Muscadine Grape Skin Extract in Biochemically Recurrent Prostate Cancer: A Randomized, Placebo‐Controlled, Biomarker‐Enriched Trial in Patients With the SOD2 Ala/Ala Variant

ABSTRACT Background 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‐tolerated, 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 SOD2 Ala/Ala variant which provided the rationale for this trial. Methods This randomized, double‐blind, placebo‐controlled trial, conducted at 14 sites, evaluated patients with BCRPC and SOD2 Ala/Ala genotype. Patients received 4000 mg MPX or placebo daily. The primary endpoint was on‐study PSA slope with comparisons between treatment arms. Secondary endpoints were PSADT, PSA response (≥ 50% decrease), and PSA progression free survival (PFS). Correlative studies included markers of oxidative stress and gastrointestinal microbiota composition. Results At interim analysis, fifty‐nine patients were randomized (MPX, n  = 29; placebo, n  = 30). On‐study PSA slopes at 12, 24, 36, and 48 weeks showed no significant differences between the MPX and placebo arms ( p  = 0.49). 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‐tolerated, with no grade 3–4 AEs attributable to the study drug. Microbiome analysis showed no significant differences in alpha diversity but revealed increased relative abundance of Roseburia faecis and Akkermansia muciniphila in the MPX group. Conclusions Although MPX supplementation had no significant effect on PSA slope in men with BCRPC and SOD2 Ala/Ala variant, this study provides a rigorous evaluation of a natural product and highlights the importance of well‐designed clinical trials in advancing evidence‐based integrative oncology. Trial registration ClinicalTrials. gov, NCT03535675.