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

Abstract

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.

Graphical abstract

Figure 1:

Flowchart for the VISION trial shows the randomization of participants and exclusion criteria for the participants included in the present analysis. * Reasons for exclusion included (a) separate fields of view, (b) incomplete field of view, and (c) imaging artifact that impeded quantification. ^‡ Reasons for exclusion included (a) use of units that could not be converted to standardized uptake value and (b) inadequate emission start time postinjection. PSMA = prostate-specific membrane antigen.

Figure 2:

Segmentation of anatomic regions and distribution of quantitative ⁶⁸Ga-PSMA-11 PET parameters. (A) Whole-body anterior coronal prostate-specific membrane antigen (PSMA) PET maximum intensity projection images in a 63-year-old White male participant with tumors in the liver, bone, and lymph node (LN) who had an initial prostate-specific antigen level of 181.9 ng/mL and Eastern Cooperative Oncology Group performance score of 0/1 show all PSMA-positive (PSMA+) disease as a single whole-body volume in red (left) and segmented according to anatomic region (right; bone lesions in blue, liver lesions in green, lymph node lesions in red). (B) Box plots show the distribution of quantitative ⁶⁸Ga-PSMA-11 PET parameters for the study sample (n = 826) included in this analysis. Data are reported as medians and IQRs from the full analysis sets for bone (n = 761), liver (n = 109), lymph node (n = 559), soft tissue (n = 334), and whole body (n = 826) and stratified according to treatment (T; ¹⁷⁷Lu-PSMA-617 plus standard of care [SOC]), control (C; SOC only), and overall (O; all participants). SUV_max = maximum standardized uptake value, SUV_mean = mean standardized uptake value.

Figure 3:

Association of quantitative ⁶⁸Ga-PSMA-11 PET parameters with efficacy outcomes in the final multivariable model. In the chart, boxes show the level of association between each PET parameter per anatomic region and each clinical outcome. Blue and orange boxes represent statistically significant associations with improved and worse clinical outcomes, respectively (P < .05). White boxes indicate that no statistically significant associations were observed (P ≥ .05). Associations are shown within the ¹⁷⁷Lu-PSMA-617 plus standard of care (SOC) treatment group (T), within the SOC only control group (C), or within the overall study sample (O), and the model was adjusted for study treatment (¹⁷⁷Lu-PSMA-617 plus SOC or SOC only). The presence of prostate-specific membrane antigen–positive (PSMA+) tumors was included as a categorical variable but is not reported here for clarity. max = maximum, ORR = overall response rate, OS = overall survival, PSA = prostate-specific antigen, rPFS = radiographic progression-free survival, SUV_max = maximum standardized uptake value, SUV_mean = mean standardized uptake value.

Figure 4:

Chart shows median radiographic progression-free survival (rPFS) and overall survival (OS) according to whole-body tumor mean standardized uptake value (SUV_mean) quartile, indicating statistically significant differences in the three upper quartiles for both rPFS and OS but not the lowest quartile. SUV_mean quartiles were derived from the SUV_mean of both study arms combined (¹⁷⁷Lu-PSMA-617 plus standard of care [SOC] and SOC only). The statistical significance of the hazard ratios (HRs) for each quartile is indicated by 95% CIs that exclude unity. NE = not evaluable, PSMA = prostate-specific membrane antigen.

Figure 5:

Kaplan-Meier curves show radiographic progression-free survival (rPFS) according to whole-body tumor mean standardized uptake value (SUV_mean) quartile for (A) ¹⁷⁷Lu-PSMA-617 plus standard of care (SOC) (n = 382) and (B) SOC only (n = 194) treatment arms (body, progression-free survival, full analysis set). SUV_mean quartiles were derived from either the SUV_mean of the ¹⁷⁷Lu-PSMA-617 plus SOC arm or the SOC only arm. PSMA = prostate-specific membrane antigen. Kaplan-Meier curves show overall survival according to whole-body tumor mean standardized uptake value (SUV_mean) quartile for (C) ¹⁷⁷Lu-PSMA-617 plus standard of care (SOC) (n = 548) and (D) SOC only (n = 278) treatment arms (body, full analysis set). SUV_mean quartiles were derived from either the SUV_mean of the ¹⁷⁷Lu-PSMA-617 plus SOC arm or the SOC only arm. PSMA = prostate-specific membrane antigen.

Figure 6:

Maximally selected rank statistics analysis for identification of optimal whole-body tumor mean standardized uptake value (SUV_mean) cut-points for (A) radiographic progression-free survival (rPFS) and (B) overall survival (OS) in the ¹⁷⁷Lu- PSMA-617 plus standard of care arm (rPFS, n = 382; OS, n = 548). For both A and B, the top panel shows the SUV_mean histogram and the bottom panel shows the standardized log-rank statistics using different SUV_mean values as cutoffs. The standardized log-rank statistics demonstrate an upward trend, suggesting no ideal cutoffs can be identified within the range of SUV_mean values in the VISION trial. grps = groups, PSMA = prostate-specific membrane antigen.