Differential Clearance of Lu-PSMA-617 from Metastatic Prostate Cancer Lesions and Normal Tissues creates a Window for Safe Application of DNA Repair Inhibitors
Russell, J.; Grkovski, M.; O'Donoghue, J. A.; Franca Velo, A.; Krebs, S. S.; Bodei, L.; Schoder, H.; Humm, J. L.
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BackgroundDNA repair inhibitors may safely enhance targeted radiotherapy if they can be administered when radioisotope has cleared from critical normal tissues. We investigated whether the kinetics of [177Lu]Lu-PSMA-617 (Pluvicto) would be consistent with such a strategy in metastatic castrate resistant prostate cancer (mCRPC). Materials and MethodsPluvicto effective t1/2 was measured for organs-at-risk (kidneys, parotid and submandibular glands) and lesions from 60 mCRPC patients. Based on this, a safe strategy for DDR inhibition was defined, and its potential benefit to the lesion was calculated, using published in vitro radiosensitivity data. ResultsPluvicto clearance is almost 3x faster in normal organs-at-risk compared to lesions. Using pre-clinical estimates of DDRi sensitization, a meaningful increase in lesion effective treatment dose could be achieved with minor additional risk to normal organs.
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