How Standard of Truth Methodology Impacts Diagnostic PSMA-Targeting Radiopharmaceutical Evaluation: Learnings from the Phase 3 SPOTLIGHT Study.

Objectives: To explore the impact of different standard of truth (SoT) methodologies on efficacy endpoints traditionally used in clinical trials of diagnostic radiopharmaceuticals, using data from the SPOTLIGHT study (NCT04186845) in patients with recurrent prostate cancer. Methods: Data from patients with baseline prostate-specific antigen (PSA) ≤ 5 ng/mL, who underwent 18F-flotufolastat imaging and had data for SoT determination, were reviewed. Majority-read patient level endpoints (verified detection rate [VDR] and patient-level positive predictive value [PPV]), and region-level PPV (in the prostate/prostate bed, pelvic lymph nodes, and extrapelvic sites) according to on-study reads by three blinded readers, were stratified by the SoT methodology (histopathology; post-PET confirmatory imaging; baseline/historic conventional imaging) used by the independent Truth Panel to verify 18F-flotufolastat-avid lesions. Differences between SoT groups for each endpoint were compared using a chi-square test (statistically significant if p < 0.0167). Results: Our analysis included 297 patients (median baseline PSA = 0.8 ng/mL): 56% (n = 166) had post-PET confirmatory imaging, 26% (n = 78) had baseline/historic conventional imaging, and 18% (n = 53) had histopathological confirmation of ≥1 PET-positive lesion. For all endpoints assessed, the highest majority-read values were achieved with histopathology SoT. For histopathology versus baseline/historic conventional imaging, VDR (77%) was 3.6-fold higher (p < 0.0001), patient-level PPV (79%) was 2.2-fold higher (p < 0.0001), and region-level PPV (50%) was 3.7-fold higher in the prostate/prostate bed (p = 0.009); smaller increases were seen in majority-read PPV in the pelvic lymph nodes (77%; 1.5-fold) and other sites (75%; 1.3-fold), but these were not of statistical significance. Conclusions: These data illustrate how SoT methods can substantially impact efficacy endpoints traditionally used in clinical trials of diagnostic radiopharmaceuticals. Notably lower endpoint values are achieved with imaging SoT than with histopathology.