{"doi":"10.1101/2025.10.08.25337591","title":"Differential Clearance of [ <sup>177</sup> Lu]Lu-PSMA-617 from Metastatic Prostate Cancer Lesions and Normal Tissues creates a Window for Safe Application of DNA Repair Inhibitors","abstract":"ABSTRACT 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 [ 177 Lu]Lu-PSMA-617 (Pluvicto) would be consistent with such a strategy in metastatic castrate resistant prostate cancer (mCRPC). Materials and Methods Pluvicto effective t 1/2 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.","journal":"medRxiv","year":2025,"id":577483,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9612,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255788,"name":"Milan Grkovski","orcid":"0000-0001-7228-9497","position":1,"is_corresponding":false},{"id":268006,"name":"Joseph A. O’Donoghue","orcid":"0000-0002-2761-0015","position":2,"is_corresponding":false},{"id":1126083,"name":"Alexandre França Velo","orcid":"0000-0001-9786-4136","position":3,"is_corresponding":false},{"id":424344,"name":"Simone Krebs","orcid":"0000-0002-9909-4531","position":4,"is_corresponding":false},{"id":107710,"name":"Lisa Bodei","orcid":"0000-0001-6930-7383","position":5,"is_corresponding":false},{"id":255787,"name":"Heiko Schöder","orcid":"0000-0002-5170-4185","position":6,"is_corresponding":false},{"id":255807,"name":"John L. Humm","orcid":"0000-0003-4245-5591","position":7,"is_corresponding":false},{"id":228775,"name":"James Russell","orcid":"0000-0003-0827-1801","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:58:04.622308Z","pmid":"41282895","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}