Intrinsic validity of molecular marker(s) detection on tissue tumor DNA to predict efficacy of 177Lutetium-PSMA-617 ([177Lu]Lu-PSMA-617) treatment for castration-resistant metastatic prostate cancer (PSMA-PRED): study protocol of a prospective multic

Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and poor survival outcomes (5-year survival rate of approximately 30%). Radioligand therapy with 177 Lutetium-PSMA-617 ([ 177 Lu]Lu-PSMA-617) improves progression-free survival (PFS) and overall survival (OS) in advanced disease but 40% of patients do not respond and there are no validated predictive biomarkers to stratify responders. This is a prospective multicentre, open-label, interventional trial involving six sites in France and sponsored by the Jean Perrin Center. PSMA-PRED plans to enroll 120 patients with advanced mCRPC who are eligible for [ 177 Lu]Lu-PSMA-617. The primary aim of PSMA-PRED study is to identify potential molecular biomarkers of radiological response (RECIST v1.1, PCWG3) to [ 177 Lu]Lu-PSMA-617 in primary prostate tissue, thereby improving personalized treatment strategies for mCRPC. Secondary objectives include evaluating correlations between tissue biomarkers and progression-free survival (radiological, biological, and clinical), overall survival, and treatment-related toxicities. We will also assess whether integrating clinical, radiological, or biological features enhances biomarker performance. Comprehensive molecular profiling (DNA, RNA, and methylation analysis) of tumor samples will be performed to identify biomarkers that correlate with radiological response to [ 177 Lu]Lu-PSMA-617, PFS and OS. By integrating clinical, molecular, and imaging data, this study aims to develop predictive models of response to [177Lu]Lu-PSMA-617 in patients with mCRPC. If biomarkers are identified on tissue, additional analyses of circulating tumor DNA will be performed later, for a less invasive monitoring approach. This study was approved by the CCP Sud Ouest et Outre Mer II Ethics Committee on May 23rd 2024. The trial was registered on Clinicaltrials.gov (NCT06600802) on 19/09/2024.