{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:51:57Z","timestamp":1790805117207,"version":"4.1.0"},"reference-count":95,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pacific Northwest Prostate Cancer SPORE","award":["P50 CA097186"],"award-info":[{"award-number":["P50 CA097186"]}]},{"DOI":"10.13039\/501100004376","name":"Terry Fox Research Institute\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/00mtf6c40","doi-asserted-by":"publisher","award":["#1109"],"award-info":[{"award-number":["#1109"]}],"id":[{"id":"10.13039\/501100004376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000994","name":"BC Cancer Foundation (BCCF)\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/03gqhbs95","doi-asserted-by":"publisher","award":["#PRRG012"],"award-info":[{"award-number":["#PRRG012"]}],"id":[{"id":"10.13039\/100000994","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1\/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) rewiring (e.g., homologous recombination repair (HRR) restoration, fork protection, checkpoint tolerance, and altered drug handling) converges with treatment-induced dormancy and quiescent therapy-tolerant residual states that sustain minimal residual disease (MRD) under androgen receptor pathway inhibition (ARPI) and PARP blockade. We synthesize clinical and translational evidence for PARPi monotherapy and PARPi-based combinations across disease states. In first-line metastatic castration-resistant prostate cancer (mCRPC), PARPi plus ARPI consistently prolongs radiographic progression-free survival, with the greatest benefit in HRR-altered tumors, and emerging overall-survival signals in selected subgroups. In later-line settings, monotherapy activity is most robust in BRCA2-mutated disease, whereas non-BRCA HRR alterations show heterogeneous and often modest responses, underscoring the need for biomarkers beyond gene panels. We also discuss combination strategies with DDR-targeting agents, radioligand therapies, and immunotherapy, and summarize ongoing phase III programs in metastatic castration-sensitive prostate cancer (mCSPC). Finally, we outline practical considerations for biomarker-informed patient selection, monitoring, sequencing, and toxicity management, with particular emphasis on intercepting MRD and resistance evolution.<\/jats:p>","DOI":"10.3390\/cells15070588","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:48:41Z","timestamp":1774532921000},"page":"588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PARP Inhibition in Prostate Cancer: Current Status, Resistance Mechanisms, and Clinical Challenges"],"prefix":"10.3390","volume":"15","author":[{"given":"Takashi","family":"Matsuoka","sequence":"first","affiliation":[{"name":"Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada"},{"name":"Department of Urologic Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusuke","family":"Akamatsu","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0175-8724","authenticated-orcid":false,"given":"Christopher J.","family":"Ong","sequence":"additional","affiliation":[{"name":"Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Urologic Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E.","family":"Gleave","sequence":"additional","affiliation":[{"name":"Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Urologic Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-8591","authenticated-orcid":false,"given":"Yuzhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada"},{"name":"Department of Urologic Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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