Baseline [(68)Ga]Ga-PSMA-11 PET/CT before [(177)Lu]Lu-PSMA-617 Radioligand Therapy: Value of PSMA-Uptake Thresholds in Predicting Targetable Lesions

SIMPLE SUMMARY: The prostate-specific membrane antigen (PSMA), a transmembrane protein frequently present on prostate cancer cells, has gained considerable interest as a target for both molecular imaging and therapy. Patients with metastatic castration-resistant prostate cancer can be successfully treated by delivery of beta particle-emitting (177)Lutetium to the prostate-specific antigen in a therapeutic concept termed radioligand therapy. Imaging with positron emission tomography (PET) plays a crucial role in patient selection prior to radioligand therapy and subsequent molecular response assessment. The presented study aims to investigate the role of quantitative uptake parameters on baseline (68)Gallium-PSMA-11 PET/CT imaging as to their association with lesion response to radioligand therapy at individual tumor sites. Special emphasis is placed on the utility of PSMA-uptake thresholds for pretherapeutic prediction of lesion response. ABSTRACT: Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [(177)Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [(68)Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [(68)Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2–6) RLT cycles. Maximum and mean standardized uptake values (SUV(max), SUV(mean)), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7–17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUV(max) decline or falling below the blood pool uptake were considered responsive; ≥30% SUV(max) increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUV(max), SUV(mean), and TLR values were associated with lesion response by a moderate but significant correlation (r(s) = 0.33, p < 0.001, r(s) = 0.32, p < 0.001, and r(s) = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUV(max), SUV(mean), and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [(68)Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [(177)Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.