{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T13:45:15Z","timestamp":1785678315134,"version":"3.56.0"},"reference-count":11,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Upfront treatment intensification with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor has become a standard approach for metastatic hormone\u2010sensitive prostate cancer (mHSPC). However, prognosis remains poor for some patients despite second\u2010generation androgen receptor antagonist\u2010based doublet therapy. Although triplet therapy with darolutamide and docetaxel is available, its added clinical value over apalutamide\u2010 or enzalutamide\u2010based doublet therapy in real\u2010world practice remains unclear. Gleason pattern 5 (GP5) reflects aggressive tumor biology and may be relevant for treatment selection. We evaluated whether triplet therapy was associated with longer castration\u2010resistant prostate cancer\u2010free survival (CRPC\u2010FS) than apalutamide\u2010 or enzalutamide\u2010based doublet therapy in systemic treatment\u2010na\u00efve mHSPC, with a particular focus on effect modification by GP5 status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective multicenter cohort study used the ULTRA\u2010J multicenter collaborative database in Japan. We included systemic treatment\u2010na\u00efve patients with mHSPC who received either doublet therapy with ADT plus apalutamide or enzalutamide, or triplet therapy with ADT, darolutamide, and docetaxel, between February 2018 and October 2024. The final analytic cohort consisted of 294 patients. Overlap weighting was used to reduce treatment\u2010selection bias. The primary endpoint was CRPC\u2010FS, and overall survival (OS) was assessed as a supportive endpoint. Progression\u2010free survival 2 (PFS2) and post\u2010CRPC docetaxel use were evaluated as exploratory post\u2010progression outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The median follow\u2010up duration estimated using the reverse Kaplan\u2010Meier method was 18.0 months in the doublet group and 11.0 months in the triplet group. In the overlap weighting\u2010adjusted overall cohort, triplet therapy was associated with longer CRPC\u2010FS than doublet therapy (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.13\u20130.64;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002). A significant interaction was observed for GP5 status (p for interaction\u2009=\u20090.037). In the GP5\u2010positive subgroup, triplet therapy was associated with longer CRPC\u2010FS than doublet therapy (HR, 0.16; 95% CI, 0.06\u20130.42;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), whereas no clear advantage of triplet therapy was observed in the GP5\u2010negative subgroup (HR, 1.85; 95% CI, 0.29\u201311.94;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.52). No clear difference in OS was observed at the current follow\u2010up.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Triplet therapy was associated with longer CRPC\u2010FS than apalutamide\u2010 or enzalutamide\u2010based doublet therapy in systemic treatment\u2010na\u00efve mHSPC. This association appeared more evident in patients with GP5\u2010positive disease. Given the shorter follow\u2010up in the triplet group, limited event numbers in subgroup and PFS2 analyses, and the nonrandomized nature of post\u2010CRPC treatment sequencing, these findings should be interpreted as hypothesis\u2010generating.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pros.70230","type":"journal-article","created":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T13:11:17Z","timestamp":1785676277000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Impact of Gleason Pattern 5 on Doublet Versus Triplet Therapy in Metastatic Hormone\u2010Sensitive Prostate Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4004-6287","authenticated-orcid":false,"given":"Saizo","family":"Fujimoto","sequence":"first","affiliation":[{"name":"Department of Urology Kindai University Hospital Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7138-3579","authenticated-orcid":false,"given":"Tsuyoshi","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Urology Kindai University Nara Hospital Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7555-6295","authenticated-orcid":false,"given":"Yutaka","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Urology Kindai University Nara Hospital Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1351-1315","authenticated-orcid":false,"given":"Teruo","family":"Inamoto","sequence":"additional","affiliation":[{"name":"Department of Urology Hamamatsu University School of Medicine Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4305-7328","authenticated-orcid":false,"given":"Keita","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Urology Hamamatsu University School of Medicine Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University Hospital Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9045-5484","authenticated-orcid":false,"given":"Ryoichi","family":"Maenosono","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University Hospital Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Urology Fujita Health University Hospital Toyoake Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4766-2074","authenticated-orcid":false,"given":"Kiyoshi","family":"Takahara","sequence":"additional","affiliation":[{"name":"Department of Urology Fujita Health University Hospital Toyoake Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seitetsu","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Department of Urology Kawasaki Medical School Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Komura","sequence":"additional","affiliation":[{"name":"Department of Urology Kawasaki Medical School Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1044-912X","authenticated-orcid":false,"given":"Wataru","family":"Fukuokaya","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5673-1553","authenticated-orcid":false,"given":"Takahiro","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-7497","authenticated-orcid":false,"given":"Kazutoshi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Urology Kindai University Hospital Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2119115"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00799"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903307"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-024-02649-2"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/iju.15498"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-024-02577-1"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24855"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jjco\/hyag005"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17020205"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04975-9"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.19.00081"}],"container-title":["The Prostate"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pros.70230","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pros.70230","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pros.70230","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T13:11:18Z","timestamp":1785676278000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pros.70230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,2]]},"references-count":11,"alternative-id":["10.1002\/pros.70230"],"URL":"https:\/\/doi.org\/10.1002\/pros.70230","archive":["Portico"],"relation":{},"ISSN":["0270-4137","1097-0045"],"issn-type":[{"value":"0270-4137","type":"print"},{"value":"1097-0045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,2]]},"assertion":[{"value":"2026-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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