Enzalutamide Plus Metformin Conveyed No Benefit for Disease Control Rate of Patients With Metastatic Castration-Resistant Prostate Cancer

Christian Rothermundt, MD, Kantonsspital St. Gallen, St. Gallen, Switzerland, discusses results from the phase 2 SAKK 08/14 – IMPROVE trial, evaluating combination enzalutamide and metformin for patients with metastatic castration-resistant prostate cancer, compared to enzalutamide alone. The randomized, open-label trial did not meet its primary end point of disease control rate at 15 months.

Dr Rothermundt noted that there were better outcomes for patients who were overweight and obese, compared to those with normal BMI. He concluded that there is a need for larger studies to confirm these findings.

These results were first presented at the 2022 European Society for Medical Oncology Congress in Paris, France.

Transcript:

Hello. My name is Christian Rothermundt. I'm a medical oncologist in St. Gallan, Switzerland, and we are here at the 2022 ESMO Congress in Paris, France. I was able to present a mini-oral on the SAKK08/14— IMPROVE study, which investigated enzalutamide versus enzalutamide plus metformin in metastatic castration-resistant prostate cancer patients after treatment failure on [androgen deprivation therapy] ADT alone. We had previously done a non-randomized study within the Swiss group of clinical cancer research which showed that metformin works in patients with metastatic castration-resistant prostate cancer. We saw disease control for about 3 months, and we saw a prolongation of [prostate-specific antigen] PSA doubling time. There is preclinical rationale for the use of metformin. Metformin activates [AMP-activated protein kinase] AMPK and there is a subsequent suppression of gluconeogenesis; and metformin also reduces circulating insulin which has inhibitory effects on the PI3K/mTOR pathway. There is also a xenograft model, which shows a synergistic effect of enzalutamide and metformin in enzalutamide resistance cells.

We performed this study from June 2016 until February 2021 at 16 Swiss sites. We accrued 169 patients, randomized 1:1 to enzalutamide or enzalutamide plus metformin at 850 milligrams twice daily, and the primary end point of the study was disease control rate at 15 months, which is a composite of complete response, partial response, or stable disease for at least 15 months. Progression was defined as either radiographic progression and PSA progression, or radiographic progression and clinical progression, or clinical progression and PSA progression.

Unfortunately, this study is negative for the primary end point, so the disease control rate in both arms was the same. Also, overall survival was the same, and very much in line with the PREVAIL data, which put enzalutamide at that place before chemotherapy in castration-resistant prostate cancer patients. There is a signal that metformin could prolong time to PSA progression, and there was also a trend toward better pain control in patients who received the combination of enzalutamide and metformin. Event-free survival was also prolonged.

Probably the most intriguing part of the data is that overweight and obese patients do better, whether they receive enzalutamide or enzalutamide plus metformin. We don't know why, as of yet, but we will do further analysis. We have a strong translation research part in the trial, and we hope to get more data. The discussion at the end of the session mentioned we should have looked for PTEN loss, and we will be able to look at that after we have collected all the data.

There is no change in practice, and I think metformin does not have a place right now in the treatment of prostate cancer. But it's still interesting to look at the repurposing of a very inexpensive drug, and there might be a population where we, in future, could use metformin. But as I said, further analyses are needed. Thank you for your attention.

Source:

Rothermundt CA. “SAKK 08/14 - IMPROVE Investigation of metformin in patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with enzalutamide vs. enzalutamide alone. A randomized, open label, phase II trial.” Presented at European Society for Medical Oncology Congress; September 9-13, 2022; Paris, France