Phase 1 Trial: Astatine-211 PSMA-5 Shows Strong Early Responses in First-in-Human Prostate Cancer Trial

Encouraging results suggest that 211At-PSMA-5, an experimental alpha-emitting radioligand targeting PSMA, may offer a promising new treatment approach for patients with metastatic castration-resistant prostate cancer (mCRPC).

The findings come from a first-in-human phase 1 study involving 15 patients whose disease had progressed following androgen receptor pathway inhibitors and taxane-based chemotherapy.

Unlike established PSMA-targeted radioligand therapy using lutetium-177, which emits beta particles, 211At-PSMA-5 uses astatine-211, an alpha-emitting radioisotope capable of delivering highly concentrated radiation over very short distances. Alpha particles can produce complex DNA damage, potentially offering strong antitumor activity, including in tumors resistant to previous treatments.

Astatine-211 also has a relatively short half-life of approximately 7.2 hours, compared with 6.7 days for lutetium-177 and 9.9 days for actinium-225. This characteristic may enable different treatment schedules and radiation delivery profiles, although its practical and clinical advantages remain to be established.

In the study, patients received three treatment cycles at four-week intervals, with escalating doses ranging from 0.875 to 3.0 MBq/kg.

The strongest responses were observed at the higher dose levels. Among six patients receiving at least 2.0 MBq/kg, five (83%) achieved a PSA reduction of at least 50% (PSA50), while four (67%) achieved a reduction of at least 80% (PSA80).

Imaging results also suggested antitumor activity. At three months after completion of treatment, PSMA PET assessments showed partial responses in 4 of 9 evaluable patients (44%), while another two patients (22%) had stable disease according to RECIP 1.0 criteria.

The initial safety findings were also encouraging. No dose-limiting toxicities were observed, even at the highest investigated dose of 3.0 MBq/kg. The most common adverse events involved the salivary glands, with grade 1–2 toxicity, and the blood, with hematological adverse events ranging from grade 1 to grade 3.

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