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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

Nature Medicine volume 31, pages 2722–2736 (2025)Cite this article

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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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Fig. 1: Study design and baseline clinical genomic correlates.
Fig. 2: Clinical outcomes by pretreatment ctDNA%.
Fig. 3: Genomic landscape of docetaxel and ARPI-treated mCRPC.
Fig. 4: Clinical outcomes by PTEN, TP53 and AR alteration status.
Fig. 5: Clinical outcomes by AR copy number and DDR defects.
Fig. 6: Resistance alterations.

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Data availability

The hg38 human reference genome was downloaded from UCSC. Germline variant population frequency is available at gnomAD v.3.0 (https://gnomad.broadinstitute.org/). ANZUP is obligated to protect the rights and privacy of trial participants, thereby necessitating restricted access to patient-level clinical and genomic sequencing data. Deidentified participant sequencing and select clinical data will be made available to researchers who are registered with an appropriate institution following publication. Methodologically sound proposals for any purpose will be considered by the trial executive committee who will have the right to review and comment on any draft manuscripts before publication. Proposals should be directed to michael.hofman@petermac.org. To gain access, data requesters will be required to sign a data access agreement. Timeframe for data access will be subject to ANZUP policy and process. Data supporting the findings of this study are available in the article in Supplementary Tables 1–11. Source data are provided with this paper.

Code availability

Our complete ctDNA somatic variant calling pipeline is available on GitHub (https://github.com/annalam/cfdna-wgs-manuscript-code) and is described in detail in a previous publication12. No additional custom software was utilized for any analysis performed herein.

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Acknowledgements

The TheraP trial (ANZUP 1603) is a collaboration between the ANZUP Trials Group, the NHMRC Clinical Trials Centre, University of Sydney and the Australasian Radiopharmaceutical Trials Network (ARTnet) in partnership with the Prostate Cancer Foundation of Australia with support from ANSTO, Endocyte (a Novartis company), Movember, The Distinguished Gentleman’s Ride, It’s a Bloke Thing and CAN4CANCER. ANZUP receives infrastructure support from the Australian government through Cancer Australia (Support for Cancer Clinical Trials Program). This correlative research study was primarily supported by the Prostate Cancer Foundation via a 2023 PCF Challenge Award to A.W.W. Additional funding support was also received from a Terry Fox New Frontiers Program Project Grant and a Canadian Cancer Society Challenge Grant (grant no. 707339). E.M.K. is supported by a Prostate Cancer Foundation Young Investigator Award and an ANZUP Synchrony Fellowship. S.H.T. is supported by a Prostate Cancer Foundation Young Investigator Award and Michael Smith Health Research BC Trainee Award. J.P.B. is supported by a Prostate Cancer Foundation Young Investigator Award and PhD support through an Australian Government Research Training Program Scholarship. A.M.S. was supported by an NHMRC Investigator Fellowship (APP1177837). I.D.D. is supported by an NHMRC Practitioner Fellowship (APP1102604). M.S.H. acknowledges philanthropic and government grant support from the Prostate Cancer Foundation, the Peter MacCallum Foundation and a NHMRC Investigator Grant and Movember. S.S. is supported by the NHMRC and additionally acknowledges grant support from the Prostate Cancer Foundation and the Peter MacCallum Foundation. The NHMRC Clinical Trials Centre was supported by NHMRC Program Grants 1037786 and 1150467. 177Lu was supplied by ANSTO. Endocyte provided PSMA-11 and PSMA-617, and additional funding support. We acknowledge and thank the 200 patients for their participation in the TheraP study; and the principal investigators, coinvestigators, study coordinators, nurses, radiopharmacists and chemists and nuclear medicine technologists at the 11 centers across Australia for their dedication and enthusiasm. We also thank members and staff of the ANZUP Board, Scientific Advisory Committee, Prostate Cancer Subcommittee, Consumer Advisory Panel and Independent Data Safety and Monitoring Committee; NHMRC Clinical Trials Centre; and ARTnet.

Author information

Author notes

  1. These authors contributed equally: Edmond M. Kwan, Sarah W. S. Ng.

  2. These authors jointly supervised this work: Ian D. Davis, Michael S. Hofman, Arun A. Azad, Alexander W. Wyatt.

Authors and Affiliations

  1. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    Edmond M. Kwan, Sarah W. S. Ng, Sofie H. Tolmeijer, Gráinne Donnellan, Cameron Herberts & Alexander W. Wyatt

  2. Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia

    Edmond M. Kwan & Ian D. Davis

  3. Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia

    Edmond M. Kwan

  4. Department of Theranostics and Nuclear Medicine, St Vincent’s Hospital, Sydney, New South Wales, Australia

    Louise Emmett & Andrew Nguyen

  5. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia

    Louise Emmett, Anthony M. Joshua, Megan Crumbaker & Andrew Nguyen

  6. Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Louise Emmett, Anthony M. Joshua & Megan Crumbaker

  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

    Shahneen Sandhu, James P. Buteau, Amir Iravani, Michael S. Hofman, Arun A. Azad, Tim Akhurst, Ramin Alipour, Alexis Beaulieu, Nattakorn Dhiantravan, Mohammad B. Haskali, Grace Kong, Kate Moodie, Declan G. Murphy, Aravind S. Ravi Kumar, Peter Roselt, Javad Saghebi, Sue Ping Thang & John A. Violet

  8. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    Shahneen Sandhu, James P. Buteau, Amir Iravani, Michael S. Hofman, Arun A. Azad, Ramin Alipour, Patricia Banks, Mohammad B. Haskali, Rodney J. Hicks, Grace Kong, Jeremy Lewin, Declan G. Murphy, Javad Saghebi, Lavinia Spain, Ben Tran, Roslyn Wallace & Scott G. Williams

  9. Division of Nuclear Medicine, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA

    Amir Iravani

  10. Fred Hutchinson Cancer Center, Seattle, WA, USA

    Amir Iravani

  11. Department of Medical Oncology, Kinghorn Cancer Centre, Sydney, New South Wales, Australia

    Anthony M. Joshua & Megan Crumbaker

  12. Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia

    Roslyn J. Francis & Terry Hung

  13. Medical School, University of Western Australia, Perth, Western Australia, Australia

    Roslyn J. Francis & Andrew D. Redfern

  14. Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia

    Vinod Subhash, Margaret M. McJannett & Nisha Rana

  15. Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia

    Sze-Ting Lee & Andrew M. Scott

  16. Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia

    Sze-Ting Lee & Andrew M. Scott

  17. School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia

    Sze-Ting Lee & Andrew M. Scott

  18. Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia

    Sze-Ting Lee & Andrew M. Scott

  19. NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia

    Andrew J. Martin, Kate Ford, Ailsa Langford, Izabella Pokorski, Shalini Subramaniam & Sonia Yip

  20. Centre for Clinical Research, University of Queensland, Brisbane, Queensland, Australia

    Andrew J. Martin & Martin R. Stockler

  21. Department of Medical Oncology, Chris O’Brien Lifehouse, Sydney, New South Wales, Australia

    Martin R. Stockler

  22. Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland

    Matti Annala

  23. Cancer Services, Eastern Health, Melbourne, Victoria, Australia

    Ian D. Davis

  24. Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada

    Alexander W. Wyatt

  25. Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia

    Dale L. Bailey, Edward Hsiao, Paul Roach & Geoffrey Schembri

  26. Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

    Louise Campbell, David A. Pattison & Paul Thomas

  27. Liverpool Cancer Therapy Centre, Liverpool Hospital, Sydney, New South Wales, Australia

    Wei Chua

  28. Department of Medical Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia

    Craig Gedye

  29. Department of Medical Oncology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

    Jeffrey C. Goh

  30. Royal North Shore Hospital, Sydney, New South Wales, Australia

    Alex D. Guminski

  31. Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Anis Hamid

  32. Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    Ian D. Kirkwood

  33. Auckland Cancer and Blood Service, Te Whatu Ora Te Toka Tumai, Auckland, New Zealand

    Nicola Lawrence

  34. Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, New South Wales, Australia

    Peter Lin

  35. Department of Nuclear Medicine, Fiona Stanley Hospital, Perth, Western Australia, Australia

    Michael McCarthy & William McDonald

  36. Department of Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia

    Siobhan Ng

  37. Department of Medical Oncology, Monash Health, Melbourne, Victoria, Australia

    David Pook

  38. Monash Health Imaging, Monash Health, Melbourne, Victoria, Australia

    Shakher Ramdave

  39. Department of Medical Oncology, Fiona Stanley Hospital, Perth, Western Australia, Australia

    Andrew D. Redfern

  40. Department of Nuclear Medicine, Hunter New England Health, Newcastle, New South Wales, Australia

    Natalie K. Rutherford

  41. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    Thean Hsiang Tan

  42. Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, Victoria, Australia

    Andrew Weickhardt

  43. Macquarie University Hospital, Sydney, New South Wales, Australia

    Alison Y. Zhang

Authors
  1. Edmond M. Kwan
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  2. Sarah W. S. Ng
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  3. Sofie H. Tolmeijer
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  4. Louise Emmett
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  5. Shahneen Sandhu
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  6. James P. Buteau
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  7. Amir Iravani
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  8. Anthony M. Joshua
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  9. Roslyn J. Francis
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  10. Vinod Subhash
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  11. Sze-Ting Lee
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  12. Andrew M. Scott
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  13. Andrew J. Martin
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  14. Martin R. Stockler
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  15. Gráinne Donnellan
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  16. Matti Annala
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  17. Cameron Herberts
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  18. Ian D. Davis
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  19. Michael S. Hofman
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  20. Arun A. Azad
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  21. Alexander W. Wyatt
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Consortia

on behalf of the TheraP Investigators and the ANZUP Cancer Trials Group

  • Edmond M. Kwan
  • , Louise Emmett
  • , Shahneen Sandhu
  • , James P. Buteau
  • , Amir Iravani
  • , Anthony M. Joshua
  • , Roslyn J. Francis
  • , Vinod Subhash
  • , Sze-Ting Lee
  • , Andrew M. Scott
  • , Andrew J. Martin
  • , Martin R. Stockler
  • , Ian D. Davis
  • , Michael S. Hofman
  • , Arun A. Azad
  • , Alexander W. Wyatt
  • , 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

Contributions

Conceptualization: E.M.K., L.E., A.J.M., I.D.D., M.S.H., A.A.A. and A.W.W. Methodology: E.M.K., S.W.S.N., S.H.T., M.A., C.H. and A.W.W. Software: E.M.K., S.W.S.N., S.H.T., M.A., C.H. and A.W.W. Validation: E.M.K., S.W.S.N., S.H.T., C.H. and A.W.W. Formal analysis: E.M.K., S.W.S.N., S.H.T., M.A., C.H. and A.W.W. Investigation: E.M.K., S.W.S.N., S.H.T., G.D., C.H. and A.W.W. Resources: M.A., I.D.D., M.S.H., A.A.A. and A.W.W. Data curation: E.M.K., S.W.S.N., S.H.T., S.S., G.D., C.H. and A.W.W. Writing—original draft: E.M.K., S.W.S.N., S.H.T., C.H. and A.W.W. Writing—review and editing: E.M.K., S.W.S.N., S.H.T., L.E., S.S., J.P.B., A.I., A.M.J., R.J.F., V.S., S.-T.L., A.M.S., A.J.M., M.R.S., M.A., C.H., I.D.D., M.S.H., A.A.A. and A.W.W. Visualization: E.M.K., S.W.S.N., S.H.T., C.H. and A.W.W. Supervision: I.D.D., M.S.H., A.A.A. and A.W.W. Project administration: E.M.K. V.S., I.D.D., M.S.H., A.A.A. and A.W.W. Funding acquisition: I.D.D., M.S.H., A.A.A. and A.W.W.

Corresponding authors

Correspondence to Ian D. Davis, Michael S. Hofman, Arun A. Azad or Alexander W. Wyatt.

Ethics declarations

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.

Peer review

Peer review information

Nature Medicine thanks David Miyamoto, Oliver Sartor and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 CONSORT diagram for sequencing and enrolment.

CONSORT diagram of participant and sample flow culminating in the formation of the biomarker participant population.

Extended Data Fig. 2 ctDNA% versus baseline PET imaging variables.

Correlation between ctDNA% and four quantitative PET imaging variables. Spearman’s rho (two-sided) is reported for each comparison, with p-values adjusted using Bonferroni correction (α = 0.05, m = 3; correcting for three pairwise comparisons within each imaging modality). A grey line represents the linear regression to illustrate the bivariate relationships. FDG, 2-[18F]fluoro-2-deoxy-D-glucose; MTV, metabolic tumour volume; PSMA, prostate-specific membrane antigen; SUV, standardised uptake value.

Extended Data Fig. 3 PTEN, TP53, and BRCA2 structural variants.

Examples of structural variants and associated focal copy number alterations in (a) PTEN, (b) TP53, and (c) BRCA2. SNP, single nucleotide polymorphism.

Extended Data Fig. 4 Relationship between ctDNA% and molecular imaging variables by PTEN and TP53 status.

Correlation between ctDNA% and two quantitative PET imaging variables (PSMA SUVmean - top, FDG MTV - bottom), stratified by genomic alteration status (PTEN - left, TP53 - right).

Extended Data Fig. 5 PFS and OS by TP53 and PTEN alteration status in all-comers.

Kaplan-Meier estimates of progression-free survival and overall survival stratified by (a) TP53 alteration status and (b) PTEN alteration status. Each survival curve includes estimates for three-levels: ctDNA <2%, intact status, and altered status. In-set summary bar plots in the progression-free survival curves represent the proportion of patients that experienced a PSA50 and PSA90 response. An alteration is defined as any mutation(s) or structural variant(s), deep deletion, or expected null gene status. Monoallelic deletions in isolation were not considered altered. In-set tables show univariable hazard ratios from a Cox proportional hazards model. CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival; NR, not reached; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; Ref, reference.

Extended Data Fig. 6 PFS and OS by AR alteration status in all-comers.

Kaplan-Meier estimates of progression-free survival and overall survival stratified by (a) AR gain (defined as ≥4 absolute AR copies) status, (b) presence of AR LBD GSRs, and (c) AR LBD mutation status. Each survival curve includes estimates for three-levels: ctDNA <2%, intact status, and altered status. In-set summary bar plots in the progression-free survival curves represent the proportion of patients that experienced a PSA50 and PSA90 response. In-set tables show univariable hazard ratios from a Cox proportional hazards model. CI, confidence interval; HR, hazard ratio; GSR, gene structural rearrangement; LBD, ligand binding domain; mPFS, median progression-free survival; NR, not reached; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; Ref, reference.

Extended Data Fig. 7 Clinical outcomes by baseline clinical variables in all-comers.

Forest plots show post-hoc sensitivity analyses for (a) PSA50 response, (b) progression-free survival, and (c) overall survival endpoints according to baseline clinical variables. The ‘All patients’ category includes those in the all-comers biomarker population (n = 178). ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group performance status; FDG, 2-[18F]fluoro-2-deoxy-D-glucose; HR, hazard ratio; MTV, metabolic tumour volume; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; Ref, reference; SUV, standardised uptake value.

Extended Data Fig. 8 PSA response by DDR alterations.

Best PSA response in the four most commonly altered DNA damage repair-related gene categories: ATM, BRCA1/2, CDK12, and mismatch repair. PSA response for each gene category is expressed at a per-treatment arm level, and further stratified by either (a) PSMA SUVmean (<10 and ≥10) or (b) ctDNA% level (medium [2–30%] and high [>30%]). MMR, mismatch repair; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; SUV, standardised uptake value.

Extended Data Fig. 9 Copy number status in tumour suppressor genes across consecutive samples.

Correlation of the copy number status of tumour suppressor genes TP53, PTEN and RB1 between consecutive ctDNA samples from the same patient. Each dot represents a consecutive sample pair (baseline and progression). Pearson’s correlation coefficient (two-sided) is reported for each comparison.

Source data

Supplementary information

Supplementary Information

Consortia authorship, collaborators, list of key sponsors and personnel, and supplementary tables.

Reporting Summary

Supplementary Tables

List of all mutations and copy number alterations.

Source data

Source Data Fig. 3

Statistical source data (genomics).

Source Data Fig. 6

Statistical source data (genomics).

Source Data Extended Data Fig. 9

Statistical source data (genomics).

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Kwan, E.M., Ng, S.W.S., Tolmeijer, S.H. et al. Lutetium-177–PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial. Nat Med 31, 2722–2736 (2025). https://doi.org/10.1038/s41591-025-03704-9

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