A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1)

Background Metformin may have anticancer effects that are independent of its hypoglycemic effects. Retrospective studies have shown that metformin use is associated with decreased incidence of prostate cancer and prostate cancer-specific mortality. Preclinical studies suggesting additive anticancer effects of combining metformin and bicalutamide prompted this clinical trial (NCT02614859). Methods This open-label, randomized, phase 2 trial enrolled non-diabetic patients with biochemically recurrent prostate cancer, a PSADT of 3–9 months, BMI > 25 and normal testosterone. Patients were randomized 1:2 to observation for an initial 8 weeks (Arm A) or metformin 1000 mg twice daily (Arm B). Bicalutamide 50 mg/day was added after 8 weeks to both arms. The primary objective was to evaluate the number of patients with undetectable PSA ( < 0.2 ng/mL) at the end of 32 weeks. Immune correlatives were assessed as exploratory endpoints. Results A total of 29 patients were enrolled from March 2015 to January 2020. No difference was seen between the 2 arms in the proportion of patients with undetectable PSA. Modest PSA decrease ranging from 4% to 24% were seen in 40.0% (95% CI: 19.1–64.0%) of patients with metformin monotherapy, compared to 11.1% (95% CI: 0.3–48.3%) in the observation arm. Metformin monotherapy reduced PD-1 + NK cells, and increased NKG2D + NK cells. The combination of metformin and bicalutamide led to greater reductions in PD-1 expressing NK, CD4 + T, and CD8 + T-cell subsets compared to bicalutamide alone. The trial was stopped early due to predicted inability to achieve its primary endpoint. Conclusions Although metformin plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. Metformin monotherapy induced modest PSA declines in 40% of patients after 8 weeks. Metformin, given alone and in combination with bicalutamide, displayed immune modifying effects, primarily within NK and T cells subsets. Trial registration Trial Registration Number: NCT02614859.