SNMMI 2021: 225Ac-PSMA-617 Targeted Alpha Therapy in Metastatic Castration Resistant Prostate Cancer Patients

( Beginning with the introduction of docetaxel for metastatic castration resistant prostate cancer (mCRPC) in 2004, there has been a dramatic and rapid proliferation of systemic therapy options in advanced prostate cancer including a number of novel hormonal therapies (including abiraterone acetate and enzalutamide), second-line chemotherapy (cabazitaxel), bone-targeting agents (radium-223) and other targeted agents (including olaparib, rucaparib, and pembrolizumab), each of which has proven survival benefits. Recently, theranostic treatment with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy, including most notably 177lutetium-PSMA-617 as well as others, has demonstrated promising activity among pre-treated individuals with mCRPC. However, most patients develop progression following treatment with 177lutetium-PSMA-617. One treatment option for these patients is further radionuclide therapy with 225Ac-PSMA-617 targeted alpha therapy. In the Cancer Radiopharmaceutical Therapy session at the 2021 Society of Nuclear Medicine & Molecular Imaging Annual Meeting, Dr. Madhav Yadav presented an assessment of the safety and therapeutic efficacy of 225Ac-PSMA-617 targeted alpha therapy in patients with mCRPC.

To do so, they identified 40 patients with mCRPC who had progressed despite prior therapies including first and second-generation anti-androgen therapies, taxane-based chemotherapies, and 177Lu-PSMA-617 therapy. Patients had to have positive 68-Ga-PSMA PET/CT and adequate organ function. These patients were treated with 225Ac-PSMA-617 (100 - 150 KBq/Kg body weight) at an interval of 8 weeks up to 9 cycles. Treatment was administered for included patients between February 2018 and December 2020, with a median follow-up of 14 months (range: 2 - 34 months). The authors assessed the primary efficacy outcomes of biochemical response according to PCWG3 criteria and progression-free survival as well as secondary outcomes of molecular tumor response per PERCIST 1 criteria, overall survival, and toxicity per CTCAE v5.0.

The authors performed hematologic, kidney, liver function tests, and prostate-specific antigen tests before and after every cycle of 225Ac-PSMA-617 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 to 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.

The mean age of included patients was 67.7 years (range: 46 - 87 years).  Most patients (n=23) had a Gleason score of 9 or 10 and the baseline median PSA was 89 ng/mL (IQR 36-312). Notably, 61% of patients had previously received 177-Lu-PSMA-617.

On the basis of baseline 68Ga-PSMA PET/CT scan, 38/40 patients had evidence of extensive PSMA avid skeletal metastases while two patients were confined to primary tumor 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 3 cycles (range 1-9 cycles per patient; 142 total cycles). Patients were subsequently followed for a median duration of 19 months.

A PSA decrease of 50% or more was seen in 23 of 41 patients (56%). A further 7 patients (15%) had any PSA decline while the remaining 11 patients (27%) had a PSA increase of more than 25%.

Assessment of molecular tumor response by PERCIST 1 criteria showed evidence of complete response in two patients (4.9%), near-complete response in 4 patients (9.8%), partial response in seven patients (17.1%), stable disease in eleven patients (26.8%), and progressive disease in 17 patients (41.5%). Thus, the overall molecular response rate was 13 of 41 patients (32%).

The median progression-free and overall survival were 12 and 15 (95% CI 13-18) months, respectively.  Twenty-two patients died during the treatment period.


In terms of toxicity, one patient experienced grade III thrombocytopenia while no patients experienced grade 3 or 4 nephrotoxicities or hepatotoxicity. Mild (grade 1 or 2) xerostomia was observed in 13/40 (32.5%) patients.

The authors, therefore, concluded that 225Ac-PSMA-671 TAT showed promising anti-tumor activity, sustained response, improved overall survival, and low treatment-related toxicities.

Presented by: Madhav P. Yadav, MD, Department of Nuclear Medicine, All India Institute of Medical Sciences, AIIMS, New Delhi, India