Background Lutetium 177 [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on ¹⁷⁷Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to ¹⁷⁷Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline ⁶⁸Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUV_mean and SUV_max), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUV_mean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUV_mean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUV_mean was the best predictor of ¹⁷⁷Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUV_mean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. ¹⁷⁷Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUV_mean quartiles versus SOC only, with no identifiable optimum among participants receiving ¹⁷⁷Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [P < .05] and 1.02-1.03 [P < .001], respectively) and OS (HR range, 1.36-2.12 [P < .006] and 1.04 [P < .001], respectively). Conclusion Baseline ⁶⁸Ga-PSMA-11 PET/CT whole-body tumor SUV_mean was the best predictor of ¹⁷⁷Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with ¹⁷⁷Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUV_mean, with evidence for benefit at all SUV_mean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.

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