{"entity":{"id":"paper-tagawa-ac225-j591-jco-2024","kind":"paper","name":"Phase I dose-escalation study of 225Ac-J591, a PSMA-targeting alpha-emitting antibody, in mCRPC","aka":[],"tldr":"The first human test of an alpha-emitting radioactive drug attached to an antibody (rather than a small molecule) against PSMA found a safe dose in men with advanced prostate cancer who had exhausted other treatments, and shrank the PSA marker in nearly half of them - including those whose cancer had already stopped responding to the more common lutetium-177 PSMA treatment.","summary":"This first-in-human phase 1 dose-escalation trial tested 225Ac-J591 - the anti-PSMA monoclonal antibody J591 labelled with the alpha emitter actinium-225 - as a single intravenous dose in 32 men with progressive metastatic castration-resistant prostate cancer who had received or were ineligible for taxane chemotherapy and an androgen receptor pathway inhibitor. Unlike PSMA-617 or PSMA-I&T, J591 is a full antibody rather than a small peptidomimetic ligand, giving different pharmacokinetics (slower clearance, longer tumour residence). Patients were treated across seven dose levels (13.3 to 93.3 kBq/kg) without pre-selection by PSMA PET.\n\nOne dose-limiting toxicity (grade 4 anaemia and thrombocytopenia) occurred at 80 kBq/kg; none occurred at the highest dose level tested (93.3 kBq/kg), so a maximum tolerated dose was not reached and the recommended phase 2 dose was set at the top studied level. Most high-grade adverse events were haematological and dose-related; non-haematological toxicity was generally low grade - a different pattern from PSMA-617-based alpha agents, where xerostomia (dry mouth) from salivary gland uptake dominates, since antibodies clear the salivary glands less than small-molecule ligands. Efficacy signals were encouraging for a phase 1, dose-finding, unselected population: 46.9% of patients had a PSA decline of 50% or more at some point, 34.4% had a confirmed PSA50 response, and 59.1% had control of circulating tumour cells, with responses seen regardless of prior 177Lu-PSMA exposure.\n\nAs one of the first published clinical results for an antibody-based (rather than small-molecule) PSMA alpha-emitter, this trial supports antibody-delivered alpha therapy as a second route to targeted alpha therapy in prostate cancer, potentially with a different toxicity trade-off (more marrow suppression, less xerostomia) than PSMA-617-based agents, and without requiring PSMA PET pre-selection.","asOf":"2026-09-22","links":[{"label":"PubMed record","url":"https://pubmed.ncbi.nlm.nih.gov/37922438/"},{"label":"ASCO Publications: full text","url":"https://ascopubs.org/doi/10.1200/JCO.23.00573"}],"tags":["alpha therapy","prostate cancer","phase 1"],"related":["ac225-psma","targeted-alpha-therapy","psma","prostate-mcrpc","oliver-sartor","beta-then-alpha","lu-177","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"JCO","year":2024,"doi":"10.1200/JCO.23.00573","pmid":"37922438","authors":"Tagawa ST, Thomas C, Sartor AO, Sun M, Stangl-Kremser J, et al.","paperType":"rct","findings":["Recommended phase 2 dose was the highest studied level, 93.3 kBq/kg; maximum tolerated dose was not reached across seven dose levels.","One dose-limiting toxicity (grade 4 anaemia and thrombocytopenia) occurred, at 80 kBq/kg; none at the highest dose level.","46.9% of patients had a PSA decline of 50% or more at any time; 34.4% had a confirmed PSA50 response.","Circulating tumour cell count control occurred in 13 of 22 evaluable patients (59.1%); responses were seen regardless of prior 177Lu-PSMA treatment.","High-grade adverse events were predominantly haematological and radioactivity-dose related; non-haematological toxicity was generally low grade."],"whatItMeans":"An alpha-emitting radioactive drug built on a PSMA-targeting antibody, rather than the small-molecule ligands used in existing PSMA therapies, was safe enough to move into further testing and shrank PSA in roughly a third to a half of heavily pre-treated men, including some whose cancer had already stopped responding to lutetium-177 PSMA therapy.","caveats":["Small, single-arm, phase 1 dose-escalation trial (32 patients) - not designed or powered to show a survival or definitive efficacy benefit.","No PSMA PET pre-selection was used, unlike VISION and TheraP, so response rates are not directly comparable to those trials.","Blood toxicity (anaemia, thrombocytopenia) tracked with dose, which will need careful management as the drug moves into larger trials."],"changedPractice":false,"participants":32},"route":"/key-papers/paper-tagawa-ac225-j591-jco-2024/","neighbours":{"drug":[{"id":"ac225-psma","kind":"drug","name":"Actinium-225 PSMA agents","route":"/drugs/ac225-psma/"}],"technology":[{"id":"targeted-alpha-therapy","kind":"technology","name":"Targeted alpha therapy","route":"/technologies/targeted-alpha-therapy/"}],"target":[{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"}],"indication":[{"id":"prostate-mcrpc","kind":"indication","name":"Metastatic castration-resistant prostate cancer","route":"/indications/prostate-mcrpc/"}],"person":[{"id":"oliver-sartor","kind":"person","name":"A. Oliver Sartor","route":"/people/oliver-sartor/"}],"pairing":[{"id":"beta-then-alpha","kind":"pairing","name":"Beta radioligand → alpha radioligand","route":"/pairings/beta-then-alpha/"}],"isotope":[{"id":"ac-225","kind":"isotope","name":"Actinium-225","route":"/isotopes/ac-225/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}]}}