{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:11:48Z","timestamp":1788909108361,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Many patients with biochemically recurrent prostate cancer (BCRPC) prefer to delay androgen deprivation therapy (ADT) due to its adverse effects, highlighting the need for better\u2010tolerated, effective alternatives. A subgroup analysis of our prior Phase II trial showed that muscadine grape skin extract (MPX) increased PSA doubling time (PSADT) in patients with <jats:italic>SOD2<\/jats:italic> Ala\/Ala variant which provided the rationale for this trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This randomized, double\u2010blind, placebo\u2010controlled trial, conducted at 14 sites, evaluated patients with BCRPC and <jats:italic>SOD2<\/jats:italic> Ala\/Ala genotype. Patients received 4000\u2009mg MPX or placebo daily. The primary endpoint was on\u2010study PSA slope with comparisons between treatment arms. Secondary endpoints were PSADT, PSA response (\u2265\u200950% decrease), and PSA progression free survival (PFS). Correlative studies included markers of oxidative stress and gastrointestinal microbiota composition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At interim analysis, fifty\u2010nine patients were randomized (MPX, <jats:italic>n<\/jats:italic>\u2009=\u200929; placebo, <jats:italic>n<\/jats:italic>\u2009=\u200930). On\u2010study PSA slopes at 12, 24, 36, and 48 weeks showed no significant differences between the MPX and placebo arms (<jats:italic>p<\/jats:italic>\u2009=\u20090.49). The study was stopped due to futility. No significant differences were observed in PSADT, PSA response, median PSA PFS, or oxidative stress biomarkers. MPX was well\u2010tolerated, with no grade 3\u20134 AEs attributable to the study drug. Microbiome analysis showed no significant differences in alpha diversity but revealed increased relative abundance of <jats:italic>Roseburia faecis<\/jats:italic> and <jats:italic>Akkermansia muciniphila<\/jats:italic> in the MPX group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Although MPX supplementation had no significant effect on PSA slope in men with BCRPC and <jats:italic>SOD2<\/jats:italic> Ala\/Ala variant, this study provides a rigorous evaluation of a natural product and highlights the importance of well\u2010designed clinical trials in advancing evidence\u2010based integrative oncology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p>ClinicalTrials. gov, NCT03535675.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.24903","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T05:59:00Z","timestamp":1746511140000},"page":"966-976","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Muscadine Grape Skin Extract in Biochemically Recurrent Prostate Cancer: A Randomized, Placebo\u2010Controlled, Biomarker\u2010Enriched Trial in Patients With the <i>SOD2<\/i> Ala\/Ala Variant"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-7280","authenticated-orcid":false,"given":"A.","family":"Mandl","sequence":"first","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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R.","family":"McKay","sequence":"additional","affiliation":[{"name":"University of California, San Diego La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"Taplin","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Z.","family":"Szmulewitz","sequence":"additional","affiliation":[{"name":"University of Chicago Medical Center Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. L.","family":"Maughan","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute at the University of Utah Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. R.","family":"Reichert","sequence":"additional","affiliation":[{"name":"University of Michigan Medical School Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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