Currently, ADT remains the cornerstone treatment regimen for mHSPC. However, long-term use of ADT may increase the risk of cardiovascular events. Recently, the data from the STAMPEDE study presented at the European Association of Urology (EAU) Congress showed that the combination of metformin and ADT can extend the overall survival of patients with high tumor burden mHSPC by 10 months (hazard ratio [HR] = 0.79). At the same time, it can also improve metabolic indicators: there is less weight gain (2.5 kg vs 4 kg) and a lower incidence of metabolic syndrome (4.9% vs 9.4%). UroStream specially invited the study presenter, Dr. Ashwin Sachdeva, a senior clinical lecturer in University of Manchester, Division of Cancer Sciences, to share the wonderful content on-site.UroStream：ADT is a cornerstone treatment for prostate cancer, but it may increase cardiovascular risk and non-prostate cancer-related death, etc. How do you deal with these side effects in clinical practice?
Dr. Ashwin Sachdeva：That’s an excellent and very important question. We now recognize that ADT—and especially when intensified with androgen receptor pathway inhibitors (ARPIs)—can significantly raise the risk of cardiovascular events and even cardiovascular-related mortality.
In fact, we published a paper in JAMA Oncology last year indicating that the risk of cardiovascular complications may double when an ARPI is added to ADT. This highlights the importance of managing patients not just for oncological outcomes but also taking a holistic approach that addresses treatment-related toxicities—particularly in areas like bone and cardiovascular health.
One clinical strategy involves proactively monitoring patients for cardiovascular risk factors, such as baseline hypertension or diabetes. In individuals with pre-existing risk, we take a more aggressive preventive approach. This may include the use of medications like beta-blockers or calcium channel blockers to manage hypertension, and careful monitoring for diabetes, with early intervention to maintain glycemic control.
Over the long term, these preventive strategies have been shown to reduce cardiovascular events. In more complex cases, we may collaborate closely with cardio-oncology specialists, while in less complicated situations, we work with community physicians to manage cardiovascular risk profiles and minimize adverse effects from treatment.
UroStream：You shared the STAMPEDE study of metformin for mHSPC at the conference. What improvements has this combined treatment strategy brought to patients? What impact will it have on future clinical practice?
Dr. Ashwin Sachdeva：Yes, we presented new data from the STAMPEDE metformin trial, specifically focusing on patients with metastatic hormone-sensitive prostate cancer (M1). In this study, we enrolled approximately 1,800 patients who were randomized to receive either standard of care alone or standard of care combined with lifelong metformin for those with metastatic disease. The trial’s primary endpoint was overall survival, while a key secondary endpoint—also the focus of my presentation today—was the metabolic impact of adding metformin. The overall survival data, which we presented at ESMO last year, showed no statistically significant benefit across the unselected population, with a hazard ratio of 0.91.
However, when we performed a pre-specified (though not pre-powered) subgroup analysis based on metastatic disease burden, we observed a nuanced pattern. In patients with low-volume disease, metformin did not confer any added survival benefit (HR 1.0). But among those with high-volume disease, as defined by the CHAARTED criteria, the addition of metformin showed a meaningful benefit—an estimated hazard ratio of 0.79—which corresponds to an approximate 10-month improvement in overall survival. These are the patients with more aggressive disease, and this subgroup appears to derive the most benefit.
Today, I presented the trial’s findings on metabolic outcomes, which are particularly relevant because, as mentioned earlier, ADT increases the risk of cardiovascular complications, diabetes, weight gain, and lipid abnormalities. We found that metformin reduced many of these side effects. For instance, weight gain was significantly less in the metformin group—on average, 2.5 kg compared to 4 kg in the standard of care group. Increases in waist circumference were also smaller in patients receiving metformin. We also saw improvements in glycemic control, total cholesterol, and LDL levels. Perhaps most notably, the incidence of metabolic syndrome—a major concern in patients on long-term ADT—was nearly halved: 9.4% in the standard of care arm versus only 4.9% in the metformin arm.
Altogether, these findings suggest that adding metformin to standard treatment not only has potential survival benefits in high-volume metastatic patients, but also meaningfully reduces the metabolic side effects commonly seen with prolonged ADT.
UroStream：Currently, ADT+ARPI has become an important treatment option for mHSPC, but the number of patients included in the study is relatively small. What do you think of the efficacy of metformin combined with ARPI+ADT?
Dr. Ashwin Sachdeva：Yes, you’re absolutely right. In the STAMPEDE metformin trial, about 85% of enrolled patients received standard of care consisting of ADT plus docetaxel. However, after a recruitment pause during the COVID-19 pandemic, the standard of care evolved to include ADT plus an ARPI agent. As a result, only around 50 to 54 patients in the metformin arm received this newer treatment combination.
In terms of what this means for clinical interpretation, the sample size for the ADT+ARPI subgroup is currently too small to draw definitive conclusions. The only way to obtain robust evidence would be to continue the trial and recruit a larger number of patients receiving ADT+ARPI.
That said, we can take comfort in what we already know: the long-term side effect profile of ADT is well established. Even when combined with an ARPI—forming a doublet backbone—the adverse effects of ADT, such as metabolic disturbances, persist and may even be amplified.
Although we don’t yet have clear data on whether metformin can directly mitigate ARPI-related side effects, we are confident that it continues to help reduce the adverse effects associated with long-term ADT alone. So based on the data presented today, I would encourage clinicians to consider starting patients on metformin, particularly those undergoing prolonged ADT, to better manage and reduce long-term toxicities.
Reference：
Sachdeva A., et al. A0516: Metabolic benefits of adding metformin to androgen deprivation therapy for patients with metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Results from the STAMPEDE metformin trial. EAU 2025
