Introduction:

Prostate-specific membrane antigen (PSMA) targeted 225Ac shows promise for metastatic castration-resistant prostate cancer (mCRPC) treatment. However, variations in treatment response across different metastatic sites, such as bone, nodal, and visceral locations, remain poorly understood. Some data point towards liver and bone/bone marrow as more commonly resistant sites to PSMA-targeted beta-radioligand therapy. Investigating these variations is essential for optimizing treatment strategies and improving patient outcomes. In this study, we explore the response to 225Ac-labeled PSMA antibody in various mCRPC metastatic sites, aiming to enhance our understanding of this therapeutic approach and its potential implications for personalized management.

Methods:

Thirty-two patients with mCRPC were treated in a prospective single ascending dose phase 1 trial of 225Ac-PSMA-J591 from 2017 to 2020. PSMA imaging expression assessment by PET was conducted in most subjects, but not used for participant selection.
We examined 20 cases with baseline 68Ga-PSMA-11 PET/CT (bPET) and post-treatment PET/CT (fPET). Overall response was assessed on fPET using PERCIST  and RECIST on conventional imaging for cases with measurable disease. A biochemical response (PSA50 response) was defined as ≥50% PSA decline post-treatment and we evaluated the circulating tumor cells in patients with liver metastases, comparing baseline to 12 week counts. 
Lesion-based analysis involved measuring SUVpeak for the three most and least avid lesions. We compared pre- and post-treatment SUVpeak and percentage decline. PET complete or partial response was evaluated at the patient and lesion levels. We also compared the frequency of  PET response  among bone, node, and visceral lesions. 
 

Results:

Twenty patients were analyzed.  A PSA50 response was observed in 55% of men and 35% had an overall objective  response on fPET. Among eight cases with measurable disease, 88% showed stable disease, and 13% progressive disease. Patients with a biochemical response showed higher probabilities of having a favorable PET response.
We analyzed data from 4 cases with liver metastases. Median for the liver metastasis SUVmax was 10.96. After treatment, a reduction ranging from 17%-88% was observed in 75% of cases; in 1 case, the liver lesions had similar PSMA avidity compared to liver uptake. 
A total of 204 lesions were measured on bPET. Post-treatment, significant SUVpeak declines were observed in all metastatic categories, with median declines of -40% in bone lesions, -52% in visceral lesions, and -23%  in nodal lesions; the objective PET response rate differed among visceral lesions (71%), bone lesions (52%) and nodal lesions (39%).

Conclusion:

Our study demonstrates that 225Ac-PSMA-J591 shows promising efficacy in treating all metastatic categories, with particularly favorable responses observed in traditionally more difficult to treat bone and visceral lesions relative to nodal lesions. The analysis of 4 patients with liver metastases revealed encouraging outcomes, showing a significant decrease in PSA post-treatment, indicative of a positive therapeutic response. Although further validation is necessary, our findings hold significant implications for future trial design and patient counseling, underscoring the therapeutic potential of 225Ac-PSMA-J591 in managing advanced prostate cancer. These results contribute to advancing personalized treatment approaches and fostering improved clinical outcomes for patients with metastatic castration-resistant prostate cancer.

Funding: N/A