²²⁵Ac-PSMA-617 Targeted Alpha Therapy in Metastatic Castration Resistant Prostate Cancer Patients

Objectives: The objective of this study was to evaluate the safety and therapeutic efficacy of ²²⁵Ac-PSMA-617 targeted alpha therapy (TAT) in metastatic castration resistant prostate cancer patients (mCRPC).

Methods: The study has been approved by the Institute Ethics Committee (IEC:518). 40 mCRPC patients refractory to therapy options including first and second generation anti-androgen therapies, taxane-based chemotherapies, and ¹⁷⁷Lu-PSMA-617 therapy were treated with ²²⁵Ac-PSMA-617 TAT (100 - 150 KBq/Kg body weight) at an interval of 8 weeks up to 9 cycles. The patients were treated from February 2018 to December 2020 with a median follow-up duration of 14 months (range: 2 - 34 months). Hematologic, kidney, liver function tests and prostate specific antigen tests were repeated before and after every cycle of ²²⁵Ac-PSMA-617 TAT at 2, 4 and 8-week intervals. Treatment related side effects were assessed every 2 weeks on the basis of physical examination, vital signs, laboratory results (hematologic, kidney and liver function levels) and adverse events graded according the CTCAE v5.0. Response assessment included biochemical and molecular tumor response which were evaluated by the trend in PSA levels and follow-up ⁶⁸Ga-PSMA PET/CT scan using PERCIST 1 criteria.

Results: The mean age of patients was 67.7 years (range: 46 - 87 years). 38/40 patients demonstrated extensive PSMA avid skeletal metastases on baseline ⁶⁸Ga-PSMA PET/CT scan and in two patients disease was confined to primary and lymph node metastases. The median activity administered was 25 MBq (700µCi) ranging from 11 MBq to 62.9 MBq (300 to 1700 µCi) with a median of 5 cycles and were followed-up over a median duration of 19 months. At 2-3 month interval after the first therapy and the end of the assessment, >50% decline in PSA was observed in 27% and 35%, respectively. One patient experienced grade III thrombocytopenia. No patient experienced grade 3 or 4 kidney or hepatotoxicity. Grade 1 or 2 xerostomia was observed in 13/40 (32.5%) patients. Molecular tumor response by PERCIST 1 criteria revealed complete response in 3/40 (7.5%), partial response in 13/40 (32.5%) patients, 8/40 (20%) with stable disease, and 16/40 (40 %) with progressive diseases. The disease control rate according to molecular response was 60%. 19 patients died during the treatment period. The median overall survival was 15 months and median progression-free survival was 12 months. CONCLUSION: ²²⁵Ac-PSMA-671 TAT showed promising anti-tumor activity, sustained response, improved overall survival and low treatment-related toxicities.