Abstract
BACKGROUND: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([(177)Lu]Lu-PSMA) is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The aim of our study was to evaluate clinical variables of patients with extreme response to PRLT and to assess its immunomodulatory potential. METHODS: This retrospective study included 36 patients from two centers achieving extreme response after [¹⁷⁷Lu]Lu-PSMA PRLT. The primary outcomes were the duration of maintained response in months (MR) and improvement post-therapy-clinically, serologically, and on molecular (PET/CT) imaging. We examined several variables, including pathology, gene sequencing, baseline PSA, Gleason score, prior therapies, number of PRLT cycles, and pattern of disease, to identify potential factors that may influence the extreme response. RESULTS: Between 2018 and mid-September 2024, 36 men with mCRPC received a mean of three cycles of [(177)Lu]Lu-PSMA PRLT. Patients were subgrouped according to clinical variables versus MR. A total of 17 patients had ≥12 months MR (17/36, 47%). The longest duration of MR was 99 months and a mean of 17.44 months (95% CI 10.05-24.84). Previous lines of treatment were evaluated for MR, p = 0.172. Pattern of disease (bone, lymph node, liver, and peritoneal) was evaluated for MR, p = 0.721. The Gleason score was evaluated for MR, p = 0.871. Patients with known BRCA sequencing status (n = 12) were analyzed with mean MR: BRCA1/2 wild-type, 6/12 (50%), 6.67 months; BRCA 1/2 negative, 1/12 (8.33%), 7 months; BRCA germline negative and somatic positive, 1/12 (8.33%), 36 months; BRCA germline negative, somatic negative, 2/12 (16.67%), 27 months; and BRCA 2 positive, 2/12 (16.67%), 43 months. CONCLUSIONS: We propose there may be intrinsic mechanisms suggesting the immunomodulatory enhancement of ionizing radiation, primarily driving extreme responses.