There is growing evidence of antineoplastic properties of metformin (MET) in prostate cancer (PCa). Many observational studies suggested that using MET was associated with improvement in overall survival in PCa patients. MET was reported to be associated with reduction of risk of development of castration-resistant state (CRPC). In addition, when MET was combined to ADT or biclutamide, it augmented the antiproliferative effect of these drugs.
(MANSMED) is a prospective randomized controlled trial. We randomly assigned high risk localized or mHSPC patients to receive standard of care (SOC) (androgen deprivation plus biclutamide 50mg) plus metformin (850 mg twice daily) or SOC alone. Primary end point was time to castrate resistant prostate cancer (CRPC). Secondary endpoint was overall survival (OS) and PSA response rate. The trial was registered at ClinicalTrials.gov ID NCT03137186.
a total of 124 men were randomly allocated into two arms (62 in MET arm, 62 in SOC arm). The baseline demographic and disease characteristics were comparable between two arms. Over a median follow up of 18 months, there were 12 deaths in the MET arm versus 17 deaths in the control arm (P= 0.2). Median time to CRPC was longer in MET arm 29 months (95%CI 25-33) compared to control arm 20 months (95% CI 16-24) (P=0.01). After subgroup analysis, the median time to progression to CRPC was longer at MET arm in high risk localized prostate cancer (P=0.02), in mHSPC patients with low tumor volume was of borderline significance (P= 0.06), and in those with node positive (N1) disease was highly significant (P=0.001). While in patients with high tumor volume, there was no significant difference regarding the median time to CRPC among the two groups (P=0.9). Regarding secondary objective, there was no significant difference between two arms in overall survival (OS) (P= 0.1) or PSA response rate (P=0.5). Notably no significant adverse events were reported in MET arm apart of self-limiting diarrhea.
Metformin potentially lengthen time to CRPC in advanced PCa patients when combined with ADT especially in those with high risk localized PCa, clinically node positive and in those with low tumor volume metastatic hormone naive patients.
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All authors have declared no conflicts of interest.