Quantitative ⁶⁸Ga-PSMA-11 PET and Clinical Outcomes in Metastatic Castration-resistant Prostate Cancer Following ¹⁷⁷Lu-PSMA-617 (VISION Trial)

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_meanand 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_meanquartiles. Results: Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median wholebody tumor SUV_meanwas 7.6 (IQR, 5.8-9.9). Whole-body tumor SUV_meanwas 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_meanincrease 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_meanquartiles 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_meanwas 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_meanlevels.