Patient Factors Help Individualize Adjuvant Endocrine Therapy and CDK4/6 Inhibitor Use in HR+ Breast Cancer

Adjuvant treatment selection for patients with hormone receptor (HR)–positive, HER2-negative breast cancer requires consideration of menopausal status, recurrence risk, and the ability to tolerate endocrine therapy, according to Matthew P. Goetz, MD. As CDK4/6 inhibitors become part of treatment for eligible patients, evaluating the expected absolute benefit remains an important component of individualized care, he added.

In an interview with OncLive^®, Goetz discussed approaches to endocrine therapy in premenopausal and postmenopausal patients, the integration of abemaciclib (Verzenio) and ribociclib (Kisqali) into adjuvant regimens, and how findings from the phase 3 monarchE (NCT03155997) and NATALEE (NCT03701334) trials have influenced practice. The discussion also addressed the importance of sustained outcomes after treatment discontinuation and the potential for oral selective estrogen receptor degraders (SERDs), including giredestrant, to reshape adjuvant endocrine therapy.

Goetz is deputy director; the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D.; a consultant in the Division of Medical Oncology and a research chair in the Department of Oncology; and the enterprise deputy director of Translational Research at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive: How do you currently approach endocrine therapy selection in the adjuvant setting for patients with HR-positive, HER2-negative breast cancer?

Goetz: A major issue here relates to menopausal status. For patients who are postmenopausal, aromatase inhibitors are currently our standard of care [SOC] for the majority of patients, although there are some patients in whom we still use tamoxifen.

Then, we will use CDK4/6 inhibitors in combination with the aromatase inhibitors for patients who are at higher risk. Those higher-risk characteristics were well outlined in 2 trials that led to the FDA approval of CDK4/6 inhibitors: the NATALEE trial and the monarchE trial.

For premenopausal patients, increasingly, we are using aromatase inhibitors plus ovarian function suppression. A meta-analysis demonstrated that aromatase inhibition plus ovarian function suppression was superior to tamoxifen plus ovarian function suppression, although that meta-analysis did not show an improvement in overall survival [(OS) with aromatase inhibition plus ovarian function suppression].

For our lower-risk patients who are premenopausal, many of us will still use tamoxifen. Tamoxifen has efficacy in the lower-risk population and does not require ovarian function suppression, which is a major issue and a cause for morbidity in young women.

How are you integrating CDK4/6 inhibitors into adjuvant treatment regimens for HR-positive, HER2-negative breast cancer?

Right now, [CDK4/6 inhibitors] have a narrow [indication]. The FDA approval of abemaciclib is for patients who have higher-risk features, [including] 4 or more positive lymph nodes, or 1 to 3 positive lymph nodes and other high-risk features, such as grade 3 disease or large tumor size, such as T3 status.¹

The eligibility criteria for the NATALEE trial were a bit broader. It included high-risk patients [with stage III or IIB disease regardless of nodal status], but it also included some lower-risk patients who had [at least] 1 positive lymph node.² For those patients, there’s still a fair amount of uncertainty about the absolute benefit of ribociclib. If you have a patient who has a relatively low risk of a distant recurrence, the absolute benefit of a drug is going to be much smaller. That is still a question mark for those patients. For example, a patient with 1 to 3 positive lymph nodes, or 1 lymph node and luminal A characteristics, would be expected to do extremely well with just standard endocrine therapy. We need more data on the role of the CDK4/6 inhibitors, specifically ribociclib, in that scenario.

The other thing is that among patients who are premenopausal, some cannot tolerate aromatase inhibitors plus ovarian function suppression. This is not uncommon because of the significant morbidity [associated with this regimen]. One of the advantages of the drug abemaciclib is that it can be combined with the drug tamoxifen, although we don’t have FDA approval for combining ribociclib with tamoxifen. That’s another consideration for when we’re integrating these drugs into practice.

How have data from monarchE and NATALEE affected CDK4/6 inhibitor use in the adjuvant HR-positive, HER2-negative breast cancer setting?

Prior to those trials, [abemaciclib and ribociclib] weren’t approved in the adjuvant setting. We now have evidence that they improve disease-free survival, and we have long-term follow-up, meaning follow-up after the drug was stopped.

In the phase 3 PENELOPE-B (NCT01864746), trial there was a small benefit that was seen with the drug palbociclib [Ibrance] while the patients were taking the drug, but as soon as they stopped the drug, [that benefit] went away. What we’re looking for when we use these therapies is a benefit that’s sustained and reduces the risk of recurrence, as well as improves survival.

That’s one of the [outcomes] that has been seen with the monarchE trial. The most recent analysis looking at OS, which was a key prespecified secondary end point, [showed] that abemaciclib reduced the risk of death.

With the NATALEE trial, although OS was not a prespecified end point that was statistically controlled for, we continue to get updates with regard to OS, and we see the confidence intervals. We’ll continue to look for those data from the NATALEE trial as time goes on.

How could oral SERDs, such as giredestrant, affect adjuvant breast cancer endocrine therapy selection in the future?

Giredestrant is an oral SERD. It’s in the same class of drugs as the drug fulvestrant [Faslodex] that we’ve used for many years. The difference is that giredestrant is oral and it’s a bit more potent.

In the metastatic setting, the data that we’re seeing emerge with regard to the oral SERDs is that in the post-CDK4/6 inhibitor space, when we use these drugs as single agents, they have antitumor activity, but mainly in tumors that have an ESR1 mutation. The activity does not seem to be any different than fulvestrant in patients in whom there’s not an ESR1 mutation, [who instead typically experience] rapid progression of disease post-CDK4/6 inhibitor.

With that in mind, and knowing the dependence of cancer cells upon estrogen receptor [ER] signaling when there is an ESR1 mutation, we were interested to begin to see the activity of these drugs in the early, endocrine-sensitive setting. We have data suggesting that these drugs reduce proliferation in neoadjuvant window trials, but the phase 3 lidERA Breast Cancer trial [NCT04961996] that was presented [at the 2025 San Antonio Breast Cancer Symposium] that directly compared giredestrant against the SOC, which is an aromatase inhibitor alone [for] postmenopausal [patients], or in combination with ovarian function suppression for premenopausal patients.

The results of the lidERA Breast Cancer trial demonstrated that giredestrant reduced the risk of recurrence and the risk of a disease even at an early time point. These are remarkable data. Simply by better targeting the ER, we’re seeing a much larger effect than I would have anticipated in terms of invasive disease–free survival [IDFS]. A 30% reduction [in the risk of invasive disease] is a large improvement.³

Giredestrant is not yet FDA approved, but we expect it to be approved soon. This will be a new way for us to escalate or to deliver better ER-targeted therapies for our patients with HR-positive breast cancer.

References

1. Abemaciclib (Verzenio). Prescribing information. Eli Lilly and Company. Revised September 2026. Accessed October 14, 2026. https://pi.lilly.com/us/verzenio-uspi.pdf
2. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi:10.1056/NEJMoa2305488
3. Bardia A, Schmid P, Martín M, et al. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: results from the global phase III lidERA Breast Cancer trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS1-10.