{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:52:27Z","timestamp":1791424347916,"version":"4.3.3"},"reference-count":13,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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":["Int J of Urology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Perioperative treatment with enfortumab vedotin (EV) plus pembrolizumab has demonstrated a high pathological complete response (pCR) rate in patients with cisplatin\u2010ineligible muscle\u2010invasive bladder cancer (MIBC). However, whether this therapeutic benefit reflects true pharmacologic synergy or can be explained by independent drug action (IDA) remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed data from EV\u2010103 cohort H (EV monotherapy), the cisplatin\u2010ineligible subset of PURE\u201001 (pembrolizumab monotherapy), and KEYNOTE\u2010905\/EV\u2010303 (EV plus pembrolizumab). An IDA model incorporating a Gaussian copula was applied to estimate the predicted pCR rate of the combination therapy. The primary analysis assumed weak positive dependence between drug responses (correlation coefficient\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.24). Sensitivity analyses evaluated the observed\u2010minus\u2010IDA\u2010predicted pCR difference across a continuous range of dependence assumptions (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.00\u20130.99).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The predicted pCR rate for EV plus pembrolizumab was 53.5%, consisting of 21.4% EV\u2010only responders, 17.1% pembrolizumab\u2010only responders, and 15.0% dual responders. The observed pCR rate in the KEYNOTE\u2010905\/EV\u2010303 trial was 57.1%, corresponding to an absolute difference of 3.6 percentage points compared with the model prediction. In sensitivity analyses, the posterior median observed\u2010minus\u2010predicted difference increased with stronger positive dependence, but the 95% credible intervals were wide and included zero across a broad range of dependence assumptions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Although modest pharmacologic synergy cannot be excluded given the uncertainty in the available data, substantial population\u2010level pharmacologic synergy is not required to explain the high pCR observed with the combination.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iju.70667","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:07:43Z","timestamp":1791421663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative Evaluation of Pharmacologic Synergy for Neoadjuvant Enfortumab Vedotin Plus Pembrolizumab in Muscle\u2010Invasive Bladder Cancer: A Copula\u2010Based Secondary Analysis"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5793-7895","authenticated-orcid":false,"given":"Riko","family":"Ikeda","sequence":"first","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-8083","authenticated-orcid":false,"given":"Soichiro","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Urology Zigong Fourth People's Hospital  Zigong Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9454-3345","authenticated-orcid":false,"given":"Motohiro","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Urology Teikyo University Hospital, Mizonokuchi  Kawasaki Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2300-8446","authenticated-orcid":false,"given":"Shugo","family":"Yajima","sequence":"additional","affiliation":[{"name":"Department of Urology National Cancer Center Hospital East  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7548-1580","authenticated-orcid":false,"given":"Hiroshi","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3632-2901","authenticated-orcid":false,"given":"Hajime","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9507-9887","authenticated-orcid":false,"given":"Hiroyuki","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2580-7460","authenticated-orcid":false,"given":"Akihiro","family":"Hirakawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6761-3229","authenticated-orcid":false,"given":"Yasuhisa","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2025.02.019"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa022148"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2023.03.012"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(10)70275\u20108"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2511674"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.16_suppl.4583"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2023.12.008"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585\u2010020\u201000394\u20105"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/14796694.2025.2482363"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201021\u20100212"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2025.07.003"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2025.110990"}],"container-title":["International 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