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

Emmett, L; Swiha, M; Papa, N; Subramaniam, S; Crumbaker, M; Joshua, AM; Nguyen, A; Weickhardt, A; Lee, ST; Ng, S; Francis, RJ; Goh, JC; Pattison, DA; Pathmanandavel, S; Hope, T; Ayati, N; Hofman, MS; Sandhu, S; Niu, C; Martin, AJ; Thomas, H; Stockler, MR; Davis, ID; Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group

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

Author(s): Emmett, L; Swiha, M; Papa, N; Subramaniam, S; Crumbaker, M; Joshua, AM; Nguyen, A; Weickhardt, A; Lee, ST; Ng, S; Francis, RJ; Goh, JC; Pattison, DA; Pathmanandavel, S; Hope, T; Ayati, N; Hofman, MS; Sandhu, S; Niu, C; Martin, AJ; Thomas, H; Stockler, MR; Davis, ID; Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group;
Details: Publication Year 2026-04,Volume 7,Issue #4,Page 622-630
Journal Title: Nature Cancer
Publication Type: Research article
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 ± (177)Lu-PSMA-617. ENZA-p is a randomized trial. Participants had mCRPC and (68)Ga-PSMA positive disease. Participants were randomized (1:1) to enzalutamide or enzalutamide + (177)Lu-PSMA-617, undergoing (68)Ga-PSMA-PET-computed tomography (CT) at baseline and day 15 of enzalutamide treatment. (68)Ga-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 + (177)Lu-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 + (177)Lu-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 (177)Lu-PSMA-617 to enzalutamide mitigated the short PSA-PFS in those with early PSMA SUV mean increase. ClinicalTrials.gov registration: NCT04419402 .
Publisher: Springer Nature
Keywords: Humans; Male; *Prostatic Neoplasms, Castration-Resistant/drug therapy/diagnostic; imaging/pathology/metabolism/mortality; Nitriles; Benzamides; *Phenylthiohydantoin/analogs & derivatives/administration & dosage/therapeutic; use; *Dipeptides/administration & dosage/therapeutic use; Aged; *Heterocyclic Compounds, 1-Ring/administration & dosage/therapeutic use; *Glutamate Carboxypeptidase II/metabolism/genetics; Positron Emission Tomography Computed Tomography; Lutetium/administration & dosage; Middle Aged; *Antigens, Surface/metabolism/genetics; Up-Regulation; Prostate-Specific Antigen; Aged, 80 and over; Radioisotopes
Department(s): Cancer Imaging; Medical Oncology
Publisher's Version: https://doi.org/10.1038/s43018-026-01140-3
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Creation Date: 2026-04-28 02:39:57

Last Modified: 2026-05-14 12:09:39