Impact of different PSMA PET-based eligibility criteria on outcome of [177Lu]Lu-PSMA radioligand therapy using [18F]rhPSMA-7/[18F]rhPSMA-7.3 (Flotufolastat)

Abstract Background [ 177 Lu]Lu-PSMA radioligand therapy (RLT) is key in treating metastatic castration-resistant prostate cancer (mCRPC). Various PSMA agents and eligibility criteria for [ 177 Lu]Lu-PSMA RLT have been described. We retrospectively assessed applicability and outcomes using Blue Earth Therapeutics’ (BET) phase I study criteria with [ 18 F]rhPSMA-7 and Flotufolastat ([ 18 F]rhPSMA-7.3), comparing them to VISION trial-based PSMA PET/CT criteria. Patients eligible for [ 177 Lu]Lu-PSMA RLT, as assessed by an interdisciplinary board, were retrospectively stratified into four groups based on whether their PSMA PET scans with Flotufolastat met BET (B + /B-) and/or VISION (V + /V-) criteria. Outcome parameters like PSA response, PSA progression-free survival (PSA-PFS), and overall survival (OS) were compared, and reasons for (in-)eligibility by BET or VISION were analyzed. Results In total, 191 mCRPC patients from our institutional database were included, of which 138 underwent [ 18 F]rhPSMA-7.3 and 53 [ 18 F]rhPSMA-7. 161 (84.3%) met both criteria (V + /B +), 13 (6.8%) were ineligible (V-/B-), and 17 (8.9%) met VISION but not BET criteria (V + /B-). No patient was BET-eligible without also fulfilling VISION criteria. Of the 30 patients excluded by BET criteria, 17 (56.7%) lacked the “majority” tumor volume criterion; 10/13 (76.9%) excluded by VISION had visceral metastases with lower PSMA expression than the liver. In the subgroups V + /B + , V + /B-, and V-/B-, a PSA response > 50% was present in 62/157 (39.5%), 2/17 (11.8%), and 0/13 (0%) patients, respectively. V + /B + patients had the significantly longest PSA-PFS compared to V + /B- and V-/B- (PSA-PFS: 4.3 months (95% CI 3.4 – 5.2) vs. 1.5 months (95% CI 1.4 – 1.6) vs. 2.8 months (95% CI 0.0 – 6.5), p = 0.002) and a trend towards longer OS (14.9 vs. 13.1 vs. 7.7 months, p = 0.065). Conclusion Multiple similarities between BET and VISION eligibility criteria (V + /B +) prior to [ 177 Lu]Lu-PSMA RLT were observed, with the majority of patients fulfilling both. Positivity in both criteria was associated with the best outcome. Data from our pilot cohort suggest that the criteria for BET’s phase I trial select patients more strictly for [ 177 Lu]Lu-PSMA RLT than VISION criteria, while OS did not significantly differ between the three different groups.