Astatine-211 PSMA-5: Scalable Alpha Therapy for Refractory Prostate Cancer

^211AtPSMA-5 emerges as a promising targeted alpha therapy for metastatic castration-resistant prostate cancer, particularly in patients who have exhausted standard treatments like androgen receptor pathway inhibitors, docetaxel, and cabazitaxel. This approach leverages astatine-211, a cyclotron-produced alpha emitter generated by bombarding abundant bismuth targets with alpha beams.

The compound’s design mirrors established PSMA ligands such as ^18FPSMA-1007, enabling efficient covalent labeling and high affinity for prostate-specific membrane antigen on cancer cells. Preclinical studies in mice bearing LNCaP xenografts revealed exceptional tumor retention (up to 40.7% of the injected dose per gram at 24 hours) outperforming earlier PSMA variants, with complete tumor growth arrest at just 0.40 megabecquerel doses. Kidney uptake remained low, and safety assessments in mice (doses up to 35 megabecquerel per kilogram) and non-human primates showed only transient bone marrow suppression and lymphopenia, with no lasting organ damage.

In an ongoing first-in-human Phase 1 dose-escalation trial, patients received 0.875 to 3.0 megabecquerel per kilogram across three cycles spaced 4-8 weeks apart, with dosimetry guided by ring PET imaging. Across 14 heavily pretreated participants, including those with Gleason 9 disease and high-volume metastases, no dose-limiting toxicities occurred. SPECT/CT scans aligned closely with pre-treatment PSMA PET, displaying intense lesion accumulation (SUVmax 4.9-17.6) and minimal bladder excretion.
Responses were swift: pelvic recurrences resolved after three cycles with sustained uptake decline over months; bone and lymph node masses vanished within four weeks of the final dose; PSA levels dropped sharply, as shown in waterfall plots favoring higher cohorts, even in cases with rapid pre-treatment PSA doubling.

Automated good manufacturing practice synthesis now achieves 30% radiochemical yield, producing 134-229 megabecquerel per run for reliable clinical supply via domestic cyclotrons. Global production infrastructure is expanding rapidly, with multiple sites in Europe, the US, and Japan ensuring scalability without reliance on scarce imported isotopes. Short half-life reducing hospitalization needs, strong efficacy comparable to lead-212 or actinium-225 PSMA therapies, and production feasibility, position ^211AtPSMA-5 to broaden access for refractory prostate cancer as trials advance toward Phase 2.

Source.

Clinical trial.