PSMA – prostate specific membrane antigen – is overexpressed 100 – 1000 x on prostate cancer cells (5 – 10 % of prostate cancers do not have excess PSMA).
- PSMA is a transmembrane glycoprotein, which acts as an enzyme involved in nutrient and folate uptake – it usually sits in cytoplasm but in malignant transformation can move to luminal surfaces of ducts
- Expressed at low levels in normal prostate tissue
- PSMA is a misnomer – it is found in other cells including small bowel, salivary glands, lacrimal glands and proximal renal tubules
PSMA-targeted small molecules or ligands (i.e. PSMA-617, PSMA-11) are paired with radionuclides.
Positron emitting radionuclides such as Gallium-68 or Fluorine-18 are labelled with PSMA ligands and detectable by PET scans for diagnostics.
Theranostics refers to PSMA-binding ligands being labelled with radionuclides which produce potent cytotoxic decay products which kill tumour cells.
- Alpha emitters – Actinium 225
- Beta emitters – Lutetium 177, Copper 67, Iodine 131
Lutetium 177 paired with PSMA-617 has tumour killing beta-particles and imageable photons detectable by planar scintography and SPECT imaging – allowing both therapy and imaging of agent distribution.
Actinium 225 paired with PSMA-617 emits alpha particles – which have higher energies which are extremely cytotoxic with shorter path length than beta particles (theoretically can kill smaller areas with less collateral damage).
Theranostic agents currently being studied in mCRPC but trials underway in earlier stages of prostate cancer.
Side effects:
- Dry mouth
- Dry eyes
- Thrombocytopenia
- Leukopenia
VISION trial – Lutetium vs SOC (ADT) – improved overall survival (15 months vs 11 months) for those treated with at least one novel antiandrogen and one taxane chemo agent.
TheraP – Lutetium vs cabazitaxel – earlier PSA response with less severe toxicity (33 vs 53 % severe toxicity) – June 2022 update showed no different in OS (19 months)