AccScience Publishing / ARNM / Online First / DOI: 10.36922/ARNM025110011
Submit to ARNM
Cite this article
8
Download
310
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Identifying lutetium-177 prostate-specific membrane antigen-617 treatment response patterns using a quantitative prostate-specific membrane antigen positron emission tomography/computed tomography traffic light workflow within the LuPIN trial

Sarennya Pathmanandavel1,2* ,  Megan Crumbaker1,2,3,4 ,  Andrew Nguyen1,4 ,  Andrew O. Yam2,3,4,5 ,  Peter Wilson6 ,  Remy Niman6 ,  Maria Ayers1 ,  Shikha Sharma1 ,  Peter Eu7 ,  Andrew J. Martin8 ,  Martin R. Stockler8 ,  Anthony M. Joshua2,3,4,9 ,  Louise Emmett1,3,4,9
Show Less
1 Department of Theranostics and Nuclear Medicine, St Vincent’s Hospital, Sydney, New South Wales, Australia
2 The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, New South Wales, Australia
3 Garvan Institute of Medical Research, Sydney, New South Wales, Australia
4 St. Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia
5 School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
6 MIM Software Inc., Cleveland, Ohio, United States of America
7 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
8 NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
9 Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
ARNM, 025110011 https://doi.org/10.36922/ARNM025110011
Received: 14 March 2025 | Revised: 8 July 2025 | Accepted: 22 July 2025 | Published online: 5 August 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
XML
Cite
Abstract

Lutetium-177 prostate-specific membrane antigen-617 (177Lu-PSMA-617) improves survival in metastatic castration-resistant prostate cancer, but more optimal tools are needed for therapeutic response assessment and early detection of resistance. We evaluated a quantitative imaging workflow using prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography to measure lesional changes following 177Lu-PSMA-617 therapy. Pre- and post-treatment gallium-68-labeled PSMA-11 PET scans from the trial were analyzed using a novel traffic light workflow (TLW), assessing lesion-specific changes in tumor volume and maximum standardized uptake value in men treated with up to six cycles of 177Lu-PSMA-617 and a radiation sensitizer (NOX66). Lesions were categorized as “reducing” (≥30% volume decrease), “stable” (<30% change), or “increasing” (≥30% increase or new lesions). Overall response was classified as “responder” (no increasing/new lesions), “low-volume progressor” (<50% of total tumor volume [TTV] increasing/new lesions), or “high-volume progressor” (>50% of TTV increasing/new lesions). TLW response classifications were compared with Response Evaluation Criteria in PSMA PET (RECIP) 1.0 and correlated with overall survival (OS). Among 37 men who underwent pre- and post-treatment PET imaging, 68% (25/37) completed six cycles, 32% (12/37) received 2–5 cycles, and 70% (26/37) had a >50% prostate-specific antigen (PSA) decline. The median PSA progression-free survival (PSA-PFS) was 8.6 months; median OS was 22.0 months. At post-treatment imaging, 54% (20/37) showed progression. TLW classified 24% as “responders,” 41% as “low-volume progressors,” and 35% as “high-volume progressors.” “Responders” had longer OS than “low-volume progressors” (median 17.7 vs. 12.0 months) or “high-volume progressors” (median 7.5 months, p=0.005). RECIP 1.0 classified 24% as partial response, 51% stable disease, and 24% as progressive disease. In summary, TLW shows potential to delineate complex response patterns. Following validation in larger cohorts, TLW will inform therapeutic decision-making.

Graphical abstract
Keywords
Metastatic prostate cancer
Theranostics
Lutetium-prostate-specific membrane antigen
Therapeutic response
Funding
The investigator-initiated study was sponsored by St Vincent’s Hospital and supported by a Cancer Institute NSW prostate translational research grant. Noxopharm Limited provided funding for the drug and PET scans, whereas AAA/Novartis provided the PSMA-617 ligand.
Conflict of interest
Louise Emmett holds an advisory position at Clarity Pharmaceuticals and receives trial support from Novartis and Astellas and grant funding from the St Vincent’s Clinic Foundation. Anthony M. Joshua holds an advisory position at Noxopharm Limited and receives institutional research funding from Novartis. Remy Niman and Peter Wilson are salaried employees of MIM Software Inc. All other authors declare no relevant conflicts of interest.
References
  1. Hofman MS, Emmett L, Sandhu SK, et al. 177Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3

 

  1. Sartor O, De Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi: 10.1056/NEJMoa2107322

 

  1. Hofman MS, Violet J, Hicks RJ, et al. [177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825-833. doi: 10.1016/s1470-2045(18)30198-0

 

  1. Gafita A, Rauscher I, Weber M, et al. Novel framework for treatment response evaluation using PSMA PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP 1.0): An international multicenter study. J Nucl Med. 2022;63:1651-1658. doi: 10.2967/jnumed.121.263072

 

  1. Grubmuller B, Senn D, Kramer G, et al. Response assessment using 68Ga-PSMA ligand PET in patients undergoing 177Lu-PSMA radioligand therapy for metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46(5):1063-1072. doi: 10.1007/s00259-018-4236-4

 

  1. Crumbaker M, Pathmanandavel S, Yam AO, et al. Phase I/II trial of the combination of 177lutetium prostate specific membrane antigen 617 and idronoxil (NOX66) in men with end-stage metastatic castration-resistant prostate cancer (LuPIN). Eur Urol Oncol. 2020;4:963-970. doi: 10.1016/j.euo.2020.07.002

 

  1. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European organization for research and treatment of cancer (EORTC) PET study group. Eur J Cancer. 1999;35(13):1773-1782. doi: 10.1016/S0959-8049(99)00229-4

 

  1. Jansen BHE, Cysouw MCF, Vis AN, et al. Repeatability of quantitative 18F-DCFPyL PET/CT measurements in metastatic prostate cancer. J Nucl Med. 2020;61(9):1320-1325. doi: 10.2967/jnumed.119.236075

 

  1. Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34(12):1402-1418. doi: 10.1200/JCO.2015.64.2702

 

  1. Pathmanandavel S, Crumbaker M, Yam AO, et al. 177Lu-PSMA-617 and idronoxil in men with end-stage metastatic castration-resistant prostate cancer (LuPIN): Patient outcomes and predictors of treatment response in a phase I/II trial. J Nucl Med. 2022;63(4):560-566. doi: 10.2967/jnumed.121.262552

 

  1. Fanti S, Goffin K, Hadaschik BA, et al. Consensus statements on PSMA PET/CT response assessment criteria in prostate cancer. Eur J Nucl Med Mol Imaging. 2020;48:469-476. doi: 10.1007/s00259-020-04934-4

 

  1. Pollard JH, Raman C, Zakharia Y, et al. Quantitative test-retest measurement of 68Ga-PSMA-HBED-CC in tumor and normal tissue. J Nucl Med. 2020;61(8):1145-1152. doi: 10.2967/jnumed.119.236083

 

  1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi: 10.1016/j.ejca.2008.10.026

 

  1. De Wreede LC, Fiocco M, Putter H. Mstate: An R package for the analysis of competing risks and multi-state models. J Stat Softw. 2011;38(7):1-30. doi: 10.18637/jss.v038.i07

 

  1. Stoffel MA, Nakagawa S, Schielzeth H, Goslee S. Rptr: Repeatability estimation and variance decomposition by generalized linear mixed‐effects models. Methods Ecol Evol. 2017;8(11):1639-1644. doi: 10.1111/2041-210x.12797

 

  1. Team RC. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Avaialble from: https://www.r-project.org [Last accessed on 2023 Oct 17].

 

  1. Pathmanandavel S, Crumbaker M, Nguyen A, et al. The prognostic value of posttreatment 68Ga-PSMA-11 PET/ CT and 18F-FDG PET/CT in metastatic castration-resistant prostate cancer treated with 177Lu-PSMA-617 and NOX66 in a phase I/II trial (LuPIN). J Nucl Med. 2022;64:69-74. doi: 10.2967/jnumed.122.264104

 

  1. Andrei G, Wolfgang W, Robert T, Matthias E. Predictive value of interim PSMA PET during 177Lu-PSMA radioligand therapy for overall survival in patients with advanced prostate cancer. J Nuclear Med. 2019;60(supplement 1):73.

 

  1. Heinzel A, Boghos D, Mottaghy FM, et al. 68Ga-PSMA PET/CT for monitoring response to 177Lu-PSMA-617 radioligand therapy in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46(5):1054-1062. doi: 10.1007/s00259-019-4258-6

 

  1. Gafita A, Calais J, Grogan TR, et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: An international, multicentre, retrospective study. Lancet Oncol. 2021;22:1115-1125. doi: 10.1016/s1470-2045(21)00274-6

 

  1. Kuo PH, Morris MJ, Hesterman J, et al. Quantitative 68Ga-PSMA-11 PET and clinical outcomes in metastatic castration-resistant prostate cancer following 177Lu-PSMA-617 (VISION trial). Radiology. 2024;312(2):e233460. doi: 10.1148/radiol.233460

 

  1. Current K, Meyer C, Magyar CE, et al. Investigating PSMA-targeted radioligand therapy efficacy as a function of cellular PSMA levels and intratumoral PSMA heterogeneity. Clin Cancer Res. 2020;26(12):2946-2955. doi: 10.1158/1078-0432.CCR-19-1485

 

  1. Paschalis A, Sheehan B, Riisnaes R, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur Urol. 2019;76(4):469-478. doi: 10.1016/j.eururo.2019.06.030

 

  1. Beltran H, Hruszkewycz A, Scher HI, et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin Cancer Res. 2019;25(23):6916-6924. doi: 10.1158/1078-0432.CCR-19-1423

 

  1. Matuszczak M, Salagierski M. Oligometastatic disease in prostate cancer. Evolving paradigm: Current knowledge, diagnostic techniques and treatment strategies. Arch Med Sci. 2022. doi: 10.5114/aoms/156170

 

  1. Pepe P, Pepe L, Curduman M, Pennisi M, Fraggetta F. Ductal prostate cancer staging: Role of PSMA PET/CT. Arch Ital Urol Androl. 2024;96(1):12132. doi: 10.4081/aiua.2024.12132

 

  1. Emmett L, Subramaniam S, Crumbaker M, et al. [177Lu] Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024;25(5):563-571. doi: 10.1016/s1470-2045(24)00135-9

 

  1. Feuerecker B, Tauber R, Knorr K, et al. Activity and adverse events of actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of lutetium- 177-PSMA. Eur Urol. 2021;79(3):343-350. doi: 10.1016/j.eururo.2020.11.013

 

  1. Sathekge MM, Bruchertseifer F, Vorster M, Morgenstern A, Lawal IO. Global experience with PSMA-based alpha therapy in prostate cancer. Eur J Nucl Med Mol Imaging. 2021;49(1):30-46. doi: 10.1007/s00259-021-05434-9

 

  1. Sathekge MM, Lawal IO, Bal C, et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): A multicentre, retrospective study. Lancet Oncol. 2024;25(2):175-183. doi: 10.1016/S1470-2045(23)00638-1

 

  1. Sartor O, Ledet E, Huang M, et al. Prediction of resistance to 177Lu-PSMA therapy by assessment of baseline circulating tumor DNA biomarkers. J Nucl Med. 2023;64(11):1721-1725. doi: 10.2967/jnumed.123.266167

 

  1. John N, Pathmanandavel S, Crumbaker M, et al. 177Lu-PSMA SPECT quantitation at 6 weeks (Dose 2) predicts short progression-free survival for patients undergoing 177Lu-PSMA-I&T therapy. J Nucl Med. 2023;64(3):410-415. doi: 10.2967/jnumed.122.264677

 

  1. Neubauer MC, Nicolas GP, Bauman A, et al. Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: Subgroup analysis of a swiss-wide prospective registry study. Eur J Nucl Med Mol Imaging. 2024;51(4):1185-1193. doi: 10.1007/s00259-023-06536-2
Share
Back to top
Advances in Radiotherapy & Nuclear Medicine, Electronic ISSN: 2972-4392 Print ISSN: 3060-8554, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept