Prognostic Value of Interim PSMA-PET Total Tumor Volume for Overall Survival Within ENZA-p, A Randomized Phase 2 Trial of Enzalutamide Versus Enzalutamide Plus [177Lu] Lu-PSMA-617 (ANZUP1901).

Interim [68Ga]Ga-prostate-specific membrane-antigen positron emission tomography/computed tomography (PSMA-PET/CT) has prognostic potential for overall survival (OS) in metastatic castrate-resistant prostate cancer (mCRPC), although evidence is limited. This ENZA-p sub-study evaluated 3-mo PSMA-total-tumor-volume (PSMA-TTV) as a prognostic biomarker for OS with enzalutamide ± [177Lu]Lu-PSMA-617. ENZA-p is a randomized, phase 2 trial. Participants with mCRPC and risk factors for early treatment failure with enzalutamide were randomized (1:1) to enzalutamide or enzalutamide + [177Lu]Lu-PSMA-617. Participants underwent baseline and 3-mo [68Ga]Ga-PSMA-11-PET/CT, quantified to derive PSMA-TTV. We evaluated the prognostic value of PSMA-TTV change, and residual PSMA-TTV at 3-mo for OS (NCT04419402). This sub-study included 152/162 (94%) randomized participants with a 3-mo PSMA-PET. Median OS was 27 mo (95% confidence interval [CI] 23-30). Baseline median PSMA-TTV 230 ml (interquartile range [IQR] 75-635) and 3-mo PSMA-TTV 103 ml (IQR 24-457). The median change in PSMA-TTV from baseline was -34% (IQR -76% to 16%) with 50/152 (33%) participants with increase in PSMA-TTV. Any increase versus decrease in PSMA-TTV at 3-mo was associated with shorter OS (HR 2.52, 95% CI 1.65-3.85) and decreased 2-yr survival 30% (95% CI 17-43) versus 67% (95% CI 56-75) (log-rank p < 0.0001). Residual 3-mo PSMA-TTV higher versus lower than the median (103 ml) was associated with shorter OS (HR 3.76, 95% CI 2.39-5.92) and lower 2-yr survival 34% (95% CI 23-45) versus 76% (95% CI 64-84) (log-rank p < 0.0001). This association was independent of treatment arm and prostate-specific antigen (PSA) response. PSMA-TTV at 3 mos was prognostic for OS independent of study treatment and PSA response in ENZA-p, warranting further prospective validation of interim PSMA-PET response criteria.