NEARLY 70% of people with breast cancer have the hormone receptor (HR)-positive, HER2-negative subtype of the disease and will choose among a variety of treatment regimens, including combinations of surgery, chemotherapy, radiation and hormone therapy. Some patients at high risk for recurrence now have an additional choice: Should they add a CDK4/6 inhibitor to their treatment to reduce the risk of recurrence?

CDK4/6 inhibitors are a type of targeted therapy called a small molecule inhibitor. They work by targeting proteins in breast cancer cells called CDK4 and CDK6, which encourage cell growth.

The Food and Drug Administration has approved three CDK4/6 inhibitors to treat HR-positive, HER2-negative advanced or metastatic breast cancer in combination with other treatments. In 2021, the agency also approved one of those CDK4/6 inhibitors, Verzenio (abemaciclib), to treat early-stage breast cancer that is likely to recur. A clinical trial found fewer people given Verzenio had breast cancer return in the three years after finishing treatment compared with people who did not receive the CDK4/6 inhibitor.

In June 2023, an early analysis of the phase III NATALEE trial was presented at the American Society of Clinical Oncology Annual Meeting. It found that adding a different CDK4/6 inhibitor, Kisqali (ribociclib), to standard-of-care treatment for stage II or III HR-positive, HER2-negative breast cancer also lowers the short-term risk of recurrence.

More than 5,000 patients with stage II and III HR-positive, HER2-negative breast cancer were divided into two groups: half received hormone therapy alone, while the other half received Kisqali with hormone therapy. All participants had been treated with surgery and chemotherapy. After about two years on their assigned regimen, 87% of patients in the standard care group had not had a breast cancer recurrence or new diagnosis compared with 90% of patients in the Kisqali group.

“That 3% difference in recurrence may not seem like a big improvement, but it represents a 25% reduction in risk beyond what chemotherapy and hormonal therapy can offer,” says Gabriel Hortobagyi, a breast oncologist at the University of Texas MD Anderson Cancer Center in Houston and the study’s co-principal investigator. “That’s a significant gain, all the more so since our standard treatments are already very effective.”

A new approval for Kisqali would be good news, says Joshua Drago, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York City who was not involved with the research. While Drago says there isn’t yet head-to-head data comparing the effectiveness of Kisqali and Verzenio, having more options would be positive for patients. He pointed out that they have different side effects, and some patients may do better on one over the other.

In the analysis, one of the most common side effects of Kisqali was neutropenia, a drop in infection-fighting white blood cells called neutrophils. “We also need to do periodic EKGs [electrocardiograms] when we start patients on [Kisqali], so the patient has to be willing to come in a bit more often at first,” says Heather McArthur, a breast oncologist at UT Southwestern Medical Center in Dallas. “With [Verzenio], almost all patients experience diarrhea within the first two months, so we have to be aggressive with antidiarrheal medications from the start.

“With either drug, it will be all about managing patients’ expectations and listening to their concerns,” adds McArthur, who was not involved with the NATALEE trial.

Another factor that will likely affect patients’ decision-making is the amount of time needed to complete CDK4/6 treatment. In studies, Verzenio was given for two years and Kisqali for three. “This can be a complex decision,” says Hortobagyi. “This group of patients needs surgery, chemotherapy and perhaps radiotherapy. Then add five to 10 years of a hormonal agent, plus the two to three years of a CDK4/6 inhibitor.”

McArthur says her patients welcome the addition of CDK4/6 inhibitors to the list of treatment options. “We discuss the fact that about one-third of women with hormone receptor-positive early-stage breast cancer will experience a recurrence over their lifetimes,” she explains. “That’s why these types of innovations that further minimize that risk are critically important.” But there is still more to learn about the effects of these treatments in early-stage breast cancer. “It is too early to say confidently whether these drugs improve overall survival—meaning do they save lives in the long run,” says Drago. “Because sometimes breast cancers can come back years after they are originally diagnosed, longer-term follow-up is needed to help determine the true benefit of these medications.”