The use of metformin to treat prostate cancer

In Australia, prostate cancer is the most common type of cancer in males, with its prevalence increasing with age, but metformin may have a role to play.

Prostate cancer is the third leading cause (12.7%) of cancer-related deaths in men, and one in seven will have a diagnosis of prostate cancer by the age of 85 years. Symptoms of localised prostate cancer include frequent urination particularly at night, pain on urination, blood in the urine or semen, a weak urine stream and back or pelvis pain. With more widespread prostate cancer, metastasis often occurs in the bones and causes pain or unexplained weight loss and fatigue.

Treatment for prostate cancer is dependent upon the stage and location of the cancer, and symptom severity. Prostate cancer tends to grow slowly, so during early stages, side effects of treatment may outweigh benefits. For patients who do not require treatment straight away, they may be managed by ‘watchful waiting’ and ‘active surveillance’. For patients needing intervention(s), options include surgery, radiotherapy and androgen-deprivation hormone therapy (e.g. antiandrogens, and gonadotrophin-releasing hormone agonists which are also known as luteinising hormone-releasing hormone agonists), cryosurgery, chemotherapy and immunotherapy.

Currently, interventions for prostate cancer are limited due to the significant impact upon quality of life, drug resistance and toxicity. For instance, the long list of side effects associated with androgen-deprivation hormone therapy can include sexual dysfunction, osteoporosis and bone fractures, vasomotor symptoms (e.g. hot flashes, changes to body composition) and metabolism (e.g. impaired glucose tolerance), risk of cardiovascular harm, kidney injury, fatigue, anemia, gynecomastia, decreased penile and testicular size, hair-thinning, and emotional and cognitive changes. As such, there is a need for therapy that is effective, well-tolerated and affordable. Interestingly, this is where metformin might have a role to play.

While metformin is most commonly associated with type 2 diabetes, it certainly is not the first medicine which comes to mind when one thinks of treatment for prostate cancer, or any cancer for that matter. However, metformin has shown positive results in clinical trials as treatment for colon, lung, breast, endometrial and pancreatic cancer.

It is commonly known that metformin reduces blood glucose levels by reducing hepatic glucose production and increasing glucose utilisation and uptake by skeletal muscle. This lowering of systemic insulin levels is thought to be one of the ways metformin exerts its anti-cancer effects. The reduced insulin levels causes down regulation of insulin receptors on cell membranes, which then reduce a cascade of downstream effects that are usually activated in cancer cells e.g. Ras/Raf/ MEK/ERK and PI3K/AKT/mTOR signaling pathways.

Metformin is also thought to work directly on the cancer cells through altering numerous signaling pathways. One example is through inhibiting mTOR signaling. This is important because mTOR activation can lead to abnormal cell proliferation, inhibition of apoptosis, and carcinogenesis.

A recent systematic review investigating the anticancer potential of metformin on prostate cancer has found a reduced risk of incidence of prostate cancer. Key findings from the various trials reported in the systematic review have also reportedly noted improvements such as disease stabilisation, improvement in survival, and improved responses to other treatments such as radiotherapy in different patient cohorts.

Numerous clinical trials are also investigating the usefulness of metformin as treatment for prostate cancer in various patient groups, and either as monotherapy, or in combination with other interventions.

TABLE 1. Metformin (oral) dosing information (AMH)

*Metformin does not have an indication for this condition – dose provided is indicative only

Conclusion

While these are only interim results, metformin may be useful for some patients who are unable to tolerate the conventional interventions used, or where the risks of the conventional interventions outweigh the potential benefits. Certainly, much more work is required to better understand the clinical utility of metformin for prostate cancer and its impact on quality of life and survival.

It is also particularly important to understand which patients would benefit from its use, its effectiveness with different stages of prostate cancer, how long metformin maintains its effectiveness as a treatment, and whether resistance develops. Nevertheless, metformin’s anticancer effects could have a profound impact on improving the quality of life for men living with prostate cancer.

References

1. Zingales V, Distefano A, Raffaele M, Zanghi A, Barbagallo I, Vanella L. Metformin: A Bridge between Diabetes and Prostate Cancer. Front Oncol. 2017:11;7:243. At: https://www.ncbi.nlm.nih.gov/pubmed/29075616
2. Zaidi S, Gandhi J, Joshi G, Smith NL, Khan SA. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis. 2019: doi: 10.1038/s41391-018-0085-2. At: https://www.ncbi.nlm.nih.gov/pubmed/30651580