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Lutetium-177 labeled PSMA radioligand therapy ([\u00b9\u2077\u2077Lu]Lu-PSMA) is an established and effective treatment option, while [\u00b2\u00b2\u2075Ac]Ac-PSMA shows promise in refractory cases. The tandem use of [225Ac] Ac and [177Lu] Lu-labeled PSMA ligands is currently being explored to harness the complementary advantages of both isotopes. This meta-analysis investigates the efficacy and safety of [\u00b2\u00b2\u2075Ac]Ac -\/[\u00b9\u2077\u2077Lu]Lu-PSMA radioligand therapy (RLT) in patients with mCRPC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A comprehensive literature search was performed in PubMed, EMBASE, Web of Science (WOS), and Scopus databases, covering all records from inception through March 2025. The primary endpoints focused on therapeutic efficacy, assessed through PSA-based biochemical responses. These included any PSA decline, a PSA decline of more than 50% from baseline, stable disease (defined as a PSA increase of &lt;\u200925% PSA increase or a decrease of &lt;\u200950%), and progressive disease (defined as an increase of \u2265\u200925% PSA) following tandem 225Ac-\/177Lu-PSMA tandem RLT. Secondary endpoints included overall survival (OS) and treatment-related adverse events. A random-effects model was used to generate pooled proportions through meta-analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eight studies, including a total of 323 patients treated with [\u00b2\u00b2\u2075Ac]-\/[\u00b9\u2077\u2077Lu]-PSMA combination therapy, were analyzed. The pooled response rates showed that 47% (95% CI: 37%\u201356%) experienced a PSA decline greater than 50%, while 78% (95% CI: 70%\u201386%) had any measurable PSA decline. The estimated median OS was 11.8 months (95% CI: 9.0\u201314.6 months). Severe toxicities were infrequent; the most common severe grade\u2009\u2265\u20093 adverse events were anemia (10%) and thrombocytopenia (6%). No cases of grade\u2009\u2265\u20093 xerostomia were reported.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>[\u00b2\u00b2\u2075Ac]Ac-\/[\u00b9\u2077\u2077Lu]Lu-PSMA RLT shows encouraging activity and manageable safety in patients with advanced mCRPC. Given the retrospective nature of the available evidence and limited data, these findings should be further evaluated in prospective trials to determine long-term efficacy and survival outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-025-07627-y","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T03:59:58Z","timestamp":1763438398000},"page":"2881-2892","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic outcomes of \u00b2\u00b2\u2075Ac\/\u00b9\u2077\u2077Lu-PSMA combination therapy in advanced metastatic Castration-Resistant prostate cancer: A systematic review and Meta-Analysis"],"prefix":"10.1007","volume":"53","author":[{"given":"Zineddine","family":"Belabaci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Brignoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milo\u0161","family":"Gruji\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issa","family":"Mohamad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akram","family":"Al-Ibraheem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6477-6655","authenticated-orcid":false,"given":"Mohamed","family":"Shelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Afshar-Oromieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"issue":"5","key":"7627_CR1","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1634\/theoncologist.2012-0478","volume":"18","author":"AS Merseburger","year":"2013","unstructured":"Merseburger AS, Bellmunt J, Jenkins C, Parker C, Fitzpatrick JM, on behalf of the European Treatment Practices Group. 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