Muscadine grape skin extract in men with biochemically recurrent prostate cancer: A phase III, randomized, multicenter, placebo-controlled clinical trial.
Authors: Mandl Adel , Zahurak Marianna , Sfanos Karen , Metri Nicole , Maughan Benjamin L. , Taplin Mary-Ellen , Shore Neal D. , McKay Rana R. , Reichert Zachery R , Szmulewitz Russell Zelig , Kessler Elizabeth R. , Heath Elisabeth I. , Dreicer Robert , Stein Cy Aaron , Marshall Catherine Handy , Markowski Mark Christopher , Denmeade Samuel R. , Antonarakis Emmanuel S. , Carducci Michael Anthony , Paller Channing Judith ,   Hopkins
Published: January 2024

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Background: Many patients prefer to delay endocrine therapy for biochemically recurrent prostate cancer (BRCPC) due to associated adverse effects, underscoring the importance of safer and effective alternatives. Muscadine grape skin extract (MPX) inhibits cancer cell growth, promotes apoptosis, and reduces cell migration without impacting normal cells in preclinical studies. Superoxide dismutase2 (SOD2), exhibits a distinctive single-nucleotide polymorphism (rs4880), resulting in either an alanine (Ala) or valine (Val) allele. Results from our prior Phase II trial indicated a significant increase in PSA doubling time (PSADT) post-MPX treatment in patients with SOD2 Ala/Ala genotype, suggesting a therapeutic response specific to this subgroup. Methods: Encouraged by these results, we conducted a multicenter, double-blind, randomized, placebo-controlled Phase III trial to assess the efficacy of MPX treatment in men with BCRPC who have the SOD2 Ala/Ala genotype and wish to defer androgen deprivation therapy. Participants were allocated 1:1 to a daily regimen of 4000 mg MPX or a placebo, with stratification based on pretreatment PSADT and grade groups. The primary endpoint was on-study PSA slope compared between treatment arms and adjusted for baseline PSA slope. Secondary endpoints included PSADT, PSA objective response, and time to PSA progression. Concurrently, we analyzed fecal samples to examine the impact of MPX treatment on gastrointestinal microbiota composition. Results: A total of 59 patients were randomized, with 29 assigned to receive MPX and 30 to receive a placebo. The on-study PSA slopes, analyzed from PSA values recorded at baseline, 12, 24, 36, and 48 weeks, demonstrated no significant difference between the placebo and MPX arms (p=0.49). There were no significant changes in paired on-study and pre-study slopes in either treatment or placebo arms. Furthermore, there was no significant difference in PSADT between the placebo and MPX arms (p=0.69), and no objective PSA response, defined as a decrease of over 50%, were observed in either arm. The median PSA PFS was 13.77 months in the placebo arm, while not reached in the MPX arm. Due to an insufficient response evidenced in the interim analysis, accrual to the trial was suspended by the DSMB for futility. Importantly, there were no drug-related CTCAE grade 3–4 adverse events. Conclusions: We have determined that MPX treatment had no significant effect on PSA slope in men with BCRPC exhibiting the SOD2 Ala/Ala genotype. Furthermore, qPCR analyses of DNA extracts from fecal samples revealed no substantial alterations in microbiome composition following 12 weeks of MPX treatment, when comparing pre- and post-treatment specimens. Consequently, we do not recommend grape skin extract supplementation as a strategy to delay the initiation of ADT in patients with BCRPC. Clinical trial information: NCT03535675 .