Adding a non-GLP-1 weight-loss drug could help breast cancer survivors achieve target weight loss when lifestyle intervention falls short, a phase 2 trial suggested.

Among women who were unable to lose 5% of their body weight after 2 months of a behavioral program, adding naltrexone-bupropion to their treatment regimen helped 42% successfully achieve that 5% threshold.

“Our findings highlight the importance of patient selection for weight-loss medications and the additive effects when combined with lifestyle modifications,” said study author Jennifer Y. Sheng, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

What the study did not identify are the specific characteristics of patients who require a pharmacologic agent to support weight loss and those who can be treated with behavioral counseling alone.

Obesity affects more than one third of breast cancer survivors and is associated with higher risks for recurrence and death, yet many survivors cannot lose enough weight through diet and exercise alone. Behavioral programs help only about half of the participants reach the 5% loss threshold that guidelines tie to better health.

Medscape Medical News has previously reported that tailored exercise alone may extend survival after breast cancer; however, GLP-1 receptor agonists, recently linked to lower breast cancer risk, are now dominating the weight-loss field, making the present intervention relatively unique.

Unlike GLP-1 receptor agonists, naltrexone-bupropion is an older oral combination that curbs appetite through the brain’s hunger and reward pathways and produces more modest weight loss, according to the investigators.

The single-arm phase 2 A-NEW trial was published in Clinical Cancer Research. It enrolled 55 women with stage 0-III breast cancer who were overweight or had obesity and had completed local therapy and chemotherapy. Women taking tamoxifen were excluded because bupropion can reduce tamoxifen’s effectiveness.

All participants began a 6-month program of remote coaching, nutrition counseling, and physical activity tracking. At 2 months, among the 53 women evaluable, the 15 women (28%) who had already lost at least 5% of their body weight continued lifestyle changes alone, whereas the 38 women (72%) who had not achieved the 5% target added naltrexone-bupropion and continued the same behavioral strategies. In the intention-to-treat analysis, 16 of 38 women who added the medication (42%) reached at least 5% weight loss by 6 months (P = .0005). These initial nonresponders, who were given naltrexone-bupropion, lost an average of 5.1% of their body weight compared with 10.8% among the women who had responded to lifestyle changes alone.

Reaching the 5% mark was tied to significantly better physical function and less pain, and women who added the drug showed significant improvements in A1c and triglyceride levels.

Gastrointestinal symptoms were common, affecting about 74% of women on the medication, but there were no serious adverse events, and only one participant stopped treatment because of adverse effects.

Women who lost weight more slowly were more often Black, premenopausal, and younger. Among Black participants who added the medication, one third reached the 5% threshold compared with nearly half of the White participants.

Jennifer A. Ligibel, MD, of Dana-Farber Cancer Institute in Boston, who led the BWEL trial and was not involved in the present research, credited A-NEW with providing clues for solving the mystery of which survivors should receive pharmacologic intervention for weight loss and when they should receive it.

“Although the medication was not one that we would currently use at this time, the premise that the medication was effective in inducing weight loss in patients that were not successful with a behavioral weight-loss program is important,” Ligibel told Medscape Medical News.

Kathryn H. Schmitz, PhD, MPH, exercise oncology researcher at the University of Pittsburgh in Pittsburgh, who was not involved in the study, on the other hand, gave several reasons why she did not see A-NEW as practice-changing.

“Behavioral programs already help many survivors, pointing to trials such as BWEL and AMPLIFY, which yielded 5%-7% weight loss without drugs,” she said.

Schmitz hypothesized that the reasons some groups lost weight more slowly than others in A-NEW lay largely outside the clinic.

“Even with the assistance of a pharmacologic agent, eating occurs in context of income, family, access, culture, and history,” she explained.

Schmitz added that the relevance of an older oral agent is also shifting because GLP-1 drugs take over and, like the investigators, called for more trials involving obesity drugs and cancer survivors.

Larger, randomized studies will be needed to confirm the present, threshold-based approach to prescribing naltrexone-bupropion and to test whether newer, more potent obesity drugs could push weight loss further, the authors concluded.

The A-NEW study was funded by the NCCN Foundation, the American Institute for Cancer Research, the Breast Cancer Research Foundation, and others; the medication was purchased from its manufacturer, Currax Pharmaceuticals LLC, which did not fund the trial. Sheng reported no relevant financial relationships, whereas several co-authors disclosed relationships with Pfizer, Astellas, and AstraZeneca. Schmitz and Ligibel reported no relevant financial relationships. 

Will Pass is a freelance medical journalist based in Fort Collins, Colorado.