PSMA-Directed Targeted Alpha Therapy Shows Activity in Heavily Pretreated Metastatic CRPC

FPI-2265 (previously ²²⁵Ac-PSMA-I&T), a prostate-specific membrane antigen (PSMA)-directed targeted α therapy, demonstrated activity in a heavily pretreated population of patients with metastatic castration-resistant prostate cancer (CRPC), according to findings from the phase 2 TATCIST trial (NCT05219500) presented during the 2024 AACR Annual Meeting.

At the March 1, 2024, data cutoff, 50% of patients who were evaluable for prostate-specific antigen (PSA) response (n = 20) achieved PSA50 responses irrespective of prior ¹⁷⁷Lu-PSMA radioligand therapy (Pluvicto) treatment; 61% of patients who had not received (n = 13) and 42% of those who did receive prior ¹⁷⁷Lu-PSMA radioligand therapy (n = 7) experienced PSA50 responses. Further, among those evaluable by RECIST 1.1 criteria (n = 9), 33% of patients achieved a partial response, 44% had stable disease, and 22% experienced progressive disease.

Findings from a case study of a 72-year-old male with an 8-year history of prostate cancer, a Gleason score of 9, and extensive skeletal disease showed that the patient achieved a biochemical response with a reduction of PSA by 99.8% and a decrease in PSMA tumor volume by 99.9%. He received 4 cycles of treatment in the TATCIST study and prior to enrollment, received prostatectomy and external beam radiation therapy followed by bicalutamide (Casodex), enzalutamide (Xtandi), apalutamide (Erleada), abiraterone acetate (Zytiga), Radium-223, olaparib (Lynparza), and cabazitaxel plus carboplatin.

Data from an exploratory analysis revealed that durable PSA responses by week 24 were observed in patients (n = 13) with a PSMA SUV_mean greater than 6, as 69% of patients achieved a PSA50 response.

Baseline Characteristics and Enrollment Criteria in TATCIST

“Targeted α-therapies have the potential to overcome limitations of β-therapies that are α-emitting radioisotopes have 1) higher probability of causing catastrophic double-strand DNA breaks and 2) a shorter radiation path length that may lessen unwanted exposure of surrounding healthy cells,” Ebrahim Delpassand, MD, chairman and medical director at Excel Diagnostics and Nuclear Oncology Center in Houston, Texas, and lead study author, and coauthors, wrote in a poster presentation of the findings.

Thus, the TATCIST study was designed to confirm the efficacy of FPI-2265, a small molecule containing a PSMA-targeting ligand coupled with the multi-α emitter ²²⁵Ac radionuclide.

Patients with progressive metastatic CRPC based on serum PSA, soft tissue, and/or bone progression and positive PSMA PET/CT scans to confirm PSMA expression were enrolled in the trial. Patients must have received at least 1 androgen receptor pathway inhibitor and prior treatment with ¹⁷⁷Lu-PSMA RLT and prior taxanes were allowed. Those with skeletal metastases presenting as superscan, known central nervous system or liver metastases, and those who received more than 4 prior therapies were excluded from the trial. Additionally, patients who were less than 6 weeks from receiving myelosuppressive therapy were not permitted.

Patients enrolled in the study were a median age of 70 years (range, 52-84) with a median PSA of 37.9 ng/mL (range, 0.14-4729) and a median Gleason score of 8 (range, 7-10). Most patients had an ECOG performance status of 0 or 1 (96%) and bone metastases (96%), but also had lymph node (20%) and visceral (32%) metastases. Additionally, the median SUV_mean was 6.3 (range, 3.7-12.6) with 60% of patients being greater than 6.

The median lines of prior anticancer therapy received was 4 (range, 1-6) including an androgen receptor pathway inhibitor (100%), chemotherapy (80%) consisting of a taxane (76%) and carboplatin (44%), ¹⁷⁷Lu-PSMA RLT (36%), radium-223 (16%), and other (24%).

FPI-2265 was given at a dose of 100 kBq/kg (±10%) intravenously every 8 weeks for up to 4 cycles. Further, the primary end point of the trial was PSA50 response; secondary end points included safety and tolerability, maximum percent PSA decline, response based on RECIST 1.1 criteria, and non-progression by PCWG3.

Examining the Safety of FPI-2265

“Safety signals were consistent with the literature, where higher graders of hematologic toxicity were observed mainly in participants with superscan or who had received multiple lines of chemotherapy,” Delpassand and coauthors wrote in the poster. “No discontinuations occurred owing to xerostomia.”

The most common treatment-related adverse effects (TRAEs) were thrombocytopenia, xerostomia, decreased white blood cell count, anemia, and decreased neutrophil count. TRAEs found in patients who did not undergo superscan also included fatigue, dry eye, nausea, and dysgeusia. Thrombocytopenia was the only grade 4 TRAE, occurring in 25% of patients. Further, 1 treatment-related death occurred on the trial due to cerebral hemorrhage secondary to thrombocytopenia.

Delpassand and coauthors also noted that a phase 2/3 trial will take place to further evaluate the efficacy and safety of FPI-2265.

Reference

Delpassand ES, Hashmi MJ, Kazakin J, et al. Preliminary efficacy and safety results from the (TATCIST) trial: A PSMA-directed targeted alpha therapy with FPI-2265 (225Ac-PSMA-I&T) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT224.