, Melbourne, Victoria, Australia. ian.davis@monash.edu.
²⁵ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. michael.hofman@petermac.org.
²⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. michael.hofman@petermac.org.
²⁷ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. arun.azad@petermac.org.
²⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. arun.azad@petermac.org.
²⁹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. alexander.wyatt@ubc.ca.
³⁰ Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada. alexander.wyatt@ubc.ca.

^# Contributed equally.

PMID: 40425844
DOI: 10.1038/s41591-025-03704-9

Abstract

The prostate-specific membrane antigen (PSMA)-targeted radioligand [¹⁷⁷Lu]Lu-PSMA-617 is a new standard treatment for metastatic castration-resistant prostate cancer (mCRPC), but predictive genomic biomarkers informing its rational use are unknown. We performed detailed dissection of prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with mCRPC from the randomized TheraP trial of [¹⁷⁷Lu]Lu-PSMA-617 (n = 97) versus cabazitaxel chemotherapy (n = 83). The primary endpoint was PSA50 biochemical response, with secondary endpoints of progression-free survival (PFS) and overall survival (OS). In this post-hoc biomarker analysis, a low pretreatment circulating tumor DNA (ctDNA) fraction predicted a superior biochemical response (100% versus 58%, P = 0.0067) and PFS (median 14.7 versus 6.0 months; hazard ratio 0.12, P = 2.5 × 10^-4) on [¹⁷⁷Lu]Lu-PSMA-617 independent of predictive PSMA-positron emission tomography imaging parameters, although this benefit did not extend to OS. Deleterious PTEN alterations were associated with worse PFS and OS on cabazitaxel, whereas ATM defects were observed in select patients with favorable [¹⁷⁷Lu]Lu-PSMA-617 outcomes. Comparing pretreatment and progression ctDNA revealed population flux but no evidence that alterations in individual mCRPC genes (or FOLH1) are dominant causes of acquired [¹⁷⁷Lu]Lu-PSMA-617 or cabazitaxel resistance. Our results nominate new candidate biomarkers for [¹⁷⁷Lu]Lu-PSMA-617 selection and ultimately expand the mCRPC predictive biomarker repertoire. We anticipate our ctDNA fraction-aware analytical framework will aid future precision management strategies for [¹⁷⁷Lu]Lu-PSMA-617 and other PSMA-targeted therapeutics. ClinicalTrials.gov identifier: NCT03392428 .

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Conflict of interest statement

Competing interests: E.M.K. has consulted or served in an advisory role for Astellas Pharma, Janssen and Ipsen, received travel funding from Astellas Pharma, Pfizer, Ipsen and Roche, received honoraria from Janssen, Ipsen, Astellas Pharma and Research Review, and received research funding from Astellas Pharma (institutional) and AstraZeneca (institutional). L.E. has consulted or served in an advisory role for Noxopharm and Clarity Pharmaceuticals, participated in a speakers’ bureau for Janssen Oncology, Mundipharma and Astellas Pharma, and received research funding from Noxopharm (institutional) and Novartis (institutional). S.S. has consulted or served in an advisory role for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Skyline Diagnostics and AbbVie, received honoraria from Bristol-Myers Squibb (institutional), Merck (institutional), AstraZeneca (institutional) and Janssen (institutional), and received research funding from Amgen (institutional), AstraZeneca (institutional), Merck (institutional), Endocyte/Advanced Accelerator Applications (institutional), Roche/Genentech (institutional), Novartis (institutional), Pfizer (institutional) and Senhwa Biosciences (institutional). A.I. has consulted or served in an advisory role for Novartis, Lantheus, Curium, ITM, Bayer, Boston Scientific, Ambrx/J&J (institutional), and received research funding from NIH (institutional), Novartis (institutional), SNMMI (institutional) and ACR (institutional). A.M.J. has consulted or served in an advisory role for Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Pfizer, Novartis, Merck Serono, Eisai, IDEAYA Biosciences, IQvia, Bayer, Astellas Pharma, Grey Wolf Therapeutics, Medison and Starpharma, has a patent or received royalties with Cancer Therapeutic Methods, owns stock or holds ownership interests in Pricilium Therapeutics and Opthea, and receives research funding from Bristol-Myers Squibb (institutional), Janssen Oncology (institutional), Merck Sharpe & Dohme (institutional), Mayna Pharma (institutional), Roche/Genentech (institutional), Bayer (institutional), Lilly (institutional), Pfizer (institutional), AstraZeneca (institutional) and Corvus Pharmaceuticals (institutional). R.J.F. consulted or served in an advisory role for AIQ Solutions, receives research funding from AIQ Solutions, and has an immediate family member employed by and owns stock in AIQ Solutions. A.M.S. has consulted or served in an advisory role for ImmunOs Therapeutics and Imagion Biosystems, has an institutional patent relating to antibodies to EGFR, HER2, PDGF-CC, FN-14, GM-CSF, EphA3, owns stock or holds ownership interests in Paracrine Therapeutics and Certis Therapeutics, and received research funding from Telix Pharmaceuticals (institutional), Curis (institutional), Isotopen Technologien (institutional), Adalta (institutional), Fusion Pharmaceuticals (institutional), AstraZeneca (institutional), EMD Serono (institutional), Cyclotek (institutional), AVID/Lilly (institutional), Merck (institutional), Humanigen (institutional) and Antengene (institutional). M.R.S. has received research funding from Astellas Pharma (institutional), Bayer (institutional), Medivation (institutional), Pfizer (institutional), AstraZeneca (institutional), Bristol-Myers Squibb (institutional), Roche (institutional), Amgen (institutional), Merck Sharpe & Dohme (institutional), Tilray (institutional), BeiGene (institutional) and Novartis (institutional). M.A. is compensated for a leadership role in Fluivia and owns stock in Fluivia. S.H.T. has received honoraria from Bayer. I.D.D. is the unremunerated chair of ANZUP Cancer Trials Group, and has received research funding from Astellas Pharma (institutional), Pfizer (institutional), Roche/Genentech (institutional), MSD Oncology (institutional), AstraZeneca (institutional), Janssen Oncology (institutional), Eisai (institutional), Bayer (institutional), Amgen (institutional), Bristol-Myers Squibb (institutional), Movember Foundation (institutional), Exelixis (institutional), Ipsen (institutional), Seagen (institutional) and ESSA (institutional). M.S.H. has consulted or served in an advisory role for Janssen, MSD and Novartis, received travel funding from Novartis and Debiopharm Group, and received research funding from Bayer (institutional), Novartis (institutional), Isotopia Molecular Imaging (institutional) and Debiopharm Group (institutional). A.A.A. has consulted or served in an advisory role for Astellas Pharma, Novartis, Janssen, Sanofi, AstraZeneca, Pfizer, Bristol-Myers Squibb, Tolmar, Telix Pharmaceuticals, Merck Sharpe & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharma, Aculeus Therapeutics and Daiichi Sankyo, participated in a speakers’ bureau for Astellas Pharma, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol-Myers Squibb and Merck Serono, received travel funding from Astellas Pharma, Sanofi, Merck Serono, Amgen, Janssen, Tolmar, Pfizer, Bayer and Hinova Pharmaceuticals, received honoraria from Janssen, Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol-Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharpe & Dohme, Noxopharm, Aculeus Therapeutics and Daiichi Sankyo, and received research funding Astellas Pharma (institutional), Merck Serono (institutional), Novartis (institutional), Pfizer (institutional), Bristol-Myers Squibb (institutional), Sanofi (institutional), AstraZeneca (institutional), GlaxoSmithKline (institutional), Aptevo Therapeutics (institutional), MedImmune (institutional), Bionomics (institutional), Synthorx (institutional), Astellas Pharma (institutional), Ipsen (institutional), Merck Serono (institutional), Lilly (institutional), Gilead Sciences (institutional), Exelixis (institutional), MSD (institutional) and Hinova Pharmaceuticals (institutional). A.W.W. has received honoraria from Janssen, Astellas Pharma, AstraZeneca, Merck, Bayer, Pfizer and EMD Serono, and received research funding from Promontory Therapeutics (institutional), ESSA Pharma (institutional) and Tyra Biosciences (institutional). The other authors declare no competing interests.

References

1. Hofman, M. S. et al. [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 397, 797–804 (2021). - PubMed
1. Hofman, M. S. et al. Overall survival with [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 25, 99–107 (2023). - PubMed
1. Sartor, O. et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 385, 1091–1103 (2021). - PubMed - PMC
1. Gafita, A. et al. Predictors and real-world use of prostate-specific radioligand therapy: PSMA and beyond. Am. Soc. Clin. Oncol. Educ. Book 42, 1–17 (2022). - PubMed
1. Buteau, J. P. et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 23, 1389–1397 (2022). - PubMed

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Lutetium-177-PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial

Collaborators

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Lutetium-177-PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial

Authors

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Abstract

Conflict of interest statement

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