Optimizing neoadjuvant ADT duration prior to radiotherapy in high-risk prostate cancer: Rationale and clinical need.

Abstract

259 Background: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for high-risk prostate cancer (HRPC). However, the optimal duration of neoadjuvant ADT (nADT) prior to definitive treatment remains unclear, as shorter durations may be insufficient for tumor control while prolonged therapy risks immune suppression and increased toxicity. Determining the ideal nADT duration should help maximize efficacy and improve outcomes. Methods: Patients with prostate cancer who underwent radical prostatectomy at Roswell Park (1995–2019; Protocol BDR 125520) were included. Data on age, race, PSA levels, Gleason score, stage, treatment details, and nADT duration were collected. The study included 43 men treated with nADT for up to one year before surgery, excluding those with prior radiotherapy or chemotherapy. A matched control cohort of 43 cases who did not receive ADT was selected based on age, stage, Gleason grade, and year of diagnosis. Tissue from FFPE blocks was analyzed using H&E staining, immunohistochemistry (IHC), RNA sequencing (RNA-seq), and quantitative multiplex immunofluorescence (qmIF) with the Vectra Polaris to evaluate the expression and spatial distribution of key markers, including CD8, CD4, CD68, FOXP3, NKX3.1, and HLADR. Spatial relationships between tumor and immune cells were quantified using PhenoptReports, providing insights into cell proximities and interactions within the tumor microenvironment. Subsequent statistical analyses were conducted using OriginPro. Results: The duration of nADT plays a critical role in shaping immune dynamics and tumor control, with its efficacy confirmed by decreased TMPRSS2 expression across all treatment durations prior to prostatectomy. Short-term nADT (≤2 months) results in limited CD8+ T-cell infiltration and spatial alignment with tumor cells, indicating weak immune engagement. Intermediate-duration nADT (3–5 months) drives robust immune activation, marked by enhanced CTLs-tumor interactions as CD8+ and CD4+ T-cells cluster near tumor cells while effectively suppressing M2 macrophage density and proximity. In contrast, prolonged nADT (≥6 months) shifts the immune microenvironment toward suppression, characterized by M2 macrophage enrichment near tumor cells, leading to immune exhaustion and reduced tumor control. Conclusions: These findings underscore the critical role of spatial dynamics and the importance of optimizing nADT duration, with 3–5 months emerging as the most effective window for maximizing survival outcome while minimizing adverse immune effects. Moreover, understanding the shift toward immune suppression over time opens avenues for strategies to counteract this effect, potentially improving long-term outcomes in the management of HRPC patients.