Predictive value of early PSMA upregulation for the response to enzalutamide ± 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: substudy of the randomized, phase 2 ENZA-p trial

Louise Emmett; Mina Swiha; Nathan Papa; Shalini Subramaniam; Megan Crumbaker; Anthony M Joshua; Andrew Nguyen; Andrew Weickhardt; Sze-Ting Lee; Siobhan Ng; Roslyn J Francis; Jeffrey C Goh; David A Pattison; Sarennya Pathmanandavel; Thomas Hope; Narjess Ayati; Michael S Hofman; Shahneen Sandhu; Claire Niu; Andrew J Martin; Hayley Thomas; Martin R Stockler; Ian D Davis; Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group

doi:10.1038/s43018-026-01140-3

Predictive value of early PSMA upregulation for the response to enzalutamide ± ¹⁷⁷Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: substudy of the randomized, phase 2 ENZA-p trial

Nat Cancer. 2026 Apr;7(4):622-630. doi: 10.1038/s43018-026-01140-3. Epub 2026 Apr 15.

Authors

Louise Emmett^{1

2

3}, Mina Swiha^{4

5}, Nathan Papa⁶, Shalini Subramaniam^{7

8}, Megan Crumbaker^{9

6

10}, Anthony M Joshua^{9

6

10}, Andrew Nguyen⁴, Andrew Weickhardt^{11

12

13}, Sze-Ting Lee¹⁴, Siobhan Ng¹⁵, Roslyn J Francis^{16

17

18}, Jeffrey C Goh^{18

19}, David A Pattison^{18

19

20}, Sarennya Pathmanandavel^{4

21}, Thomas Hope²², Narjess Ayati^{4

9

6}, Michael S Hofman²³, Shahneen Sandhu²⁴, Claire Niu⁷, Andrew J Martin⁷, Hayley Thomas⁷, Martin R Stockler^#^{7

25}, Ian D Davis^#^{26

27

28}; Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group

Affiliations

¹ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia. louise.emmett@svha.org.au.
² St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia. louise.emmett@svha.org.au.
³ Garvan Institute of Medical Research, Sydney, New South Wales, Australia. louise.emmett@svha.org.au.
⁴ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia.
⁵ Molecular Imaging and Theranostics Division, Department of Medical Imaging, University of Western Ontario, London, Ontario, Canada.
⁶ Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
⁷ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
⁸ Department of Medical Oncology, Bankstown-Lidcombe Hospital, Sydney, New South Wales, Australia.
⁹ St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, New South Wales, Australia.
¹¹ Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, Victoria, Australia.
¹² School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
¹³ Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
¹⁴ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia.
¹⁵ Department of Oncology, Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia.
¹⁶ Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
¹⁷ Medical School, University of Western Australia, Perth, Western Australia, Australia.
¹⁸ Royal Brisbane & Women's Hospital, Herston, Queensland, Australia.
¹⁹ School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
²⁰ Department of Nuclear Medicine & Specialised PET Services, Royal Brisbane and Women's Hospital, Herston, Brisbane, Queensland, Australia.
²¹ Department of Nuclear medicine, St George Hospital Sydney, Sydney, New South Wales, Australia.
²² Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
²³ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
²⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
²⁵ University of Sydney, Sydney, New South Wales, Australia.
²⁶ Monash University Eastern Health Clinical School, Melbourne, Victoria, Australia.
²⁷ Eastern Health, Melbourne, Victoria, Australia.
²⁸ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, New South Wales, Australia.

^# Contributed equally.

PMID: 41986500
DOI: 10.1038/s43018-026-01140-3

Abstract

Prostate-specific membrane antigen (PSMA) receptor expression alters with androgen blockade in metastatic castrate-resistant prostate cancer (mCRPC). We evaluated the frequency and significance of early PSMA-positron emission tomography (PET) standardized uptake value (SUV) mean change with enzalutamide ± ¹⁷⁷Lu-PSMA-617. ENZA-p is a randomized trial. Participants had mCRPC and ⁶⁸Ga-PSMA positive disease. Participants were randomized (1:1) to enzalutamide or enzalutamide + ¹⁷⁷Lu-PSMA-617, undergoing ⁶⁸Ga-PSMA-PET-computed tomography (CT) at baseline and day 15 of enzalutamide treatment. ⁶⁸Ga-PSMA-PET-CT were quantified for SUV mean. The study evaluated early SUV mean change, and prostate-specific-antigen (PSA) progression-free survival (PSA-PFS), 50% PSA-decline and overall survival. We randomized 162 participants, of whom 154 of 160 (96%) treated participants had PSMA-PET at day 15. SUV mean increased in 105 of 154 (68%) participants. Median PSA-PFS with increasing SUV mean was 5.8 (95% confidence interval (CI) 4.0-8.7) versus 13.1 (95%CI 10.5-17.0) months for enzalutamide versus enzalutamide + ¹⁷⁷Lu-PSMA-617 (hazard ratio (HR) 0.38, 95%CI 0.25-0.58; log-rank P < 0.001). With decreasing SUV mean, median PSA-PFS was 12.5 (95%CI 3.2-23.6) versus 13.3 (95%CI 9.6-22.2) months for enzalutamide versus enzalutamide + ¹⁷⁷Lu-PSMA-617 (HR 0.80, 95%CI 0.42-1.53; log-rank P = 0.5). The interaction between SUV mean increase or decrease and treatment arm for PSA-PFS was P = 0.055. Early PSMA-SUV mean increase is frequent, predicting shorter PSA-PFS with first-line enzalutamide in mCRPC. The addition of ¹⁷⁷Lu-PSMA-617 to enzalutamide mitigated the short PSA-PFS in those with early PSMA SUV mean increase. ClinicalTrials.gov registration: NCT04419402 .

Publication types

Randomized Controlled Trial
Clinical Trial, Phase II

MeSH terms

Aged
Aged, 80 and over
Antigens, Surface* / genetics
Antigens, Surface* / metabolism
Benzamides
Dipeptides* / administration & dosage
Dipeptides* / therapeutic use
Glutamate Carboxypeptidase II* / genetics
Glutamate Carboxypeptidase II* / metabolism
Heterocyclic Compounds, 1-Ring* / administration & dosage
Heterocyclic Compounds, 1-Ring* / therapeutic use
Humans
Lutetium / administration & dosage
Male
Middle Aged
Nitriles
Phenylthiohydantoin* / administration & dosage
Phenylthiohydantoin* / analogs & derivatives
Phenylthiohydantoin* / therapeutic use
Positron Emission Tomography Computed Tomography
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant* / diagnostic imaging
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / metabolism
Prostatic Neoplasms, Castration-Resistant* / mortality
Prostatic Neoplasms, Castration-Resistant* / pathology
Radioisotopes
Up-Regulation

Substances

Nitriles
enzalutamide
Benzamides
Phenylthiohydantoin
Dipeptides
Heterocyclic Compounds, 1-Ring
Glutamate Carboxypeptidase II
FOLH1 protein, human
Lutetium
Antigens, Surface
PSMA-617
Prostate-Specific Antigen
Lutetium-177
Radioisotopes

Associated data

ClinicalTrials.gov/NCT04419402

Grants and funding

Challenge Award 2023/Prostate Cancer Foundation (PCF)