[Lu] Lu-PSMA-617 treatment for metastatic castration-resistant prostate cancer (mCRPC) with cerebral and cerebellar metastases.

[BACKGROUND] Central nervous system (CNS) metastases in prostate cancer are rare but pose a significant treatment challenge and are linked to poor prognosis. Data on the outcomes of this specific patient subgroup treated with radioligand therapy (RLT) remain scarce. In this study, we aim to leverage real-world clinical data to evaluate the outcomes of RLT with [Lu] Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC) and CNS metastases.

[METHODS] Clinical and imaging data of patients who received their initial dose of [Lu] Lu-PSMA-617 between March 2022 and April 2024 were retrospectively reviewed. All patients who were known to have at least one parenchymal CNS metastasis confirmed radiologically through dedicated neuroimaging, with or without histopathological confirmation, were included in the study. Central nervous system metastases (CNS) were defined as metastatic lesions involving the cerebrum, cerebellum, or spinal cord. The mCRPC patients with dural metastases but without parenchymal CNS disease were excluded.

[RESULTS] A total of 589 patients underwent RLT with [Lu] Lu-PSMA-617 for mCRPC, of whom 12 (2%, 12/589) had CNS metastases. Among these, eight patients (67%, 8/12) had pre-existing CNS lesions, while the remaining four patients (33%, 4/12) were diagnosed with CNS metastases after initiating RLT. Patients received no additional systemic or focal therapies concurrently with RLT. The mean follow-up period was 5.7 ± 6.9 months. The median overall survival from the initial dose of RLT was 4.5 months (range: 1.1-29.87 months). Among eight patients with pre-existing CNS metastases, CNS lesions resolved completely or nearly completely in three patients (37.5%, 3/8), while two patients (25%, 2/8) exhibited a mixed response, and three patients (37.5%, 3/8) experienced CNS disease progression following RLT. Among four patients diagnosed with CNS metastases after initiating therapy, three patients (75%, 3/4) experienced a rapid clinical decline necessitating urgent intervention, while the remaining patient (25%, 1/4) responded well to the therapy without developing new or worsening neurological symptoms. None of the patients were able to complete the full six cycles of RLT, with discontinuation mainly due to overall disease progression or infection-related complications.

[CONCLUSIONS] Our study suggests that patients with CNS metastases, whether diagnosed before or after therapy, exhibited a poor prognosis, with a median survival of 4.5 months after initiation of RLT. Although a complete/near-complete radiologic response in the CNS lesions was observed in 25% of the patients, only two patients were able to complete more than three cycles of therapy. Given the small sample size, larger multicenter studies are needed to validate these findings.