PSMA-PRED protocol plans biomarker search for lutetium-PSMA treatment response

The prospective PSMA-PRED trial will test whether molecular markers in tumor tissue can predict response to [177Lu]Lu-PSMA-617 in 120 patients with advanced metastatic castration-resistant prostate cancer. The six-site French study is designed to identify potential biomarkers of radiological response and examine their relationships with progression-free survival, overall survival and treatment-related toxicities. It is a study protocol, so its methods and objectives do not yet demonstrate that any marker can predict treatment benefit.

Researchers will enroll patients across six French sites who have advanced metastatic castration-resistant prostate cancer and are eligible for [177Lu]Lu-PSMA-617, also called 177Lutetium-PSMA-617. The Jean Perrin Center is the trial sponsor. Primary prostate tumor tissue will be used as the principal source for the biomarker analysis, with the central objective of identifying molecular features associated with radiological response under RECIST v1.1 and PCWG3 criteria.

The protocol addresses a clinical evidence gap in metastatic castration-resistant prostate cancer, which the investigators describe as having limited treatment options and poor survival outcomes, with an approximate five-year survival rate of 30%. Radioligand therapy with [177Lu]Lu-PSMA-617 has improved progression-free survival and overall survival in advanced disease, according to the protocol, but approximately 40% of patients do not respond. There are currently no validated predictive biomarkers for stratifying responders, and PSMA-PRED will evaluate whether molecular characteristics of tumor tissue can supply that information.

PSMA-PRED is designed as a prospective, multicentre, open-label interventional trial. Researchers will conduct comprehensive molecular profiling of tumor samples, including DNA, RNA and methylation analyses. Candidate markers will be evaluated for their association with radiological response, while the study’s secondary objectives include examining relationships between tissue biomarkers and radiological, biological and clinical progression-free survival, as well as overall survival and treatment-related toxicities.

The investigators also plan to test whether integrating molecular data with clinical, radiological or biological features can improve the performance of potential biomarker models. The protocol’s stated aim is to develop predictive models of response to [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer by integrating clinical, molecular and imaging data. The study was approved by the CCP Sud Ouest et Outre Mer II Ethics Committee on May 23, 2024, and registered on ClinicalTrials.gov on September 19, 2024, under the identifier NCT06600802.

These dates describe the regulatory approval and registration of the planned research. Because the published paper is a protocol, it contains no results showing that DNA, RNA or methylation markers have been discovered or validated in the enrolled population. If tissue biomarkers are identified, the investigators plan to conduct additional analyses of circulating tumor DNA at a later stage, with the aim of exploring a less invasive monitoring approach.

That work is conditional on the initial tissue findings and is not presented as an established component with completed validation. The protocol also specifies a planned cohort of 120 patients at six sites in France, limiting the current evidence to the design and scope of this multicentre study rather than establishing performance across broader populations or clinical settings. Ultimately, PSMA-PRED is intended to generate and evaluate candidate predictive biomarkers for [177Lu]Lu-PSMA-617 using a combination of tissue profiling, imaging and patient data.

Its planned endpoints include treatment response, survival measures and toxicities, allowing molecular associations to be assessed across several outcomes. Whether the resulting markers are accurate, reproducible or useful for treatment selection remains unanswered until the prospective study produces data; for now, the protocol provides a structured research framework rather than a clinically validated molecular test.

Subject of Research: Molecular biomarkers associated with response to lutetium-PSMA radioligand therapy in metastatic castration-resistant prostate cancer

Article Title: 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 multicentre clinical trial

Article References: Passildas, J., Ferreira, M.-C., Mahammedi, H., Merlin, C., Kelly, A., Molnar, I., Durando, X., Penault-Llorca, F., & Herrmann, T. (2026). 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 multicentre clinical trial. BMC Cancer. https://doi.org/10.1186/s12885-026-17143-3

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17143-3

Keywords: PSMA-PRED, prostate cancer, lutetium-PSMA-617, radioligand therapy, tumor biomarkers, molecular profiling, circulating tumor DNA, clinical trial protocol, Intrinsic, validity, molecular, marker