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

Prostate Cancer and Prostatic Diseases volume 25, pages 735–740 (2022)Cite this article

Subjects

Abstract

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.

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Fig. 1: Consort flow diagram.
Fig. 2: Difference in % change in refined PBMC subsets after 8 and 32 weeks of treatment (vs baseline) between Arms.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the patients and associated study staff for their participation in this trial. The authors also thank Bonnie L. Casey for editorial assistance in the preparation of this manuscript. The authors additionally thank Ariana Sabzevari, Angie Schwab, and Keanan Wright for technical assistance with immune assays, and Dr. Samuel Litwin for his assistance with the statistical design for the trial.

Funding

This work was supported in part by a grant to the Fox Chase Cancer Center (#P30CA006927) from the National Cancer Institute, National Institutes of Health, and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. Marijo Bilusic

    Present address: Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, 33136, USA

Authors and Affiliations

  1. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Marijo Bilusic, Susan Wroblewski, Fatima Karzai, Ravi A. Madan, William L. Dahut & James L. Gulley

  2. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Nicole J. Toney, Renee N. Donahue & Jeffrey Schlom

  3. Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Matthew Zibelman, Pooja Ghatalia, Elizabeth R. Plimack & Daniel M. Geynisman

  4. Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Eric A. Ross

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Contributions

Conception/Design: MB, ERP, DMG. Provision of study material or patients: MZ, PG, RAM, FK, WLD, JLG, MB. Collection and/or assembly of data: SW, RND, NJT, JS, MB, DMG. Data analysis and interpretation: RND, NJT, JS, JLG, MB, DMG, ER. Manuscript writing: MB, RND, NJT, DMG. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Marijo Bilusic.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study protocol was approved by the Institutional Review Boards of the Fox Chase Cancer Center, Temple University, and the Center for Cancer Research, National Cancer Institute. The study was conducted according to the principles of the Declaration of Helsinki and was performed in compliance with Good Clinical Practice guidelines. Written informed consent was obtained from each patient.

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Bilusic, M., Toney, N.J., Donahue, R.N. et al. A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1). Prostate Cancer Prostatic Dis 25, 735–740 (2022). https://doi.org/10.1038/s41391-022-00492-y

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