The therapeutic landscape for hormone receptor–positive, HER2-negative breast cancer is currently undergoing a paradigm shift, characterized by the expansion of oral selective estrogen receptor degraders (SERDs) and targeted therapies into earlier lines of treatment and the integration of molecular monitoring to preempt endocrine resistance.1 This shift, supported by maturing survival data from landmark trials such as the phase 3 monarchE (NCT03155997) and NATALEE (NCT03701334) trials, as well as emerging “early switch” strategies leveraging ESR1 mutation detection via circulating tumor DNA (ctDNA) from the phase 3 SERENA-6 (NCT04964934), reflects a transition towards from reactive treatment modification to more proactive, biology-guided disease management.

Accordingly, current clinical strategies are increasingly focused on personalizing the escalation of therapy in the adjuvant setting while simultaneously developing highly potent, next-generation oral SERDs to address the limitations of traditional endocrine backbones. By combining CDK4/6 inhibition with next-generation SERDs and serial molecular monitoring, oncologists could offer treatments designed to overcome resistance and extend survival while rigorously maintaining patients’ quality of life (QOL).

“We are entering an era of precision medicine in hormone receptor–positive breast cancer where every treatment decision is increasingly informed by the molecular landscape of the tumor and the unique priorities of the patient,” Ruta Rao, MD, panel moderator, stated during an OncLive Peer Exchange®.

Against this backdrop, Rao and other leading oncologists Rebecca Shatsky, MD; Nerea Lopetegui Lia, MD; and Megan Kruse, MD, convened to contextualize the evolving standards of care (SOC) and the biological rationale for modern interventions in hormone receptor–positive breast cancer, as informed by data and presentations from the 2025 San Antonio Breast Cancer Symposium (SABCS).

How has CDK4/6 inhibition evolved in both the early-stage and metastatic disease settings?

The introduction of CDK4/6 inhibitors has fundamentally altered the SOC for patients with hormone receptor–positive, HER2-negative breast cancer across the disease spectrum.

“First [used] in the metastatic setting, [CDK 4/6 inhibitors have] been around since around 2016 and have [basically] been the gold standard ever since,” Shatsky shared. “The National Comprehensive Cancer Network [NCCN] Guidelines say that a CDK4/6 inhibitor and an aromatase inhibitor [AI] should be [the preferred] first-line therapy for most patients with metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer.”

The most impactful recent shift involves the use of these agents in early breast cancer, and their transition into the adjuvant setting. Per the NCCN Guidelines, ribociclib (Kisqali) plus an AI remains a category 1 preferred CDK4/6 inhibitor–based regimen in frontline hormone receptor–positive/HER2-negative metastatic breast cancer.2 Abemaciclib (Verzenio) and palbociclib (Ibrance) also hold recommendations as preferred regimens in combination with an AI in this setting. Additionally, both ribociclib and abemaciclib hold Category 1 recommendations in combination with fulvestrant (Faslodex) in the first-line.

Abemaciclib also holds a Category 1 recommendation in combination with endocrine therapy for ER-positive, HER2-negative, node-positive and high-risk early breast cancer, based on data from the monarchE trial. Findings from the primary overall survival (OS) analysis of monarchE trial presented at the 2025 ESMO Congress showed that at a median follow-up of 76 months, adjuvant abemaciclib plus endocrine therapy significantly reduced the risk of death by 15.8% vs endocrine therapy alone in patients with hormone receptor–positive, HER2-negative, high-risk early breast cancer (HR, 0.842; 95% CI, 0.722-0.981; P = .0273).3 Additional efficacy data showed that the abemaciclib combination reduced the risk of invasive disease–free survival (IDFS) events by 26.6% compared with endocrine therapy alone (HR, 0.734; 95% CI, 0.657-0.820; nominal P < .0001).

“We were all waiting to see that OS benefit,” Lopetegui Lia noted.1 “In practice, we’ve been using adjuvant abemaciclib plus endocrine therapy in the adjuvant setting for some time, and we knew that there was an IDFS [benefit], so it’s reassuring to see that OS benefit [as well].”

In October 2024, the NCCN updated its Clinical Practice Guidelines in Oncology for breast cancer to recommend ribociclib plus an AI as a category 1 preferred CDK4/6 inhibitor–based regimen for the adjuvant treatment of hormone receptor–positive/HER2-negative early breast cancer.4 This update followed the September 2024 FDA approval of adjuvant ribociclib plus an AI for the treatment of patients with hormone receptor–positive, HER2-negative stage II/ III early breast cancer at high risk of recurrence, including those with node-negative disease.5

NATALEE utilized a different dosing strategy than monarchE: eligible patients were given a 400 mg dose via a 3-weeks-on, 1-week-off dosing schedule over a longer duration of 3 years, in combination with a nonsteroidal AI for at least 5 years, or a nonsteroidal AI alone.6

According to data from the 5-year prespecified analysis of NATALEE, at a median follow-up of 55.4 months, the 36-month IDFS rate was 90.8% with ribociclib (n = 2594) and 88.0% with an AI-alone (n = 2552); respective 60-month IDFS rates were 85.5% vs 81.0%. NATALEE’s broader eligibility criteria included high-risk node-negative disease, where ribociclib demonstrated an HR of 0.606.

“It’s great to have an option for these patients that we know are still at risk,” Kruse stated.1 “Even though their risk [status] may not be as high as the patients that we saw in the monarchE trial, many times our patients with node-negative disease are still concerning, and we get these genomic assays that tell us that they do have a very reasonable and clinically meaningful risk of distant recurrence. To have an option that we can add to their endocrine backbone is really important here.”

Although real-world evidence from the retrospective P-VERIFY study (NCT06495164), leveraging the Flatiron Health database, suggest no meaningful OS differences among palbociclib, ribociclib, and abemaciclib in routine clinical practice 7, the clinical survival data from NATALEE and monarchE have a substantial influence on CDK4/6 inhibitor selection.1

“[There are] overlapping patient populations in these 2 trials…right now, [however], the data are more mature for the monarchE population, and that OS benefit does influence decisions in my clinic quite a bit,” Shatsky explained. “In my highest-risk populations, I am using abemaciclib based upon the current available evidence…in the more intermediate[-risk populations], I’m still using riboclcib. [However,] when we look at the time points for interim analyses, NATALEE is younger, and the data actually look quite similar. I don’t think we can rule out that ribociclib may have an OS benefit in the future.”

Despite these advancements, real-world gaps in CDK4/6 inhibitor use persist.1 The panelists noted data from discussions held at the 43rd Annual Miami Breast Cancer Conference in March 2025, suggesting that many eligible patients are not receiving these life-extending adjuvant therapies due to concerns over treatment fatigue or the logistics of long-term monitoring.

“Education is the key to all of this,” Shatsky emphasized. “[We have to] make sure that [patients] understand that there really is a benefit. One of the problems with breast cancer data reporting is we often report 5-year risks, when hormone receptor–positive breast cancer can recur up to 25 or 30 years later in some patients, and a third of patients experience recurrence and develop metastatic breast cancer. It makes for lengthy visits, and there is some aspect of treatment fatigue amongst patients, but [sharing this information with patients] could be saving a lot of lives when you look at long-term outcomes.”

What is the role of ESR1 mutation monitoring in early intervention?

A key mechanism of acquired resistance to AI therapy is the development of somatic mutations in the ESR1 gene, which emerge in approximately 30% to 40% of patients during first-line endocrine therapy for advanced disease.8

In January 2023, the FDA approved elacestrant (Orserdu)for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following progression on at least 1 line of endocrine therapy based on data from the phase 3 EMERALD trial (NCT03778931).9 In the ESR1-mutated population, elacestrant (n = 115) reduced the risk of progression or death by 45% vs fulvestrant or an AI (n = 113), with a median PFS of 3.8 months (95% CI, 2.2-7.3) vs 1.9 months (95% CI, 1.9-2.1) with these respective regimens (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).10

“To aid in treatment selection, [ASCO guidelines] now recommend routine testing for ESR1 mutations at [the time of recurrence or] progression, as identifying these patients allows us to pivot to more effective agents like elacestrant,” Lopetegui Lia explained.1,11

The field is now moving toward even earlier intervention through continuous molecular monitoring, as evidenced by the SERENA-6 trial.1,12 SERENA-6 evaluated the investigational SERD camizestrant and utilized a novel “early switch” design where patients receiving a first-line AI plus a CDK4/6 inhibitor underwent ctDNA monitoring every 2 to 3 months, rather than waiting for clinical or radiographic progression. If an ESR1 mutation was detected, patients were randomly assigned to either continue their AI or switch the endocrine component to camizestrant while maintaining the same CDK4/6 inhibitor.

Updated data presented during the 2025 SABCS found that this early intervention produced a median PFS of 16.6 months (95% CI, 14.7-19.4) with camizestrant (n = 157) vs 9.2 months (95% CI, 7.2-9.7) with the control (n = 158; HR, 0.46; 95% CI, 0.34-0.62; P < .00001). The time to first subsequent therapy also favored the camizestrant arm (HR, 0.47; 95% CI, 0.35-0.62).

“The results from SERENA-6 represent a potential shift in clinical practice, suggesting that we can extend the benefit of first-line therapy by acting on the earliest molecular signals of resistance,” Shatsky said.1“Testing for ESR1 mutations has become exceedingly important…we don’t want to miss out on a patient who is eligible for these very well-tolerated drugs.”

Beyond camizestrant, several other next-generation SERDs are poised to reshape treatment in the post–CDK4/6 inhibitor setting. Imlunestrant (Inluriyo), a brain-penetrant oral SERD with pure antagonistic properties, was approved by the FDA in September 2025 for the treatment of adult patients with ER-positive, HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations whose disease progressed following 1 or more prior lines of endocrine therapy, based on data from the phase 3 EMBER-3 trial (NCT04975308).13

Updated data from EMBER-3 presented at the 2025 SABCS and simultaneously published in the New England Journal of Medicine showed that the PFS benefit with imlunestrant monotherapy was sustained in patients with ESR1-mutated metastatic breast cancer (n = 256).14 At a median follow-up of 28.5 months, the median PFS in this patient population was 5.5 months (95% CI, 3.9-7.4) with imlunestrant alone (n = 138) vs 3.8 months (95% CI, 3.7-5.5) with endocrine therapy (HR, 0.62; 95% CI, 0.47-0.82; P = .0007). At 50% maturity, the median OS was 34.5 months (95% CI, 25.4-not reached) vs 23.1 months (95% CI, 18.4-28.9) with these respective regimens (HR, 0.60; 95% CI, 0.43-0.86; P = .0043).

Similarly, giredestrant is being evaluated alongside the mTOR inhibitor everolimus (Afinitor) in the phase 3 evERA study (NCT05306340) for patients with ER-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor.15 Primary results from evERA presented at the 2025 ESMO Congress showed that in the intention-to-treat (ITT) population, the median PFS was 8.77 months (95% CI, 6.60-9.59) with giredestrant plus everolimus compared with 5.49 months (95% CI, 4.01-5.59) with SOC (HR, 0.56; 95% CI, 0.44-0.71; P < .0001). Notably, in a subgroup defined by the presence of an ESR1 mutation, the giredestrant combination elicited a median PFS of 9.99 months (95% CI, 8.08-12.94) vs 5.45 months (95% CI, 3.75-5.62) with SOC (HR, 0.38; 95% CI, 0.27-0.54; P < .0001).

Additional results from a clinical and biomarker subgroup analysis of evERA, presented at the 2025 SABCS, showed a consistent PFS benefit with giredestrant plus everolimus in patients with ESR1 mutations and the ITT population, irrespective of PIK3CA/AKT1/PTEN alterations.16

“As we see more data from EMBER-3 and evERA, the potential for all-oral, SERD[-based] combinations to become the new standard post-CDK4/6 inhibition is becoming increasingly clear,” Kruse stated.1

What are the best strategies for integrating these therapies into real-world practice, managing related toxicities, and preserving QOL?

Successfully integrating these potent therapies into the clinic requires a nuanced understanding of their safety profiles and a commitment to shared decision-making, panelists agreed.1

“We shouldn’t be fearful of dose adjustment,” Kruse said. “We should [tell our] patients that we’re confident that these drugs, even if we have to [administer them] at a little lower dose, are not going to hurt them.” She further emphasized the patient-centric approach. “It really comes down to [a patient’s] personal preferences. What are we balancing in terms of being on therapy for potentially a shorter period of time with toxicity.”

In the adjuvant setting, the choice between abemaciclib and ribociclib often hinges on the patient’s ability to tolerate specific adverse effects (AEs) over a 2- to 3-year period. For example, ribociclib requires monitoring for QTc interval prolongation, neutropenia, and liver enzyme elevations.17 In the NATALEE trial, the 400-mg starting dose of ribociclib was specifically chosen to minimize these AEs, and 5-year data showed that 20% of patients discontinued the drug due to toxicity. Most AEs occurred early, with median times to dose reduction and discontinuation of 3 and 4 months, respectively.

“Proactive symptom management is the cornerstone of adherence,” Kruse emphasized. “By managing liver enzyme elevations or QTc shifts early, we ensure that patients maintain the necessary dose intensity to derive the full IDFS benefit.”

In the metastatic setting, preserving QOL is paramount as patients live longer with advanced disease. Patient-reported outcomes (PROs) from the EMBER-3 trial shared during the 2025 ASCO Annual Meeting showed that global health status and functional domains were well maintained across treatment arms.18 In patients with ESR1 mutations, imlunestrant was favored over SOC endocrine therapy regarding physical, role, and social functioning, and it was associated with a longer median time to deterioration of QOL (5.6 months vs 3.8 months). However, oral SERD combinations can introduce new burdens; for instance, imlunestrant plus abemaciclib was associated with more frequent nausea and diarrhea vs imlunestrant alone.

“When discussing treatment options for metastatic disease, we must balance the impressive PFS gains of our new SERD combinations with the daily impact of their toxicity profiles on a patient’s lifestyle,” Lopetegui Lia reiterated.

The emerging data also highlight the importance of “molecular response” as a surrogate for clinical benefit.19 In the EMBER study, deep declines in ctDNA levels (≥50%) after 1 cycle of imlunestrant were strongly associated with longer PFS. This suggests that serial ctDNA testing could be used to identify patients who may benefit from an even more intensified approach.

Panelists noted that practical challenges to implementing these findings include logistical and financial barriers, along with selection of the optimal testing modality. Although blood-based ctDNA is the preferred monitoring tool due to its sensitivity, panel members highlighted concerns regarding payer coverage for regular testing.1,20 Moreover, emerging research suggests that analyzing genomic DNA from circulating tumor cells (CTCs) may provide complementary information. In some cases, ESR1 mutations are detectable in CTCs even when they are absent in paired plasma-cfDNA samples, suggesting that multi-modal liquid biopsy approaches might eventually be required to fully capture tumor heterogeneity and guide individualized therapy.

“The logistical hurdle of regular liquid biopsies is offset by the clinical utility of finding an ESR1 mutation early, as it allows us to transition the patient to a therapy like elacestrant or an investigational SERD comb that is biologically matched to their tumor’s resistance profile,” Shatsky noted.1

As therapies move into earlier lines, panelists noted that sequencing naturally becomes more complex.1 Although standard chemotherapy remains an option, the future of the field likely lies in the strategic use of SERDs and antibody-drug conjugates (ADCs). However, the panelists agreed that all endocrine-based strategies should be exhausted before transitioning to chemotherapy or ADCs.

ReferencesAdvancing care in HR+ breast cancer: integrating CDK4/6 inhibition, SERDs, and early intervention strategies. OncLive Peer Exchange. OncLive.com. December 10, 2025. Accessed December 22, 2025.NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, Version 5.2025. Accessed December 22, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdfJohnston 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.2025.10.005Novartis ribociclib (Kisqali) recognized as category 1 preferred breast cancer adjuvant treatment by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). News release. Novartis. October 24, 2024. 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Real-world progression-free survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR-positive/HER2-negative metastatic breast cancer in United States routine clinical practice. ESMO Open. 2025;10(9):105570. doi:10.1016/j.esmoop.2025.105570Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 Phase III trial. News release. AstraZeneca. February 26, 2025. Accessed December 22, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.htmlFDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed December 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/Bidard FC, Kaklamani VG, Neven P, et al. 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