Adjuvant CDK4/6 Inhibition Gains Further Ground in HR+/HER2– Early Breast Cancer With Ribociclib Approval

Arielle Heeke, MD

In The incorporation of CDK4/6 inhibitors into the adjuvant treatment of patients with hormone receptor (HR)–positive, HER2-negative early-stage breast cancer has introduced an additional strategy to reduce recurrence risk following standard multimodal therapy, according to Arielle Heeke, MD, who noted that the recent addition of ribociclib (Kisqali) to the adjuvant treatment arsenal has broadened the applicability of this approach.

In October 2021, the FDA approved abemaciclib (Verzenio) in combination with endocrine therapy for the treatment of patients with HR-positive, HER2-negative, early-stage breast cancer at high risk of recurrence and a Ki67 score of 20% or greater based on results from the phase 3 monarchE trial (NCT03155997).1 Notably, the FDA’s subsequent expansion of this indication in March removed the Ki-67 score requirement for patient selection. 2

In September 2024, the FDA approved ribociclib plus an aromatase inhibitor (AI)for the treatment of patients with HR-positive, HER2-negative stage II/III early breast cancer at high risk of recurrence, based on data from the phase 3 NATALEE (NCT03701334).3

“CDK4/6 inhibitors can be prescribed to patients with stage II or [higher] breast cancer, and the data are strong for both [abemaciclib and ribociclib]. [Accordingly, selecting between these agents] can be based on patient and/or provider preference,” Heeke said during an interview with OncLive® following a State of the Science Summit™ on breast cancers. “Over time, [however], we will probably lean into [using] ribociclib in the non-metastatic setting.”

In the interview, Heeke highlighted the role of CDK4/6 inhibitors in the HR-positive, HER2-negative, early-stage breast cancer treatment paradigm; key clinical considerations when choosing between abemaciclib and ribociclib; and how the FDA approval of the PARP inhibitor olaparib (Lynparza) has improved the treatment arsenal in this space.

Heeke is a clinical associate professor in the Department of Hematology and Oncology at Wake Forest University School of Medicine and a physician at Atrium Health Levine Cancer Institute in North Carolina.

OncLive: How have CDK4/6 inhibitors in the adjuvant setting changed the treatment paradigm for patients with HR-positive, HER2-negative early-stage breast cancer?

Heeke: [This is] a tough diagnosis to get, [although] patients [with this disease] have [many] treatment options. There’s potentially chemotherapy, obviously surgery and radiation, endocrine therapy for 5 to 10 years, ovarian suppression, and now CDK4/6 inhibitors. We are using them a lot because they're helpful, especially when you have somebody that, at the end of all that other [treatment], still has a high risk of recurrence. [For example, if they have a risk of recurrence of] 30%, and they're interested in [receiving CDK4/6 inhibitors,] that could reduce approximately 7% of their risk. However, it doesn't take the risk of recurrence down to 0%, which is the tough thing. We wish we could promise people that, but a 30% or even 20% risk of recurrence after completion of their other therapies is uncomfortably high. Therefore, if they can get it down closer to 10%, it's often worth it to the patient.

We're lucky to have 2 [CDK 4/6 inhibitors] now. Abemaciclib is helpful because it's only [taken for] 2 years. The data [showing its efficacy] are strong, but the control arms are a little different. Ribociclib is generally a little easier to tolerate. In practice, I recommend CDK4/6 inhibitors for patients with lymph node–positive disease. The NATALEE study has certainly challenged that a little bit, because it's available for lymph node–negative disease as well. [That study has] shown that all subgroups were benefiting similarly from the addition of ribociclib to [endocrine therapy], which speaks to how we don't know exactly [which] patients need the therapy. It could be in both groups. Personally, I hope that circulating tumor DNA will help us better select [the appropriate patient population].

What are some key clinical considerations when selecting CDK4/6 inhibitors for your patients?

When ribociclib was FDA approved [for this indication], I was still more fond of the abemaciclib, just because the absolute benefit seemed greater. We had gotten comfortable with patients taking it already and although it wasn't necessarily the most fun [treatment], patients were [taking it] and getting through the 2 years [of treatment]. With it, I wasn't admitting people to the hospital because of horrible diarrhea or any [adverse effects] like that. It was a quality-of-life damper, but the patients were getting through it okay. Now that I've [come to know] the data a little bit better between monarchE and NATALEE and have a better understanding of the calculated differences in the experimental and control arms, with patients in the control arm on NATALEE doing better, I'm feeling much more comfortable leaning into ribociclib. The only caveat there is the 3-year treatment duration—I haven't had that experience of trying to keep somebody on therapy for the full 3 years. However, in terms of tolerance of the patients that I've put on the ribociclib in the adjuvant setting, they seem to tolerate it better than when we put them on adjuvant abemaciclib. In the metastatic setting, the 600 mg dose of ribociclib is challenging. People do struggle with fatigue and cytopenias, but the 400 mg [dose] is generally well tolerated.

How has the addition of olaparib (Lynparza) to the treatment toolbox in BRCA-mutated, high-risk early breast cancer improved patient outcomes?

First, there aren’t that many patients with BRCA mutations. Second, they have to be high risk. Patients were mostly undergoing some sort of therapy before surgery. For [patients with] triple-negative breast cancer, for example, they must have residual disease. Now, with our 5-drug immunotherapy regimen, approximately 35% of patients are going to have residual disease. Within that 35%, how many are going to be BRCA mutation carriers? It’s a pretty uncommon mutation. For patients with HR-positive disease, they must have multiple lymph nodes involved.

I've only had 3 patients who have been eligible [for olaparib and] whom I've given the drug to, and it was fairly well tolerated. My patients all have been bummed about it because by the time they get done the chemotherapy and surgery, it's already been a long journey, and then they have [to undergo] another year of therapy. They just didn't quite expect that. However, mechanistically, we believe in the value of olaparib for their specific needs.

References

1. FDA approves abemaciclib with endocrine therapy for early breast cancer. FDA. Updated October 13, 2021. Accessed April 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer
2. US FDA broadens indication for Verzenio (abemaciclib) in HR+, HER2-, node-positive, high risk early breast cancer. News release. Eli Lilly and Company. March 3, 2023. Accessed May 2, 2025. https://investor.lilly.com/news-releases/news-release-details/
3. FDA approves ribociclib with an aromatase inhibitor and ribociclib and letrozole co-pack for early high-risk breast cancer. FDA. September 17, 2024. Accessed April 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ribociclib-aromatase-inhibitor-and-ribociclib-and-letrozole-co-pack-early-high-risk