Systemic therapy–associated differences in intracranial disease in metastatic prostate cancer: A real-world study.

Abstract

e17080 Background: Brain or leptomeningeal involvement in prostate cancer has historically been rare. As systemic therapies with distinct biological targets have expanded, it remains unclear whether patterns of intracranial metastases or related disease phenotypes, such as neuroendocrine transformation, have changed over time. Real-world evidence is limited. Methods: A retrospective, multicenter analysis was conducted using the TriNetX federated electronic health record network. Adult males (≥18 years) with metastatic prostate cancer (ICD-10 C61, C77-79) were stratified by treatment era (2015-2017 vs 2021-2023) and by exposure to conventional systemic therapies. Brain (C79.31) and meningeal (C79.32) metastases were primary endpoints, and neuroendocrine transformation (C7A, C7B) was the secondary endpoint. Cohorts were compared after 1:1 propensity score matching for age at index event, race, ethnicity, surgeries of the prostate, radiation, PSA, TNM staging, Olaparib/Rucaparib use. Regimens of interest were androgen receptor signaling inhibitors (ARSI), Docetaxel, Cabazitaxel and 177Lu-PSMA-617. Treatment exposure was limited to on or before 12/31/2024, and those reaching endpoints before exposure were excluded.Intracranial (IC) disease did not include base of skull involvement. Results: Across time periods, patients diagnosed in 2021–2023 demonstrated a significantly lower incidence of IC metastases when compared with 2015–2017 at both 1-year (p = 0.0006) and 3-year follow ups (p < 0.0001). In contrast, the incidence of neuroendocrine disease was significantly higher in the 2021–2023 cohort at 1-year (p = 0.007) and 3-years (p = 0.0005). In treatment-based analyses, patients receiving ARSI had a lower 1-year incidence of IC metastases than the docetaxel group (p < 0.0001), with no significant difference in neuroendocrine disease (p = 0.4). Among ARSI-treated patients, abiraterone was associated with a lower 1-year incidence of IC metastases compared with enzalutamide (p = 0.0478), while neuroendocrine incidence remained similar (p = 0.39). In late line comparisons, 177Lu-PSMA-617 was associated with a lower 1-year IC incidence than cabazitaxel(p = 0.0159); neuroendocrine events were too few to analyze. Upon stratification by therapy combinations and treatment line, no increase in neuroendocrine disease was observed. Conclusions: Modern treatments for metastatic prostate cancer appear to have influenced patterns of intracranial involvement, with some therapies potentially reflecting improved disease control. In contrast, increasing neuroendocrine involvement remains unexplained and may be due to underlying selective pressure on androgen signaling, new pathways for progression with evolving disease biology, or survival-related selection rather than treatment-driven induction, highlighting the need for mechanistic and prospective studies.