{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T17:33:15Z","timestamp":1790530395430,"version":"4.1.0"},"reference-count":113,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T00:00:00Z","timestamp":1754697600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2025,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Metastatic castration\u2010resistant prostate cancer (mCRPC) remains a lethal stage of disease progression despite substantial therapeutic advancements. Driven largely by androgen receptor (AR) signaling, prostate cancer eventually develops resistance to AR\u2010directed therapies, necessitating alternative strategies. In recent years, several novel agents have received US Food and Drug Administration approval for mCRPC, including next\u2010generation AR\u2010signaling inhibitors, poly(adenosine diphosphate\u2010ribose) polymerase inhibitors, targeted radioligand therapy, and immunotherapy. Although these treatments have extended survival, resistance mechanisms and optimal sequencing remain key challenges. Molecular profiling has uncovered distinct genomic alterations\u2014such as defects in homologous recombination repair genes and mismatch repair alterations\u2014that guide therapeutic decision making. In parallel, novel treatment modalities are being explored, including AR degraders, antibody\u2013drug conjugates, T\u2010cell engagers, and epigenetic modulators. This review critically evaluates current US Food and Drug Administration\u2010approved therapies for mCRPC, examines emerging therapeutic strategies under clinical development, and discusses evolving biomarker\u2010driven approaches that aim to personalize treatment and improve outcomes.<\/jats:p>","DOI":"10.1002\/cncr.70037","type":"journal-article","created":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T16:15:32Z","timestamp":1754756132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Optimizing treatment for metastatic castration\u2010resistant prostate cancer: Food and Drug Administration\u2010approved therapies, emerging strategies, and biomarker\u2010driven approaches"],"prefix":"10.1002","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1194-2792","authenticated-orcid":false,"given":"Faisal","family":"Saeed","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob E.","family":"Berchuck","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4003-1103","authenticated-orcid":false,"given":"Mehmet Asim","family":"Bilen","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jatin S.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6385-1329","authenticated-orcid":false,"given":"Bassel","family":"Nazha","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T.","family":"Brown","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Schuster","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashesh B.","family":"Jani","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jindan","family":"Yu","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"},{"name":"Department of Urology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara R.","family":"Harik","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Winship Cancer Institute Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,9]]},"reference":[{"key":"e_1_2_7_2_1","volume-title":"Cancer Facts & Figures 2024","author":"American Cancer Society","year":"2024"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2007.12.4487"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2020.09.002"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010019\u20100780\u2010z"},{"key":"e_1_2_7_6_1","volume-title":"NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines\u00ae). Prostate Cancer Version 1.2025","author":"National Comprehensive Cancer Network (NCCN)","year":"2024"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2003892"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1815671"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1800536"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2001342"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1715546"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2020.08.011"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(14)71205\u20107"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(12)70379\u20100"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1207506"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1405095"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201019\u20103023"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13215417"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci122819"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.1341"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2016.70.1961"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.18.01731"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa040720"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(10)61389\u2010x"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6548"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13407"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1200\/po.18.00283"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100078\u2010z"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1902651116"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585\u2010022\u201000580\u20107"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30808"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1911440"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2022485"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.01035"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2214676"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010022\u201001648\u20105"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.09.2748"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2019.02.002"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.02105"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.cd\u201021\u20100007"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.cd\u201013\u20100172"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aam7479"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1056\/evidoa2200043"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.6_suppl.lba16"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.01649"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.5_suppl.lba18"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(23)01055\u20103"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.01868"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2024.09.003"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.115078"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.10547"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071752"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1603144"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.5801"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.01638"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(20)30445\u20109"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco\u201024\u201001283"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.00233"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.09.2721"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2107322"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(24)01653\u20102"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(23)00529\u20106"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.124.267730"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29070400"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1911206"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.1828"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.001"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2022.09.004"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2024.109486"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201085969\u2010x"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2022.40.6_suppl.017"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2024.42.16_suppl.5011"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.20517\/cdr.2024.173"},{"key":"e_1_2_7_74_1","volume-title":"Oncternal Therapeutics announces termination of its clinical studies and exploration of strategic alternatives [news release]","author":"Oncternal Therapeutics","year":"2024"},{"key":"e_1_2_7_75_1","volume-title":"ESSA Pharma announces termination of phase 2 study evaluating masofaniten combined with enzalutamide in patients with metastatic castration\u2010resistant prostate cancer [news release]","author":"ESSA Pharma Inc","year":"2024"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.09.2715"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.23922"},{"key":"e_1_2_7_78_1","unstructured":"Ambrx.Abbrx Announces ARX517 a PSMA\u2010Targeted ADC Demonstrates a Promising 52% PSA50 (\u226550% Reduction) and a Highly Differentiated Safety and PK Profile in Patients with mCRPC who Progressed on Multiple FDA\u2010Approved Treatments Urology Today;2023. Accessed February 20 2025.https:\/\/www.urotoday.com\/conference\u2010highlights\/esmo\u20102023\/esmo\u20102023\u2010press\u2010releases\/147585\u2010ambrx\u2010announces\u2010arx517\u2010a\u2010psma\u2010targeted\u2010adc\u2010demonstrates\u2010a\u2010promising\u201052\u2010psa50\u201050\u2010reduction\u2010and\u2010a\u2010highly\u2010differentiated\u2010safety\u2010and\u2010pk\u2010profile\u2010in\u2010patients\u2010with\u2010mcrpc\u2010who\u2010progressed\u2010on\u2010multiple\u2010fda\u2010approved\u2010treatments.html"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/pcan.2016.49"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010023\u201002284\u2010w"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.2308"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.1148\/rg.240080"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.am2023\u2010ct159"},{"key":"e_1_2_7_84_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17050774"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1150777"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1200\/po.19.00399"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2019.09.036"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.04.034"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00666"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201021\u20104302"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2018.9"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clgc.2022.11.017"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.04.008"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.05.006"},{"key":"e_1_2_7_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clgc.2021.07.014"},{"key":"e_1_2_7_96_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.01576"},{"key":"e_1_2_7_97_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.6_suppl.tps287"},{"key":"e_1_2_7_98_1","volume-title":"Update on CAPItello\u2010280 phase III trial of Truqap in metastatic castration\u2010resistant prostate cancer [news release]","author":"AstraZeneca","year":"2025"},{"key":"e_1_2_7_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(21)00580\u20108"},{"key":"e_1_2_7_100_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201001042\u20107"},{"key":"e_1_2_7_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-91367-6.00024-6"},{"key":"e_1_2_7_102_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.ccr\u201018\u20101589"},{"key":"e_1_2_7_103_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.cd\u201020\u20100751"},{"key":"e_1_2_7_104_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2019.37.15_suppl.tps5089"},{"key":"e_1_2_7_105_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2021.39.15_suppl.tps5085"},{"key":"e_1_2_7_106_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523\u2010023\u201000949\u20107"},{"key":"e_1_2_7_107_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.035"},{"key":"e_1_2_7_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.1684"},{"key":"e_1_2_7_109_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.6_suppl.tps282"},{"key":"e_1_2_7_110_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.5_suppl.tps288"},{"key":"e_1_2_7_111_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.5_suppl.tps287"},{"key":"e_1_2_7_112_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.am2024\u20106586"},{"key":"e_1_2_7_113_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2024.100616"},{"key":"e_1_2_7_114_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100146"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.70037","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:44:48Z","timestamp":1760406288000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.70037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,9]]},"references-count":113,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,8,15]]}},"alternative-id":["10.1002\/cncr.70037"],"URL":"https:\/\/doi.org\/10.1002\/cncr.70037","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,9]]},"assertion":[{"value":"2025-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70037"}}