PSMA Expression Predicts Early Biochemical Response in Patients with Metastatic Castration-Resistant Prostate Cancer under (177)Lu-PSMA-617 Radioligand Therapy

SIMPLE SUMMARY: Prostate-specific membrane antigen (PSMA) is a promising target for both imaging and radioligand therapies (RLT) for men with prostate cancer. However, not all patients respond to RLT and some even progress early in the treatment course. We aimed to identify parameters to forecast which patients will achieve therapy response prior to commencing RLT. Therefore, we tested whether the tumor volume, the level of PSMA expression or a combination of both in metastases derived from PSMA-targeted molecular imaging prior to RLT can inform the treating physician whether a patient will respond to RLT. Compared to tumor volume, the level of PSMA-expression can better identify patients responding to RLT early in the treatment course. ABSTRACT: (177)Lu-Prostate-specific membrane antigen (PSMA)-radioligand therapy (RLT) is a promising treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to determine the predictive value of pretherapeutic PSMA-ligand positron emission tomography (PET) and established clinical parameters for early biochemical response after two cycles of RLT. In total, 71 mCRPC patients who had undergone PET/computed tomography (CT) with (68)Ga-PSMA-11 prior to two cycles of (177)Lu-PSMA-617 RLT were included. Malignant lesions on pretherapeutic PET/CTs were manually segmented and average maximum PSMA expression (maximum standardized uptake values, SUV(max)), whole-body PSMA-tumor volume (TV), and whole-body total lesion (TL)-PSMA were calculated. We then tested the predictive performance of these parameters for early biochemical response (defined as prostate-sepcific antigen (PSA) decrease of ≥50% according to PCWG2) after two cycles of RLT, relative to established clinical parameters. Early PSA response was observed in 34/71 patients. PSA change after two cycles of RLT correlated with pretherapeutic SUV(max) (r = −0.49; p < 0.001), but not with PSMA-TV (r = 0.02; p = 0.89) or TL-PSMA (r = −0.15; p = 0.22). A cut-off of 19.8 for SUV(max) and 75.5 years for age was defined by receiver operating characteristics and revealed a significant outcome difference for early biochemical response between patients with adversely low vs. high PSMA expression and low vs. high age (p < 0.001). Multivariate analysis identified SUV(max) (HR, 7.94, p = 0.001) and age (HR, 8.05, p = 0.002) as independent predictors for PSA response early in the treatment course. Thus, high age and high PSMA expression in patients scheduled for RLT identify patients with early biochemical response. This study provides a rationale for further prospective studies exploring PET-guided treatment intensification in selected patients.