Clinical Trial

. 2025 Sep;26(9):1168-1177.

doi: 10.1016/S1470-2045(25)00339-0. Epub 2025 Jul 30.

Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial

Louise Emmett¹, Nathan Papa², Shalini Subramaniam³, Megan Crumbaker⁴, Andrew Nguyen⁵, Anthony M Joshua⁴, Shahneen Sandhu⁶, Andrew Weickhardt⁷, Sze-Ting Lee⁸, Siobhan Ng⁹, Roslyn J Francis¹⁰, Jeffrey C Goh¹¹, David A Pattison¹², Thean Hsiang Tan¹³, Ian D Kirkwood¹⁴, Narjess Ayati¹⁵, Claire Niu¹⁶, Michael S Hofman¹⁷, Andrew James Martin¹⁸, Hayley Thomas¹⁶, Ian D Davis¹⁹, Martin R Stockler²⁰; ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Collaborators, Affiliations

Collaborators

ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group:
Louise Emmett, Nathan Papa, Shalini Subramaniam, Megan Crumbaker, Andrew Nguyen, Anthony M Joshua, Shahneen Sandhu, Andrew Weickhardt, Sze-Ting Lee, Siobhan Ng, Roslyn J Francis, Jeffrey C Goh, David A Pattison, Thean Hsiang Tan, Maddison Bills, Jasmine Brady, Ian D Kirkwood, Narjess Ayati, Claire Niu, Michael S Hofman, Andrew J Martin, Hayley Thomas, Ian D Davis, Martin R Stockler, Nicole Tankard, Samantha Oakes, Alison Y Zhang, Jennifer Thompson, Thida Thein, Thomas Cusick, Shikha Sharma

Affiliations

¹ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia. Electronic address: louise.emmett@svha.org.au.
² Garvan Institute of Medical Research, Sydney, NSW, Australia.
³ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Bankstown-Lidcombe Hospital, Sydney, NSW, Australia.
⁴ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁵ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
⁷ Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
⁸ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
⁹ Department of Oncology, Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia.
¹⁰ Department of Nuclear Medicine, Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia.
¹¹ Department of Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Queensland University of Technology, Brisbane, QLD, Australia.
¹² Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹³ Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁴ Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
¹⁵ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁶ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
¹⁷ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC) and Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; ULTRA The University of Queensland Clinical Trials Capability, Centre for Clinical Research, Brisbane, QLD, Australia; Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.
¹⁹ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia; Monash University Eastern Health Clinical School, Melbourne, Australia; Eastern Health, Melbourne, VIC, Australia.
²⁰ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.

PMID: 40752515
DOI: 10.1016/S1470-2045(25)00339-0

Clinical Trial

Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial

Louise Emmett et al. Lancet Oncol. 2025 Sep.

. 2025 Sep;26(9):1168-1177.

doi: 10.1016/S1470-2045(25)00339-0. Epub 2025 Jul 30.

Authors

Collaborators

ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group:
Louise Emmett, Nathan Papa, Shalini Subramaniam, Megan Crumbaker, Andrew Nguyen, Anthony M Joshua, Shahneen Sandhu, Andrew Weickhardt, Sze-Ting Lee, Siobhan Ng, Roslyn J Francis, Jeffrey C Goh, David A Pattison, Thean Hsiang Tan, Maddison Bills, Jasmine Brady, Ian D Kirkwood, Narjess Ayati, Claire Niu, Michael S Hofman, Andrew J Martin, Hayley Thomas, Ian D Davis, Martin R Stockler, Nicole Tankard, Samantha Oakes, Alison Y Zhang, Jennifer Thompson, Thida Thein, Thomas Cusick, Shikha Sharma

Affiliations

¹ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia. Electronic address: louise.emmett@svha.org.au.
² Garvan Institute of Medical Research, Sydney, NSW, Australia.
³ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Bankstown-Lidcombe Hospital, Sydney, NSW, Australia.
⁴ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁵ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
⁷ Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
⁸ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
⁹ Department of Oncology, Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia.
¹⁰ Department of Nuclear Medicine, Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia.
¹¹ Department of Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Queensland University of Technology, Brisbane, QLD, Australia.
¹² Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹³ Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁴ Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
¹⁵ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁶ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
¹⁷ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC) and Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; ULTRA The University of Queensland Clinical Trials Capability, Centre for Clinical Research, Brisbane, QLD, Australia; Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.
¹⁹ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia; Monash University Eastern Health Clinical School, Melbourne, Australia; Eastern Health, Melbourne, VIC, Australia.
²⁰ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.

PMID: 40752515
DOI: 10.1016/S1470-2045(25)00339-0

Abstract

Background: Quantitative parameters derived from gallium-68 [⁶⁸Ga]Ga-prostate-specific membrane antigen (PSMA)-11 PET-CT (PSMA-PET-CT) such as whole-body standardised uptake value (SUV)mean and total tumour volume (PSMA-TTV) have shown prognostic value for response to lutetium-177 [¹⁷⁷Lu]Lu-PSMA-617 monotherapy in patients with prostate cancer. Adding [¹⁷⁷Lu]Lu-PSMA-617 to enzalutamide improved overall survival compared with enzalutamide in patients with metastatic castration-resistant prostate cancer in the ENZA-p trial. This prespecified substudy of ENZA-p evaluated baseline PSMA-PET quantitative parameters as predictive and prognostic biomarkers for enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 and enzalutamide monotherapy.

Methods: ENZA-p was an open-label, randomised, phase 2 trial done in 15 hospitals in Australia. Participants were aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had not previously been treated with docetaxel or androgen receptor pathway inhibitors (abiraterone permitted) for metastatic castration-resistant prostate cancer, had [⁶⁸Ga]Ga PSMA-PET-CT-positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Patients were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to either enzalutamide 160 mg daily (oral) or enzalutamide 160 mg daily plus adaptive-dosed (two or four doses) intravenous [¹⁷⁷Lu]Lu-PSMA-617 7·5 GBq every 6-8 weeks. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been reported previously. All participants underwent baseline [⁶⁸Ga]Ga-PSMA-11 PET-CT to assess eligibility (SUVmax >15 at a single site and SUVmax >10 at all larger tumour sites). PSMA-PET parameters were quantified with semi-automated software to derive PSMA-TTV and SUVmean and correlated with overall and PSA progression-free survival in a prespecified analysis, with the primary endpoint of this substudy being overall survival. Thresholds were based on SUVmean highest quartile (Q4 vs Q1-3) and PSMA-TTV median at baseline. We used the Kaplan-Meier method and Cox regression models and analysed patients on a treatment received basis. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete.

Findings: Between Aug 17, 2020, and July 26, 2022, 162 participants were randomly assigned to enzalutamide (n=79) or enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 (n=83). This substudy included the 160 of the 162 randomly assigned patients who received study treatment (79 in the enzalutamide group and 81 in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group). Median follow-up at the final data cutoff (July 31, 2024) was 34 months (IQR 29-39), with 96 overall survival events (53 with enzalutamide and 43 with enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617). Baseline median SUVmean was 7·7 (IQR 6·5-9·8) and median PSMA-TTV was 234 mL (76-687). Median overall survival for PSMA-TTV below or above the median in the enzalutamide group was 39 months (95% CI 31-not estimable) versus 20 months (13-24; HR 0·23 [95% CI 0·13-0·42], log-rank p<0·0001). The corresponding median overall survival for PSMA-TTV below or above the median in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group was 35 months (95% CI 32-37) versus 28 months (26-34; HR 0·66 [0·36-1·21], log-rank p=0·18). The test for interaction between PSMA-TTV and treatment group for overall survival was p=0·0078. Median overall survival for SUVmean Q4 versus Q1-3 in the enzalutamide group was 29 months (95% CI 17-39) versus 25 months (21-31; HR 0·84 [0·44-1·60], log-rank p=0·59). For enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617, median overall survival for SUVmean Q4 versus Q1-3 was 32 months (95% CI 21-not estimable) versus 34 months (27-35; HR 0·80 [0·38-1·68], log-rank p=0·56). The test for interaction between SUVmean (Q4 vs Q1-3) and treatment group for overall survival was p=0·88.

Interpretation: Baseline PSMA-TTV is prognostic for overall survival and predictive for a beneficial effect on overall survival with the addition of [¹⁷⁷Lu]Lu-PSMA-617 to enzalutamide as first-line treatment for high-risk metastatic castration-resistant prostate cancer. By contrast, PSMA SUVmean was not prognostic for PSA progression-free survival or overall survival when [¹⁷⁷Lu]Lu-PSMA-617 was administered with enzalutamide.

Funding: The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), Prostate Cancer Foundation Challenge Award, St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, Endocyte (a Novartis company), and Astellas.

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Conflict of interest statement

Declaration of interests LE reports research grant support (to their institution) from Novartis and Clarity Pharma; consulting fees for lectures or advisory boards from Astellas, Janssen, AstraZeneca, Clarity, Novartis, Advancell, and Telix in the past 5 years; and philanthropic grant support from the Prostate Cancer Foundation, St Vincent's Clinic Research Foundation, and Curran Foundation. SSa reports grants from Novartis/AAA, AstraZeneca, Merck Sharp & Dohme, Genentech, Pfizer, Amgen, and Senhwa to their institution; and personal fees from AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, and AstraZeneca to their institution, outside the submitted work. MSH reports grants and receipt of equipment, materials, drugs, medical writing, gifts, or other services from the Prostate Cancer Foundation, the NHRMC, Movember, US Department of Defense, Medical Research Future Fund, Bayer, Peter MacCallum Foundation, Isotopia, and the Australian Nuclear Science and Technology Organisation; consulting fees from Merck Sharp & Dohme and Novartis; honoraria from Janssen, Novartis, AstraZeneca, and Astellas; support for meetings from Merck Sharp & Dohme, Novartis, Janssen, AstraZeneca, and Astellas; leadership or fiduciary role in other board from Australian Friends of Sheba; and other financial or non-financial interests from Peter MacCallum Cancer Centre and the University of Melbourne. DAP reports personal fees from Ipsen and Eisai, all outside the submitted work. RJF reports institution funding and consulting fees from AIQ Solutions (outside the submitted work), and committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). MRS reports grants to his institution from the NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray, all outside the submitted work. IDD reports grants from the NHMRC, during the conduct of the study; reports institutional payments to support prostate cancer trials from Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, and Merck Sharp & Dohme, outside the submitted work; and is unremunerated Chair of the ANZUP Cancer Trials Group and is supported in part by an Australian NHMRC Investigator Grant (grant number 2016274). AMJ reports consulting or advisory roles (to their institution) from Janssen Oncology, Pfizer, and Astellas Pharma, and research funding (to their institution) from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, Lilly, Pfizer, and AstraZeneca. AW declares consulting fees from MSD, Eisai, Bristol Myers Squibb, and Astellas; honoraria from Eisai and MSD; and participation on an advisory board from Loxo-Lilly, MSD, and Astellas. All other authors declare no competing interests.

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Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial

Collaborators

Affiliations

Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial

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Abstract

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