A phase 2, single-arm trial evaluating ¹³¹I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer

Background Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. I-131-PSMA-1095 (also known as I-131-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. Methods We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of I-131-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent F-18-DCFPyL PET and F-18-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of I-131-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. Results Eleven patients were screened for inclusion and nine patients received I-131-PSMA-1095. The median baseline PSA was 162 mu g/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. Conclusion I-131-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of I-131-PSMA-1095 compared to Lu-177-PSMA-617.