In addition to the monarchE trial, the NATALEE trial and new real-world analyses can inform adjuvant CDK4/6 inhibitor use in HR+/HER2- early-stage breast cancer, as discussed at the 2026 ASCO Annual Meeting. Patient selection requires attention to tumor biology, recurrence risk, trial eligibility, treatment tolerability, and patient motivation for multiyear oral therapy.

Following these presentations, featured expert Harold J. Burstein, MD, PhD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Burstein on these findings are presented here.

The most important studies on the adjuvant use of CDK4/6 inhibitors are the monarchE trial, which looked at abemaciclib, and the NATALEE trial, which looked at ribociclib. Both are oral CDK4/6 inhibitors that had already been approved by the US Food and Drug Administration (FDA) in the metastatic setting based on improvements in progression-free survival (PFS), and both adjuvant trials were very large studies that went out of their way to enroll relatively high-risk patients with HR+/HER2- early-stage breast cancer.

This high-risk design matters when we think about how to use these drugs in practice. In monarchE, patients had to have node-positive disease, along with high-risk clinical features such as multiple positive lymph nodes, high-grade disease, or high Ki-67 index. NATALEE had overlapping goals but somewhat broader eligibility. It included patients with stage II or III disease and extended the observations into some node-negative patients whose tumors had high-risk features based on grade, Ki-67, or genomic risk. Both trials showed benefit to adding a CDK4/6 inhibitor to endocrine therapy, but they did not enroll identical populations, and that distinction is important when we move from trial eligibility to real-world patient selection.

Most of the patients who received adjuvant CDK4/6 inhibitors in these trials had HR+/HER2- breast cancers with high-risk features, and approximately 90% of the patients in these trials received chemotherapy. So, the first thing to say is that, if you do not think a patient is a candidate for chemotherapy, it is often the case that they would not be a candidate for a CDK4/6 inhibitor. We really only have the data for using these drugs in patients with sufficient risk to justify chemotherapy treatment.

These drugs also have side effects, so it is important to make sure that patients are robust enough in their general health and laboratory values to tolerate the medications. Patients also have to be motivated. We are talking about 2 to 3 years of taking oral targeted therapies that have side effects, so this has to be a highly motivated group of patients, selected based on their own preferences and tumor biology.

At ASCO 2026, one of the more useful analyses for refining this conversation came from the NATALEE trial. This retrospective analysis by Stephen K.L. Chia, MD, FRCPC, and colleagues looked at outcomes by tumor intrinsic subtype using a genomic assay that classifies tumors as luminal A, luminal B, HER2-enriched, or basal-like (abstract 501). As expected, most patients had luminal A or luminal B cancer. Ribociclib lowered the risk of recurrence across the cohorts, but the biggest numerical advantages were seen in the higher-risk subtypes of HER2-enriched and basal-like tumors; similarly, a more robust signal was seen in luminal B disease than in luminal A. I think that this is helpful when talking to patients about the biology of their tumor and beginning to frame who may be most likely to benefit from ribociclib treatment.

Not surprisingly, studies presented at this year’s ASCO meeting unmasked practical challenges. These adjuvant CDK4/6 inhibitor therapies are multiple-year treatments, and they cause side effects. For example, abemaciclib is associated with gastrointestinal cramps and diarrhea. Ribociclib has the upfront risks of electrocardiogram changes with QTc prolongation and liver function test abnormalities. Fatigue can be an issue with either drug.

An abstract at ASCO 2026 by Carolyn T. Thorpe, PhD, MPH, and Richa Gairola, MPH, looked specifically at real-world abemaciclib dosing and discontinuation (abstract e12718). In nearly 900 patients with HR+/HER2- early-stage breast cancer, 25% discontinued treatment, and a substantial fraction, particularly on the 150-mg twice-daily starting dose, required dose reductions within 1 year of starting treatment. Of the patients started on the 150-mg dose, 48% required a dose reduction to 100 mg. This is not surprising to clinicians who prescribe this drug regularly.

Another abstract presented at ASCO 2026 asked whether real-world data could be used to compare ribociclib and abemaciclib outcomes (abstract 11167). This is an important question, but there are no head-to-head clinical trials, and retrospective analyses are shaped by clinician choice and patient selection. In this study, which used the TriNetX US Collaborative Network database (TriNetX, LLC), Chinenye M. Okafor, MD, MPH, et al found that the 1-year survival appeared numerically higher with ribociclib than with abemaciclib, but the difference did not persist at 3 or 5 years. I would take these data with a grain of salt. At 1 year, having 8% to 10% of patients die from early-stage breast cancer, as suggested in this real-world study, would be very unusual.

In practice, people are getting more familiar with these drugs, although several points remain important. Ribociclib should not be given with tamoxifen, so abemaciclib is generally preferred for patients receiving tamoxifen rather than an aromatase inhibitor. Pneumonitis is rare but possible with CDK4/6 inhibitors, so cough or shortness of breath should prompt attention. Finally, either drug can cause general unwellness over several years. Many patients do very well on ribociclib or abemaciclib, but others struggle, making dose modification essential. Ultimately, the real-world challenge is not only identifying patients whose recurrence risk justifies adjuvant CDK4/6 inhibition but also giving these medicines as safely and conveniently as possible so that patients can stay on therapy long enough to experience benefit.