Blood-based tumor and immune markers for risk stratification and monitoring treatment response in oligometastatic prostate cancer

About This Grant

PROJECT SUMMARY/ABSTRACT This project aims to refine the individualized management of patients with oligometastatic castration- sensitive prostate cancer (omCSPC) by integrating blood-based markers to identify a subset of omCSPC patients who will benefit from stereotactic body radiation therapy (SBRT) alone versus those necessitating treatment intensification with systemic therapy. While the current advanced molecular imaging modalities (e.g. PSMA and Choline PET) have limitations in detecting subclinical disease, our innovative approach addresses this gap by evaluating prostate cancer-derived extracellular vesicles (PC-EVs) and circulating tumor DNA (ctDNA) as blood markers of both visible and invisible tumor burden. Furthermore, we will study specific circulating immune markers based on our prior research to identify and predict patients with clinical responses to SBRT and delineate immunosuppressive signals for future therapeutic intervention studies. We hypothesize that proposed blood-based tumor biomarkers and anti-tumor immune markers will aid in predicting patient response to SBRT alone or in combination with systemic therapy using randomized patient samples from Specific Aim 1, thus guiding personalized treatment decisions for future omCSPC patients. In order to achieve our goal, we will conduct a randomized phase 2 trial in omCSPC to evaluate SBRT alone or in combination with 6 months doublet therapy (ADT+ARPI) with modified radiographic PFS as primary endpoint in Specific Aim 1. In Specific Aim 2, we will prospectively validate PC-EV cutoff values predetermined using patients samples from ORIOLE and STOMP-like cohorts for risk stratification and prediction of response to therapy. We will also evaluate the performance of cell-free ctDNA as an additional blood-based marker of tumor burden and minimal residual disease. In Specific Aim 3, we will validate tumor-reactive CD8 T cells (previously published using prostate and melanoma patient samples) as a marker of durable response to SBRT. We will also perform a comprehensive profiling of peripheral immune cells and cytokines to examine the effect of ADT/ARPI to SBRT in anti-prostate cancer immune response. The identification of patients who can safely avoid ADT/ARPI after SBRT will significantly impact clinical decisions, reducing morbidity and cost associated with unnecessary systemic therapies. If successful, this study will allow up to 20% of patients to avoid unnecessary toxicities associated with systemic androgen deprivation treatments. Finally, by shedding light on key players of antitumor immunity, this work will serve as the foundation for future mechanistic studies that can lead to the design of a rational combination of SBRT and immunotherapy. By advancing the paradigm of personalized prostate cancer care through the integration of fluid-based tumor and immune assays with existing imaging techniques, this research holds significance for the National Cancer Institute's priorities for significantly improving patient outcomes and optimizing the management of omCSPC.