medRxiv : the preprint server for health sciences · 2025
Differential Clearance of [177Lu]Lu-PSMA-617 from Metastatic Prostate Cancer Lesions and Normal Tissues creates a Window for Safe Application of DNA Repair Inhibitors.
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Russell James, Grkovski Milan, O'Donoghue Joseph A, Franca-Velo Alexandre, Krebs Simone, Bodei Lisa, Schöder Heiko, Humm John L
Аннотация
BACKGROUND: DNA 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 METHODS: Pluvicto 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.
RESULTS: Pluvicto clearance is almost 3× 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.
MATERIALS AND METHODS: Pluvicto 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.
RESULTS: Pluvicto clearance is almost 3× 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.