Adjuvant CDK4/6 Inhibitors Gain Ground as Oral SERDs Emerge to Tackle Endocrine Resistance in Early HR+ Breast Cancer

Recent readouts from the phase 3 monarchE (NCT03155997) and NATALEE (NCT03701334) trials are reinforcing adjuvant CDK4/6 inhibition as a standard strategy for patients with node-positive or high-risk node-negative hormone receptor–positive breast cancer, while parallel efforts to bolster adjuvant endocrine therapy—particularly through the development of oral selective estrogen receptor degraders (SERDs)—underscore a broader shift toward earlier intervention against endocrine resistance, according to Erica L. Mayer, MD, MPH.

“Patients with higher-risk cancers, particularly those that involve lymph nodes or have higher-risk biologic features, are still at risk of recurrence despite [having] some of the best advances in adjuvant endocrine therapy, such as extended-duration treatment or the use of ovarian function suppression in premenopausal patients,” said Mayer, who serves as the director of breast cancer clinical research at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts. “Therefore, we need improvements in our therapies and in our strategies to help maximally reduce the risk of disease recurrence for these early-stage patients.”

In an interview with OncLive^®, Mayer discussed recent advancements in the management of high-risk, early-stage hormone receptor–positive, HER2-negative breast cancer; detailed ongoing efforts to leverage oral SERDs in ESR1-mutant disease, with a particular focus on the phase 3 ELEGANT trial (NCT06492616) of elacestrant (Orserdu) in a purely high-risk population; and encouraged enrollment onto these studies in order to help bring this active, promising drug class into earlier settings.

OncLive: What recent shifts have we seen with respect to treatment in patients with high-risk, hormone receptor–positive, HER2-negative breast cancer?

Mayer: Over the years, we have seen better outcomes for our patients with hormone receptor–positive, HER2-negative early breast cancer. However, we know that there remains a residual risk for these patients, and that is a risk of either local or distant recurrence. An individual person’s risk may reflect different aspects of their disease and their presentation, including their anatomic stage—particularly whether the regional lymph nodes are involved with breast cancer—as well as tumor biology. This is reflected in some of the clinicopathologic features that we obtain from the pathology lab, including tumor grade, oncotype or genomic test status, and sometimes Ki-67 [expression levels].

What are some ongoing adjuvant trials seeking to reduce or minimize this risk of recurrence?

One of the biggest strategies that has been employed over the past several years has been the introduction of CDK4/6 inhibitors into the adjuvant setting. This includes the [FDA] approvals of abemaciclib [Verzenio], based on [data from] the monarchE trial, and ribociclib [Kisqali], based on [data from] the NATALEE trial. Taking one of these medications in addition to ongoing adjuvant endocrine therapy significantly reduces the risk of cancer recurrence.

At the 2025 ESMO Congress, we saw that patients who have received adjuvant abemaciclib, which is given for 2 years after initial diagnosis, not only maintained a reduction in the risk of disease recurrence, but also experienced [a significant] improvement in overall survival [(HR, 0.842; 95% CI, 0.722-0.981; P = .0273) vs endocrine therapy alone].¹ This means that the use of adjuvant abemaciclib appears to be helping us cure patients with early-stage disease. With ribociclib, we also saw [5-year] follow-up [data confirming] that adjuvant ribociclib maintained improvements [in invasive disease-free survival (HR, 0.716; 95% CI, 0.618-0.829; 1-sided P < .0001) vs endocrine therapy alone] and reduced the risk of cancer recurrence [beyond a] 3-year window.² We also saw more data supporting the use of ribociclib in node-negative patients, which is a very large population of patients who are also at risk of disease recurrence.³ These recent updates solidify the role of adjuvant CDK4/6 inhibitors for node-positive or higher-risk node-negative patients.

Another major strategy under study in ongoing trials is the attempt to optimize [available] endocrine therapies used in the adjuvant setting. Traditionally, we have had aromatase inhibitors available, as well as tamoxifen, [which is] typically used for premenopausal patients. However, there is a very exciting category of drugs being developed in both the metastatic and early-stage settings: oral SERDs. These medications are potent and can target the estrogen receptor [ER] to help reduce estrogen-related stimulation of cancer cells; they also have the ability to target the ER when it has mutated, which can be a form of detectable endocrine resistance, particularly in patients with metastatic disease. At this point in time, there are 2 approved oral SERDs for patients with metastatic hormone receptor–positive, HER2-negative breast cancer: [elacestrant and imlunestrant (Inluriyo)]. However, there are ongoing efforts to translate the benefits seen with oral SERDs in the metastatic setting to earlier stages.

What are some of the distinguishing features of trials evaluating oral SERDs?

The trials designed in the early-stage setting fall into two main categories. One category includes trials offering the adjuvant SERD versus an AI as the initial first step. For example, the [phase 3] CAMBRIA-2 trial [NCT05952557], which uses the oral SERD camizestrant [AZD9833], randomly assigned patients to the oral SERD vs an aromatase inhibitor at the time of adjuvant endocrine therapy initiation. Then there is a category of trials in which patients who have been on adjuvant endocrine therapy for anywhere between 2 to 5 years are then randomly assigned to either stay on their aromatase inhibitor or switch to one of the new oral SERDs. For example, the ongoing ELEGANT trial, which uses the oral SERD elacestrant, is enrolling patients with higher-risk, node-positive breast cancer who have completed at least 2 years of adjuvant endocrine therapy. [These patients are] then randomly assigned to complete 5 years of elacestrant or 5 years of their ongoing standard of care [SOC] adjuvant endocrine therapy.

Importantly, these trials are designed to capture patients around the time they are completing their adjuvant CDK4/6 inhibitor. We already know that a patient who is completing 2 years of abemaciclib or 3 years of ribociclib may be a higher-risk patient because they had enough risk to require a CDK4/6 inhibitor. As patients complete those agents, they could become eligible to join one of the adjuvant oral SERD trials. For example, a patient with high-risk, node-positive disease who receives 2 years of abemaciclib [could] pivot to the ELEGANT trial upon completion of that [regimen]. This patient [could be offered treatment with] the oral SERD in the extended-duration adjuvant endocrine space. This really speaks to the current SOC, where patients with higher-risk disease will receive anywhere between 7 to 10 years of adjuvant endocrine therapy. Thus, the trials fit very well into the current paradigms for how we prefer to take care of these patients.

What preclinical and clinical rationale do we have to support early switching in patients with ESR1-mutant disease?

Oral SERDs are particularly well-suited to treat patients whose cancers have developed an ESR1 mutation, which is a resistance mutation that tends to develop over time while a patient is receiving adjuvant aromatase inhibitor therapy. We do know that these mutations are quite prevalent in pretreated patients with metastatic hormone receptor–positive, HER2-negative breast cancer. In the early-stage setting, these mutations may not be as frequent, but given that our SOC provides many years of adjuvant endocrine therapy, it is possible—with that continued pressure—that these mutations could develop and be a mechanism of resistance or lead to metastatic disease. [Accordingly], there is a rationale for using an oral SERD to help prevent the development of ESR1 mutations and help prevent the development of a resistant biology. Additionally, in some of the metastatic trials, we have seen that oral SERDs are extremely well-tolerated with very favorable adverse effect profiles, perhaps more favorable than our SOC aromatase inhibitors. Having a potential agent that is very active, may help prevent resistance, and is well-tolerated is very attractive. If the trials are successful, this would be a wonderful addition to the early-stage space.

What is your final message to colleagues regarding the importance of ongoing investigations of oral SERDs?

The adjuvant oral SERD trials are global trials, and they are open not only throughout the United States but throughout the world. I would encourage anyone who has access to these trials to try to enroll patients; the sooner we meet accrual in these very important trials, the sooner we will have answers as to whether we can extend oral SERDs into the early-stage setting for our patients. I would encourage any providers who [have patients who] are eligible for the [ELEGANT] study to try and identify a site where they can get access.

Disclosures: Mayer has served as a consultant for AstraZeneca, Lily, Novartis, Genentech, and Atkis Oncology.

References

1. Johnston S, Martin M, O’Shaughnessy J, et al. Overall survival with abemaciclib in early breast cancer. Ann Oncol. Published online October 17, 2025. doi:10.1016/j.annonc.2025.10.005
2. Crown J, Stroyakovskii D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/ HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival. ESMO Open. 2025;10(11):105858. doi:10.1016/j.esmoop.2025.105858
3. Novartis Kisqali 5-year NATALEE data demonstrate 28% reduction in risk of recurrence in the broadest early breast cancer patient population. News release. Novartis. October 17, 2025. Accessed January 7, 2026. https://www.novartis.com/news/media-releases/novartis-kisqali-5-year-natalee-data-demonstrate-28-reduction-risk-recurrence-broadest-early-breast-cancer-patient-population