Investigation of Resistance Mechanisms and Tumor Diversity in Metastatic, Anti-Hormone-Resistant (Castration-Resistant) Prostate Cancer

Prostate cancer (prostate carcinoma) is one of the most common cancers in men. The risk of developing this disease increases with age, a family history of the disease, or due to hormonal factors. This cancer usually develops slowly in the prostate, a small gland located below the bladder that plays a role in reproduction. The disease can metastasize, meaning that cancer cells spread to other organs. The disease often goes unnoticed for a long time because it does not initially cause any symptoms. In more aggressive forms, treatment is necessary, for example, through surgery, radiation therapy, or anti-hormone therapy. As part of anti-hormone therapy, the sex hormone testosterone is removed from the body with the help of medication. The goal is to lower testosterone to what is known as a castration level (very low levels, similar to those after removal of the testicles). Testosterone promotes the growth of prostate cancer cells, and blocking the hormone is intended to halt tumor growth. If the tumor continues to grow despite hormone deprivation, it is considered castration-resistant prostate cancer.

A current treatment approach for metastatic castration-resistant prostate cancer is 177LuPSMA radioligand therapy (RLT), in which radioactively labeled molecules bind to PSMA-expressing cancer cells and destroy them through localized radiation. Prostate-specific membrane antigen (PSMA) is a surface protein that occurs naturally on prostate cells and can be detected in increased levels on prostate cancer cells and the cancer cells in metastases. However, in some patients, this treatment is observed to be ineffective—meaning the cancer is resistant to the therapy. Possible reasons for the inadequate response to therapy may include, among other things, tumor heterogeneity (differences in the activity and composition of tumor cells) and tumor-biological adaptations (altered metabolic pathways and alternative survival strategies).

The aim of this study is to investigate this heterogeneity and adaptive resistance mechanisms in prostate cancer tumors. As part of the study, two primary endpoints will be examined within two cohorts. In Cohort A, the study will investigate whether the metabolic activity of the tumor differs within a single metastasis and between different metastases as measured by positron emission tomography (PET). PET is a modern imaging technique primarily used to visualize active tumor cells. In Cohort B, resistance mechanisms will be identified using biopsies of the metastases (tissue samples) taken before and after 177Lu-PSMA-RLT. In addition, in both cohorts, patients’ blood will be tested for tumor-specific mutations in circulating cell-free DNA (ctDNA). The study is prospective and non-interventional, meaning that no medications or new forms of treatment are being evaluated as part of the study.

Men aged 18 to 99 with metastatic castration-resistant prostate cancer are eligible to participate in this study. PSMA-positive metastases must be detected, and the standard criteria for a 177Lu-PSMA RLT must be met. Individuals with severe psychiatric disorders and congenital bleeding disorders are not eligible to participate.