A first-in-human trial of actinium-225-PSMA-617

Among the more interesting developments in radiation oncology/nuclear medicine in recent years are novel therapies created by attaching radioactive isotopes to molecules (called ligands) that attach to the prostate-specific membrane antigen (PSMA). PSMA is found on the surface of most metastatic prostate cancer cells.

We have seen several small studies conducted throughout Germany using Lu-177-PSMA (see this link for the latest update). Lu-177 is a beta- (β-) particle emitter — its radioactivity is produced when a neutron decays into a proton and an energetic electron — a beta particle. Xofigo is an alpha- (α-) particle emitter — its radioactivity occurs when the radium-223 nucleus releases two protons and two neutrons — an alpha particle or helium nucleus. There are advantages and disadvantages to each (see table in this link).

Lu-177-PSMA was developed at the University of Heidelberg. The research group there has also developed a targeted therapy using an alpha-emitter called actinium-225 (Ac-225). Ac-225-PSMA-617 can potentially be used in some situations where Xofigo or Lu-177-PSMA cannot. Xofigo only treats bone metastases because radium is biologically similar to calcium and replaces it in areas of active bone growth, like metastases. Ac-225-PSMA-617 has several theoretical advantages:

  • It can target metastases in any tissue or fluid, including undetectable, systemic micrometastases.
  • Because its alpha particles are very short range, it doesn’t destroy very much healthy bone marrow.
  • Because the alpha particles are highly energetic, they destroy nearby cells very effectively.
  • Because it attaches to PSMA instead of calcium-active sites in bone or other tissue, it may be less toxic to other healthy tissue.

Kratochwil et al. report a proof-of-concept in two patients treated with Ac-225-PSMA-617. They used Ga-68-PSMA-11, which shows up on a PET scan, to detect metastases that were positive for PSMA and to detect response to the alpha-emitter. The two patients selected had progressed under other treatments and were in “highly challenging clinical situations,” which included tumor infiltration into the red bone marrow. After bi-monthly treatments, both patients:

  • Exhibited complete PSA response, becoming undetectable
  • Exhibited complete tumor response on PET imaging
  • Exhibited no hematological toxicity; that is, no bone marrow suppression
  • Exhibited dry mouth from decreased saliva (xerostomia)

This is a first-in-human trial, and larger trials will be needed to prove efficacy and safety. However, it is an early encouraging development worth taking note of.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

7 Responses

  1. The link to the table didn’t work for me — URL is missing.

  2. Sounds very promising.

  3. Tom: The link is fixed.

  4. I reached out to Scott Tagawa, who has conducted some early pilot trials of Lu-177-PSMA-J591 in the US and has an expanded multi-centric one going now for men who are non-metastatic, castrate-resistant, and have a high or rapidly rising PSA (NCT00859781). He is working on an expanded trial using Lu-177-PSMA-617 for metastatic, castrate-resistant men. He is also working on a trial of Ac-225 using the ligand J591 instead of PSMA-617. He believes there will be less toxicity with J591. I know there is a lot of interest in this, so we will report it as soon as clinical trials open for recruitment.

  5. Allen:

    Please can you explain in layman’s terms what the differences and/or relative advantages/disadvantages are between the lutetium and the actinium PSMA protocols.

    We have a couple of Aussies who are regular participants in our virtual support call that are in the Lu-177 trial in Oz.

    Many thanks,


  6. Lu-177 puts out beta particles, which are very tiny — they are electrons. Being small, they travel relatively far, and destroy cancer cells and maybe some healthy cells that they come into contact with. Ac-225 puts out alpha particles (2 protons and 2 neutrons). They are thousands of times heavier than beta particles, so they don’t travel as far. They also pack a much bigger wallop — very effectively killing anything they come into close contact with. So the Lu-177 might kill relatively larger tumors, while the Ac-225 might be good for micromets where there may be sensitive tissue (like bone marrow) nearby. Ra-223 accomplishes a similar purpose using alpha particles, but it only goes to bone mets. The table that is in the link summarizes the differences between Xofigo and Lu-177-PSMA.

  7. Many thanks Allen!

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