According to results from a phase 2 study, the addition of metformin to letrozole and abemaciclib induced deeper responses and longer progression-free survival (PFS) for patients with estrogen receptor-positive recurrent endometrial cancer.

These results were first presented by Panagiotis Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2025 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.

According to Dr Konstantinopoulos and coauthors, “preclinical studies have demonstrated synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways.” In this trial, metformin, which “suppresses PI3K signaling directly…and indirectly” was added to letrozole, an aromatase inhibitor, and abemaciclib, a CDK4/6 inhibitor.

This phase 2 trial enrolled 25 patients with recurrent estrogen receptor-positive endometrioid endometrial cancer with measurable disease. Patients could have had any number of prior therapies but could not have previously received any CDK4/6 inhibition and could not currently be using metformin. All patients received 150 mg abemaciclib twice daily, 500 mg metformin once daily, and 2.5 mg letrozole once daily. The primary end point was objective response rate (ORR) and PFS rate at 6 months.

With a median follow-up duration of 17 months, there were 8 patients for an objective response for an ORR of 32%. There were 3 complete responses, 5 partial responses, and 16 patients with stable disease. The estimate of PFS rate at 6 months was 69.7% with a median PFS of >19.3 months. According to pharmacokinetic analyses, “metformin plasma concentrations were nearly threefold higher when metformin was combined with letrozole/abemaciclib compared to metformin monotherapy,” study authors described. For patients with TP53 mutated disease and no specific molecular profile disease with RB1 or CCNE1 alterations, there were no objective responses. Among only patients with no specific molecular profile endometrial cancer without RB1 and CCNE1, the ORR was 50% with a 6-month PFS of 87.5%. Responses were observed regardless of progesterone receptor expression. The most common grade ≥3 treatment-related adverse events were neutropenia and fatigue. There were no treatment discontinuations due to toxicity.

Dr Konstantinopoulos et al concluded, “The addition of metformin (at plasma concentrations sufficient to inhibit the PI3K pathway) to letrozole/abemaciclib is feasible and safe and appears to induce deeper responses (including complete responses) and more prolonged PFS than letrozole/abemaciclib alone.” They added no specific molecular profile tumors “without RB1 and CCNE1 alterations derive the most benefit from this regimen.”

Source:

Konstantinopoulos P, Zhou N, Penson R, et al. Phase II study of letrozole, abemaciclib, and metformin in estrogen receptor-positive recurrent endometrial cancer. Presented at the 2025 SGO Annual Meeting on Women’s Cancer. Abstract LBA 938179.