Liquid Biopsy Biomarkers in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Prostate-Specific Membrane Antigen Radioligand Therapy: Protocol for a Prospective, Longitudinal Multicenter Observational Study.

Background: Prostate cancer is the second leading cause of cancer-related mortality in men worldwide. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has emerged as a theranostic strategy for metastatic castration-resistant prostate cancer (mCRPC), with [177Lu]Lu-PSMA-617 demonstrating survival benefits in the VISION trial. However, clinical responses are heterogeneous, and resistance mechanisms remain poorly understood. Liquid biopsy (LBx), particularly circulating tumor DNA (ctDNA), may provide a minimally invasive approach to assess tumor heterogeneity, monitor response, and detect emerging resistance. Objective: The LOOPS (Liquid Biopsy as a Biomarker in Patients Treated with PSMA Radioligand Therapy) study aims to prospectively investigate the prognostic and predictive value of ctDNA in patients undergoing PSMA RLT. Methods: LOOPS is a prospective, multicenter observational biomarker trial recruiting 100 patients with mCRPC eligible for PSMA RLT across 3 Bavarian cancer research centers in Germany. Patients will undergo up to 6 cycles of [177Lu]Lu-PSMA-617. Blood samples for ctDNA analysis will be collected longitudinally (at baseline and after cycles 1, 2, 4, and 6) and processed according to standardized protocols. Imaging with PSMA positron emission tomography-computed tomography and clinical and biochemical data will be systematically collected. The primary end points are the prognostic and predictive value of baseline ctDNA for treatment response, defined by imaging- and prostate-specific antigen (PSA)-based response criteria after 2 cycles of PSMA RLT. Predictive performance will be evaluated using receiver operating characteristic analyses, including the determination of optimal ctDNA cutoffs, sensitivity, specificity, positive and negative predictive values, and multivariable logistic regression models adjusting for relevant clinical confounders. Secondary end points assess the concordance and correlation between ctDNA dynamics, systematically assessed PSMA positron emission tomography-computed tomography response, and PSA changes, as well as associations between ctDNA and clinical or laboratory (eg, age, Gleason score, and other) characteristics at baseline and during follow-up. Exploratory analyses will investigate early molecular response patterns based on short-term ctDNA changes and will characterize clonal dynamics and potential resistance mechanisms under therapy. Results: The study has been funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) since July 2025. Patient recruitment has already commenced, and in January 2026, a total of 63 patients have been enrolled. Analysis of LBx samples was initiated in January 2026, while recruitment and data collection are ongoing. Conclusions: The LOOPS study will provide the first prospective, systematic evaluation of ctDNA as a biomarker in PSMA RLT. By integrating molecular, imaging, and clinical data, it aims to clarify the role of LBx in response monitoring and the early identification of resistance. The results could pave the way toward personalized therapeutic strategies in mCRPC.