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

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 ± Lu-PSMA-617. ENZA-p is a randomized trial. Participants had mCRPC and Ga-PSMA positive disease. Participants were randomized (1:1) to enzalutamide or enzalutamide + Lu-PSMA-617, undergoing Ga-PSMA-PET-computed tomography (CT) at baseline and day 15 of enzalutamide treatment. 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 + 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 + 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 Lu-PSMA-617 to enzalutamide mitigated the short PSA-PFS in those with early PSMA SUV mean increase. ClinicalTrials.gov registration: NCT04419402 .