{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:15:32Z","timestamp":1792088132643,"version":"4.4.0"},"reference-count":30,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Investigation remains incomplete regarding potential variations in the effect of androgen receptor pathway inhibitors, including apalutamide, based on baseline tumor burden in patients with metastatic castration\u2010sensitive prostate cancer (mCSPC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The authors analyzed individual participant\u2010level data from 1052 patients with mCSPC who were randomized in the TITAN trial (apalutamide vs. placebo, both with androgen\u2010deprivation therapy). Outcomes included radiographic progression\u2010free survival (PFS), second PFS (PFS2), and overall survival (OS). Multivariable Cox proportional hazards regression models, with and without restricted cubic splines, were used to determine the association between apalutamide benefit and bone metastasis count or visceral metastasis. Subgroup treatment effects were quantified based on inverse probability of treatment weighting\u2010adjusted hazard ratios (HRs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis using restricted cubic splines indicated that apalutamide provided less benefit for PFS2 and OS in patients with fewer bone metastases. The authors also found evidence of a heterogeneous effect of apalutamide on PFS2 and OS between patients with two or less bone metastases and those with three or more bone metastases. In patients who had two or less bone metastases, there was no evidence of a benefit from apalutamide for radiographic PFS (HR, 0.65; 95% confidence interval [CI], 0.35\u20131.22), PFS2 (HR, 1.18; 95% CI, 0.66\u20132.12), or OS (HR, 1.05; 95% CI, 0.60\u20131.83). No evidence of an association was noted between visceral metastasis and apalutamide benefit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The addition of apalutamide to androgen\u2010deprivation therapy may provide less benefit in patients with mCSPC who have fewer bone metastases. Counting baseline bone metastases may help identify optimal candidates for apalutamide treatment of mCSPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trials registration<\/jats:title><jats:p>NCT02489318<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain language summary<\/jats:title><jats:p>\n<jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In an analysis of individual participant data from a trial (the TITAN trial) in patients with metastatic (spreading) castration\u2010sensitive prostate cancer, treatment intensification based on the addition new drugs to standard androgen\u2010deprivation therapy (ADT) was analyzed and compared with the effects in patients who received only standard ADT.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Compared with ADT alone, the survival benefit of adding the new drug apalutamide to standard ADT varied according to the number of bone metastases, but no association was observed between the spread of cancer to soft tissues and organs and a survival benefit from adding apalutamide.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The results indicate that counting the number of bone metastases may help identify which patients with metastatic castration\u2010sensitive prostate cancer are optimal candidates for treatment intensification with the addition of apalutamide to standard ADT.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.35819","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T12:40:33Z","timestamp":1742388033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tumor burden and heterogenous treatment effect of apalutamide in metastatic castration\u2010sensitive prostate cancer"],"prefix":"10.1002","volume":"131","author":[{"given":"Wataru","family":"Fukuokaya","sequence":"first","affiliation":[{"name":"Department of Clinical Biostatistics Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Urology The Jikei University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichiro","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7410-0712","authenticated-orcid":false,"given":"Takafumi","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Urabe","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Rajwa","sequence":"additional","affiliation":[{"name":"Second Department of Urology Center of Postgraduate Medical Education  Warsaw Poland"},{"name":"Division of Surgery and Interventional Science University College London  London UK"},{"name":"Department of Urology Comprehensive Cancer Center Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Briganti","sequence":"additional","affiliation":[{"name":"Department of Urology Vita\u2010Salute San Raffaele University  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrokh F.","family":"Shariat","sequence":"additional","affiliation":[{"name":"Department of Urology Comprehensive Cancer Center Medical University of Vienna  Vienna Austria"},{"name":"Department of Urology Weill Cornell Medical College  New York New York USA"},{"name":"Department of Urology University of Texas Southwestern  Dallas Texas USA"},{"name":"Karl Landsteiner Institute of Urology and Andrology  Vienna Austria"},{"name":"Department of Urology Second Faculty of Medicine, Charles University  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology National Cancer Center Hospital East  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Urology The Jikei University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Hirakawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Biostatistics Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21763"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.2246"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1503747"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1704174"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1903307"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2119115"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1903835"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.00193"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.00799"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.00041"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(23)00063\u20103"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003\u20104819\u2010147\u20108\u2010200710160\u201000010"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.03488"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr597"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1109\/tac.1974.1100705"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/67.1.145"},{"key":"e_1_2_10_18_1","unstructured":"GreiferN.Weighting for Covariate Balance in Observational Studies. Accessed December 4 2024.https:\/\/ngreifer.github.io\/WeightIt\/"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/00273171.2011.568786"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2019.04.002"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)90006-X"},{"issue":"2","key":"e_1_2_10_22_1","first-page":"746","article-title":"An introduction to multiplicity issues in clinical trials: the what, why, when and how","volume":"46","author":"Li G","year":"2017","journal-title":"Int J Epidemiol"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2003.08.009"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20105347(05)64059\u20101"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejm199810083391504"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.113290"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41391\u2010021\u201000436\u2010y"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(21)02437\u20105"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.01535"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2020.05.003"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/s2666\u20107568(22)00186\u20106"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.35819","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:55:25Z","timestamp":1760298925000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.35819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,19]]},"references-count":30,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/cncr.35819"],"URL":"https:\/\/doi.org\/10.1002\/cncr.35819","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,19]]},"assertion":[{"value":"2024-12-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e35819"}}