Metformin helps reduce ADT-related complications in prostate cancer patients

Metformin seems inadequate in reducing the risk of metabolic syndrome (MS) in patients with prostate cancer receiving androgen deprivation therapy (ADT), results of the PRIME study have shown.

However, its use has significantly improved body weight (BW), waist circumference (WC), and haemoglobin A1c levels, suggesting its potential in preventing ADT-related complications.

"[A]lthough the PRIME study did not meet its primary endpoint of preventing MS, improvements appreciated in secondary outcomes with metformin with significant reductions in BW, WC, and BMI suggest a role for metformin in mitigating ADT-associated complications,” the researchers said.

A total of 166 normoglycaemic patients with prostate cancer planned for at least 9 months of ADT were enrolled in the phase III PRIME study between July 2018 and November 2023. They were randomly allocated 2:1 to receive metformin 850 mg or placebo twice daily orally for 18 months. The researchers then compared the proportions of MS at 18 months between the two treatment arms.

The trial ceased prematurely on 24 November 2023 due to drug supply cessation and failure to meet the planned enrolment numbers (n=300). The final analysis involved 90 patients in the metformin arm and 45 in the placebo arm. The median follow-up was 24 months.

At baseline, the proportion of MS between the two groups was 42 percent with metformin and 58 percent with placebo (p=0.09). This increased to 55 percent and 68 percent, respectively, at 18 months (p=0.2). [J Urol 2025;214:496-508]

The use of metformin led to significant reductions in mean BW at 9 (—9 vs 1.8 kg; p<0.001) and 12 months (—0.33 vs 1.8; p=0.004) and mean HbA1c at 9 (—0.02 percent vs 0.08 percent; p=0.02) and 12 months (0.03 percent vs 0.08 percent; p=0.03).

Furthermore, mean WC showed significantly smaller increments with metformin at 9 (0.8 vs 2.9 cm; p=0.03), 12 (1.9 vs 3.3 cm; p=0.15), and 18 months (1.8 vs 3.8 cm; p=0.03).

“In terms of the absolute differences in MS rates between the two groups, this was not very different at baseline (16 percent) and at subsequent follow-up time points (12 percent at 9 months and 13 percent at 18 months),” the researchers said. 

“The lack of significant changes in MS from metformin, in contrast to the secondary outcome changes observed, probably reflects the complex nature of MS which is a collection of variables that have varying effects from metformin,” they added.

Complications

ADT is important in the treatment of locally advanced and metastatic prostate cancer, and recent advances in hormonal therapies have improved outcomes for patients with prostate cancer. However, such improvements have also led to longer exposures to ADT and the development of related toxicities. [Lancet Oncol 2010;11:1066-1073; N Engl J Med 2019;381:1494-1495; Lancet 2022;399:1695-1707]

ADT toxicity is driven by adverse metabolic and anthropometric changes that result in progressive worsening of the individual components of MS. This leads to complications such as obesity, cardiovascular, and cerebrovascular events. [J Urol 2015;193:1956-1962; Eur Urol 2014;65:816-824; J Clin Oncol 2015;33:1243-1251; Front Oncol 2022;12:914875]

"[The current] study confirmed that within 9 months of starting ADT, patients experienced significant weight gain, increases in abdominal obesity, and deteriorating glucose metabolism,” the researchers said. “As patients live longer with the use of novel systemic treatments, prevention of these detrimental effects is all the more clinically relevant.”