For women with recurrent or late-stage endometrial cancer, including metformin as part of a standard chemotherapy regimen offered no additional benefit, a phase II/III study indicated.
In the trial of over 450 patients, all of whom received carboplatin plus paclitaxel, median overall survival (OS) was 34.6 months in the metformin group as compared with 30.4 months in the placebo group, a non-significant advantage (HR 0.89, 95% CI 0.68-1.16, P=0.185), reported Victoria Bae-Jump, MD, PhD, of the University of North Carolina at Chapel Hill.
The findings, presented at the Society of Gynecologic Oncology (SGO) annual meeting webinar series, also failed to demonstrate a significant progression-free survival (PFS) benefit for metformin over placebo (9.0 vs 8.5 months, HR 0.89, 95% CI 0.71-1.10).
"Paclitaxel-carboplatin-metformin was well tolerated, with no unexpected serious toxicities -- there was a little less hyperglycemia on the metformin arm," said Bae-Jump. "However, the addition of metformin to paclitaxel-carboplatin did not significantly improve progression-free survival or overall survival."
Response rates were similar between the metformin and placebo arms (62% vs 60%, respectively).
Epidemiological data have suggested that metformin may lower cancer risk (including endometrial) among patients taking the drug for diabetes, and preclinical studies have reported antitumor activity. A recent randomized trial of metformin in metastatic prostate cancer also showed no significant survival benefit.
Results of the current trial -- NRG Oncology/GOG 286B -- further confirm the racial disparities in endometrial cancer, as black women were far less likely to respond to treatment than whites (43% vs 64%), and black race was significantly associated with worse PFS (8.4 vs 9.0 months; HR 1.50, 95% CI 1.10-2.02).
"Even more alarming was the difference in overall survival between the black and white women on the study," said Bae-Jump, pointing to a median OS of 18.3 months for black women versus 36.9 months in the white women (HR 2.03, 95% CI 1.43-2.89).
"As you would expect, there was a greater proportion of African-American patients that had serous tumors than white women, but despite similar response rates between serous and endometrioid histology, response rates of African-American women compared to white women were worse," said SGO discussant Melissa Geller, MD, of the University of Minnesota in Minneapolis.
She said the researchers are performing targeted sequencing on 800 genes from the tumors of the 61 African-American women enrolled in the trial, and that these "critical data" could shed light on the observed differences in treatment response and outcomes.
From 2014 to 2018, the phase II/III study randomized 469 women with recurrent or stage III/IV endometrial cancer to chemotherapy plus metformin or placebo. The trial's primary endpoints were PFS for phase II and OS for phase III.
About 80% of the study cohort were white and 13% were black. The study was stratified by BMI, but this was not predictive of OS in the metformin arm. Overall, higher rates of obesity were seen for black (64%) versus white women (48%) in the trial.
The researchers also examined outcomes by patients' expression of metformin transporter proteins (MATE2/OCT3) and phosphorylated IGF1-R, but these too were not predictive of survival outcomes.
"The translational science on metformin continues to evolve and further trials in early-stage endometrial cancer with metformin are being performed to determine what role this drug may play," Geller said.
In the control arm, patients received intravenous paclitaxel (175 mg/m2) plus carboplatin (target AUC 5) every 3 weeks for up to 10 cycles plus maintenance placebo until disease progression or unacceptable toxicity. In the investigational arm, patients received the same chemotherapeutic regimen plus oral metformin (850 mg once daily) as maintenance.
Baseline characteristics were well balanced between the two arms, with more than 70% of women being age 60 or older. Just over 70% had measurable disease and a majority (57%) were receiving either of the two regimens as their primary treatment.
Disclosures
Bae-Jump disclosed relevant relationships with NovaTarg, Merck, Oncoceutics, Sphaera, Tesaro, Eisai, and Rakuten.
Primary Source
Society of Gynecologic Oncology
Bae-Jump V "A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: an NRG Oncology/GOG study" SGO 2020; Abstract LBA11.