225Ac-PSMA-J591 active in mCRPC with difficult-to-treat metastatic sites

The PSMA-targeted alpha-radioligand therapy ²²⁵Ac-PSMA-J591 showed promising efficacy across different metastatic sites in patients with metastatic castration-resistant prostate cancer (mCRPC), including sites shown to be resistant to beta-emitting PSMA radionuclide therapies, such as ¹⁷⁷Lu-PSMA-617 (lutetium Lu 177 vipivotide tetraxetan; Pluvicto), according to findings shared at the 2023 SUO Annual Meeting.¹

Regarding next steps, Ricaurte-Fajardo said, “We want to see if we can use 225Ac-PSMA-J591 in earlier stages of the disease.” He added that another goal is to see how patients do with 225Ac-PSMA-J591 after being treated with 177Lu-PSMA-617.

“Variations in [PSMA-targeted radioligand] treatment response across different metastatic sites, such as bone, nodal, and visceral locations, remain poorly understood. Investigating these variations is essential for optimizing treatment strategies and improving patient outcomes,” first study author Andres Ricaurte-Fajardo, MD, a post-doctoral fellow in Radiology/Molecular Imaging and Therapeutics at Weill Cornell Medicine, said when explaining the study background in an interview with Urology Times at the SUO meeting.

“In this study, we explored 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,” added Ricaurte-Fajardo.

The poster Ricaurte-Fajardo shared at the SUO meeting consisted of data from a post-hoc analysis of a prospective phase 1 single ascending dose trial. The prospective trial included 32 patients treated with ²²⁵Ac-PSMA-J591 from 2017 to 2020. The post-hoc analysis included 20 patients who had baseline ⁶⁸Ga-PSMA-11 PET/CT and post-treatment PET/CT.

According to the Ricaurte-Fajardo, “Overall response was assessed on post-treatment PET/CT using PERCIST and RECIST on conventional imaging for cases with measurable disease.” The investigators assessed responses at the patients and lesion levels.

Overall, 35% of men had an objective response on post-treatment PET/CT. Additionally, 55% of the men had a PSA50 response (biochemical response), defined as a decline in PSA level of at least 50% between baseline and follow-up. Among 8 patients with measurable disease, conventional imaging showed that 87% had stable disease and 13% had disease progression. Men who had a biochemical response were more likely to have a positive PET response, according to Ricaurte-Fajardo.

Overall, there were 204 lesions measured on baseline PET. The researchers assessed response by type of metastasis. Ricaurte-Fajardo noted that, “Some previous data point toward liver and bone/bone marrow as more commonly resistant sites to PSMA-targeted beta-radioligand therapy (¹⁷⁷Lu-PSMA-617).”

A comparison of pre- and post-treatment SUV_peak showed median declines of -52%, -40%, -23% in visceral, bone, and nodal lesions, respectively. The objective response rate was 71% in visceral lesions, 52% in bone lesions, and 39% in nodal lesions.

“Here, the interesting thing is there was a statistically significant difference when we compared [the change in median SUV_peak values] for visceral lesions versus nodal lesions [P = .042]; however, there was not a statistically significant difference between the [change in median SUV_peak median values] in visceral lesions vs bone lesions [P = .17] or in bone lesions verses nodal lesions [P = .32],” said Ricaurte-Fajardo.

Ricaurte-Fajardo et al also assessed a small sample of 4 patients with liver metastases. “These patients usually do worse than other patients,” explained Ricaurte-Fajardo.

The median for the liver metastasis SUV_max in these patients was 10.96%. After treatment, a tumor volume reduction ranging from 17% to 88% was observed in 3 of 4 cases. One patient had circulating tumor cell “conversion to favorable or undetectable,” noted Ricaurte-Fajardo.

Regarding next steps, Ricaurte-Fajardo said, “We want to see if we can use ²²⁵Ac-PSMA-J591 in earlier stages of the disease.” He added that another goal is to see how patients do with ²²⁵Ac-PSMA-J591 after being treated with ¹⁷⁷Lu-PSMA-617.

Reference

1. Ricaurte-Fajardo A, Stangl-Kremser J, Martinez-Fundichel A, et al. Assessment of PSMA PET imaging response in metastatic castration-resistant prostate cancer after 225Ac-J591 therapy: Post-hoc patient-level analysis of a prospective clinical trial. Presented at: 2023 Society of Urologic Oncology Annual Meeting. November 28 – December 1, 2023; Washington, DC. Poster 249.