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 .
Nature cancer. 2026 Apr 15 [Epub ahead of print]
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
Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia. ., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia., Garvan Institute of Medical Research, Sydney, New South Wales, Australia., NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia., St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia., Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, Victoria, Australia., Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia., Department of Oncology, Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia., Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia., Royal Brisbane & Women's Hospital, Herston, Queensland, Australia., Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA., Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia., Monash University Eastern Health Clinical School, Melbourne, Victoria, Australia.