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"Adding metformin to standard care for advanced prostate cancer appeared to lengthen time to castration-resistant disease in a small, randomized trial.
“According to our data, metformin potentially prolongs the time to progression … when combined with androgen deprivation therapy,” said investigator Reham ALGhandour, MD, PhD, an assistant lecturer of medical oncology at Mansoura (Egypt) University.
Dr. ALGhandour presented the data at the European Society for Medical Oncology Virtual Congress 2020.
Prior observational studies have indicated that metformin may benefit patients with prostate cancer. A meta-analysis of cohort studies suggested metformin can significantly improve overall, cancer-specific, and recurrence-free survival in prostate cancer patients.
To explore this further, Dr. ALGhandour and colleagues conducted a randomized trial. They enrolled 124 men with high-risk locally advanced or metastatic hormone-sensitive prostate cancer.
The investigators randomized 62 patients to testosterone suppression with or without antiandrogen, and 62 others to a standard regimen plus metformin at 850 mg twice daily.
All patients had an Easter Cooperative Oncology Group performance score of 0-2, were set to receive androgen deprivation therapy long term, and had no prior metformin use. Docetaxel was permitted for metastatic patients, and external beam radiation therapy was used for localized and regional disease.
Results: ‘Dramatic’ but not ‘definitive’
At a median follow-up of 18 months, there was a significant difference in time to castration-resistant prostate cancer. The median time to progression was 29 months with metformin and 20 months with standard therapy alone (P = .01).
Subgroup analyses showed a benefit with metformin in men with N1 disease (P = .001) and men with localized disease/low tumor burden (P = .008).
There was no significant difference in overall survival between the treatment arms (P = .1). The median overall survival was not reached in either arm.
About 4% of metformin patients had grade 2 diarrhea, but adverse events were otherwise comparable between the arms and mostly related to androgen deprivation.
“The authors have got some pretty dramatic findings,” said Noel Clarke, MBBS, a consultant urologist at Salford Royal Hospital and The Christie, Manchester, England, who was a discussant for the study.
Dr. Clarke said the data are “hypothesis generating,” but, because of small numbers, the study “really falls well short of anything that is definitive.”
“We’ll have to wait for bigger studies,” Dr. Clarke said, adding that one arm of the STAMPEDE trial has recruited 2,200 prostate cancer patients to standard of care plus metformin.
“We will report on this trial presently,” he said. “Hopefully, this will add to the body of literature which will determine whether or not metformin is useful with standard of care in this disease.”
Dr. Clarke said the possible benefits of metformin are probably related to energetics in prostate cancer.
“AMPK [AMP-activated protein kinase] is the energy superhighway regulator,” he explained. “[I]t slows down the effects of cell proliferation and energy usage, and it promotes the use of energy storage mechanisms.
“Metformin, because it acts on AMPK to up-regulate it … enhances the effect of AMPK, shutting down the catabolic elements and impeding other elements of prostate cancer migration. So AMPK inhibits epithelial to mesenchymal transition, which is well known as a metastatic mechanism.”
There was no outside funding for this study, and the investigators didn’t report any disclosures. Dr. Clarke disclosed relationships with Janssen, Astellas, Sanofi, and AstraZeneca.
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SOURCE: ALGhandour R et al. ESMO 2020, Abstract 617MO.
Management of the Metastases in Oligometastatic Prostate Cancer 
