{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T14:10:53Z","timestamp":1768572653271,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,9]]},"group-title":"Oncology","reference-count":16,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    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 [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-PSMA-617 (Pluvicto) would be consistent with such a strategy in metastatic castrate resistant prostate cancer (mCRPC).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>\n                    Pluvicto effective t\n                    <jats:sub>1\/2<\/jats:sub>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    radiosensitivity data.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Pluvicto clearance is almost 3\u00d7 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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.08.25337591","type":"posted-content","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:30:22Z","timestamp":1760056222000},"source":"Crossref","is-referenced-by-count":0,"title":["Differential Clearance of [\n                  <sup>177<\/sup>\n                  Lu]Lu-PSMA-617 from Metastatic Prostate Cancer Lesions and Normal Tissues creates a Window for Safe Application of DNA Repair Inhibitors"],"prefix":"10.64898","author":[{"given":"James","family":"Russell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7228-9497","authenticated-orcid":false,"given":"Milan","family":"Grkovski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2761-0015","authenticated-orcid":false,"given":"Joseph A.","family":"O\u2019Donoghue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9786-4136","authenticated-orcid":false,"given":"Alexandre","family":"Franca-Velo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9909-4531","authenticated-orcid":false,"given":"Simone","family":"Krebs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6930-7383","authenticated-orcid":false,"given":"Lisa","family":"Bodei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5170-4185","authenticated-orcid":false,"given":"Heiko","family":"Sch\u00f6der","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4245-5591","authenticated-orcid":false,"given":"John 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