Roxanne Nelson

April 02, 2012

April 2, 2012 (Chicago, Illinois) — The diabetic drug metformin has shown an effect on prostate cancer in a small phase 2 study involving 24 patients.

When given to men before prostatectomy, metformin appeared to reduce the growth rate of prostate cancer in a proportion of patients, according to study results presented here at the annual meeting of the American Association for Cancer Research.

Metformin, commonly used to treat type 2 diabetes mellitus, was approved in Europe in 1975 and the United States in 1995, explained lead author Anthony M. Joshua, MBBS, PhD, staff medical oncologist at the Princess Margaret Hospital, University Health Network in Toronto, Ontario, Canada. "Subsequently it has been explored as a treatment and a preventative treatment for cancer, based on a conglomeration of laboratory, epidemiological and clinical data."

Metformin reduces insulin, which may promote tumor growth, he noted during a press briefing. "It may also have both direct and indirect effects on the mTOR [mammalian target of rapamycin] pathway, which contributes to cancer growth."

On the basis of the significant preclinical and epidemiologic studies that suggest a role for metformin in chemoprevention, Dr. Joshua and colleagues evaluated its use in the treatment of prostate cancer.

Reduction in Markers

The phase 2 study included 24 patients with localized prostate cancer, all of whom had at least 20% of at least 1 unfragmented biopsy core. These patients had a median age of 64 years and a median prostate-specific antigen (PSA) level of 6 ng/mL (range, 3.22 - 36.11 ng/mL). Any patients taking any drugs used to treat any form of diabetes were excluded.

In this study, metformin was used in the neoadjuvant setting, said Dr. Joshua. "There was a window of opportunity to test the effect of metformin on prostate tissue — from the point of the initial biopsy tissue to the point of the prostate removal."

All patients received metformin, 500 mg 3 times per day, a dosage lower than that prescribed to patients with diabetes, he pointed out. The median duration of drug treatment was 41 days (range, 18 - 81 days), and all patients underwent prostatectomy with no adverse effect related to metformin use.

"So the 'crunch' of the study was that if we compared the biopsied tumor tissue to the prostates that were surgically removed, it did seem to slow the rate of the cancer," said Dr. Joshua. "But it did not stop the cancer from growing."

Metformin reduced Ki67, a marker of cell proliferation, by an absolute value of 1.65, which is a relative decrease of 32% compared with the original proliferation, he pointed out. This was accompanied by a decrease in the staining of the mTOR pathway, so that marker was significantly reduced in the samples taken after metformin treatment.

However, Dr. Joshua commented that Ki67 is also not a clinically relevant endpoint. "It doesn't tell us if the men will benefit or not; it is simply a marker of how quickly the cancer cells proliferate."

The researchers also found that metformin significantly reduced serum insulin-like growth factor-1 levels (P = .02), fasting glucose levels (P = .03), body mass index (P < .01), and waist-to-hip ratio (P < .01). In addition, there was a trend for a PSA reduction (P = .08).

The drug did affect PSA levels, but Dr. Joshua noted that he was not "confident that it was acting on the PSA."

"There may be other reasons why the PSA goes up and down, and it is intriguing but it is not something that I am comfortable pointing out as an advantage of the drug," he said.

There were no other correlations between any metabolic, morphometric, or cancer-related serum indices.

Dr. Joshua cautioned that the study does have several limitations, including the facts that it is still ongoing and that there is no control group.

Very Interesting Model

Approached by Medscape Medical News for an independent comment, Jose Baselga, MD, noted that "this is an interesting study for several reasons, one is that this is a drug that interferes with metabolism and it has been proposed to have a role in cancer prevention and therapy."

"The authors are also proposing a very interesting model, as neoadjuvant therapy in prostate cancer, and this can be something that can be applied to other indications as well," said Dr. Baselga, chief of hematology/oncology at Massachusetts General Hospital Cancer Center in Boston.

He added that metformin and phosphoinositide 3-kinases (PI3-kinases) inhibitors are synergistic, "so in a way it's very attractive."

There is strong evidence that some members of the PI3-kinase family have an important role in cancer. "Investigational PI3 kinase inhibitors induce hyperglycemia and metformin inhibits hyperglycemia, so this could be a spectacular combination," said Dr. Baselga. "There are a number of trials ongoing with these experimental agents. In clinical trials with PI3 kinase inhibitors, whenever we see hyperglycemia, we give the patients metformin."

Dr. Joshua and Dr. Baselga have disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) Annual Meeting. Abstract #CT-04. Presented March 31, 2012.

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