Revisiting CDK4/6 inhibition and SERDs: EMBER-3 and the path forward

Estrogen receptor-positive, HER2-negative (ER+/HER2−) metastatic breast cancer is a heterogeneous disease characterized by complex and evolving patterns of endocrine sensitivity and resistance throughout the course of the disease. While endocrine therapy (ET) remains the foundation of systemic treatment, resistance almost invariably arises, posing significant therapeutic challenges (1). The incorporation of CDK4/6 inhibitors in the first-line has significantly extended both progression-free and overall survival; however, optimal strategies following progression on CDK4/6 inhibitors remain undefined. The question of whether to reintroduce CDK4/6 inhibition after progression has been addressed in trials such as MAINTAIN (2), PALMIRA (3), postMONARCH (4), and PACE (5). Collectively, these studies were relatively small and underpowered. Although MAINTAIN and postMONARCH demonstrated statistically significant but clinically modest improvements in progression-free survival (PFS), the absolute benefit across these trials was limited, supporting the notion that CDK4/6 rechallenge has thus far yielded modest and often disappointing results.

Furthermore, we have no validated biomarkers to guide patient selection in this setting. In parallel, the expanding role of precision oncology has highlighted the relevance of ESR1 mutations (ESR1m), a common mechanism of acquired resistance to aromatase inhibitors that sustains ER signaling. The emergence of oral selective estrogen receptor degraders (SERDs), engineered to overcome ESR1-driven resistance while offering improved pharmacological and practical characteristics, represents a promising therapeutic avenue (6). This dual rationale—optimizing the endocrine backbone while continuing cell cycle inhibition—provided the conceptual foundation for the design of the EMBER-3 trial (7).

The EMBER-3 trial was designed to evaluate the efficacy of imlunestrant, a potent, orally bioavailable, brain-penetrant SERD that functions as a pure estrogen receptor antagonist with favorable pharmacokinetic properties. In this open-label, multicenter, phase 3 study, 874 patients with ER+/HER2− advanced breast cancer—who had previously progressed on aromatase inhibitors, with or without CDK4/6 inhibitors—were randomly assigned to three treatment arms: imlunestrant monotherapy, standard ET (either fulvestrant or exemestane, per investigator’s choice), or imlunestrant in combination with abemaciclib. The combination arm was added following a protocol amendment after recruitment to the first two treatment arms had already begun. Consequently, the comparison between imlunestrant plus abemaciclib and imlunestrant alone was restricted to the concurrently randomized cohort, consisting only of patients enrolled after this amendment. ESR1m status, determined centrally using circulating tumor DNA, was incorporated into the study design as a predefined stratification factor. The trial had three primary endpoints: investigator-assessed PFS in the ESR1-mutant subgroup comparing imlunestrant versus standard therapy; PFS in the overall population for the same comparison; and PFS comparing imlunestrant plus abemaciclib versus imlunestrant alone in the concurrently randomized cohort. This allowed for the prospective evaluation of biomarker-defined subgroups and facilitated analysis of differential treatment effects according to ESR1 mutational status (7).

The population enrolled in EMBER-3 was representative of a contemporary cohort of patients with endocrine-resistant ER+/HER2− advanced breast cancer. The median age was 61 years, most patients had visceral metastases, and approximately 60% had previously received a CDK4/6 inhibitor. Notably, nearly 40% of the patients harbored ESR1m detected in circulating tumor DNA, and the vast majority were considered to have secondary endocrine resistance, as defined by the international ABC guidelines (8).

The results of the EMBER-3 trial revealed a nuanced efficacy profile for imlunestrant. As monotherapy, imlunestrant did not demonstrate a significant improvement in PFS compared to standard ET in the overall population (median PFS 5.6 vs. 5.5 months; hazard ratio 0.87; P=0.12). However, among patients with ESR1m—a prespecified subgroup comprising approximately 39% of the study population—imlunestrant was associated with a statistically significant improvement in PFS. In this subgroup, the difference in restricted mean survival time at 19.4 months favored imlunestrant by 2.6 months (P<0.001), and a numerically longer overall survival was also observed, although formal statistical significance was not reached. The most compelling finding of the study, however, came from the comparison between imlunestrant plus abemaciclib and imlunestrant alone, restricted to the cohort enrolled after the addition of the combination arm. In this group, the addition of abemaciclib resulted in a clear PFS benefit (median 9.4 vs. 5.5 months; hazard ratio 0.57; P<0.001), with consistent results across clinically relevant subgroups, including those with and without ESR1m and those with prior exposure to CDK4/6 inhibitors. The safety profile of imlunestrant, both as monotherapy and in combination with abemaciclib, was consistent with known class effects. No new safety signals were identified, and adverse events were largely manageable, with diarrhea, fatigue, and neutropenia being the most commonly reported in the combination arm (7). Importantly, the tolerability of the imlunestrant-abemaciclib combination did not appear to substantially compromise dose intensity compared to historical abemaciclib-based regimens, suggesting that treatment adherence remains feasible in real-world settings.

The EMBER-3 findings align with observations from prior studies evaluating novel endocrine therapies, particularly oral SERDs. In the EMERALD trial (9), elacestrant demonstrated a modest benefit over standard ET, with greater efficacy in patients harboring ESR1m. More recently, the Phase 3 trial of vepdegestrant (10)—a PROTAC-based estrogen receptor degrader—also showed a PFS advantage over fulvestrant in patients with previously treated ER+/HER2− advanced breast cancer, reinforcing the notion that ER-directed therapies retain clinical activity beyond CDK4/6 inhibition, especially in biomarker-selected populations. Collectively, these findings suggest that the therapeutic benefit of these agents as monotherapy is limited in unselected populations and primarily driven by activity in ESR1-mutant tumors.

In this context, the significant improvement observed with imlunestrant plus abemaciclib in EMBER-3 is particularly relevant. It supports a strategy that positions oral SERDs not as standalone alternatives, but rather as optimized endocrine backbones within combination regimens—similar to the role played by fulvestrant in pivotal trials of CDK4/6 inhibitors. Importantly, unlike previous trials that explored the continuation or rechallenge of CDK4/6 inhibitors after progression, EMBER-3 provides evidence of clinical benefit with second-line abemaciclib in a population where the majority of patients had already been exposed to a CDK4/6 inhibitor. This finding raises the hypothesis that the combination with a more potent endocrine partner may be a key determinant in restoring CDK4/6 sensitivity.

Biologically, this hypothesis is plausible. Profound ER depletion achieved by a high-potency SERD may reverse functional states of endocrine resistance and restore dependency on the cyclin D-CDK4/6-Rb axis. Mechanistically, enhanced ER degradation may lead to reduced cyclin D1 expression, re-establishment of Rb-mediated cell cycle control, modulation of Rb phosphorylation status, and attenuation of compensatory bypass pathways such as CDK2-cyclin E activation and PI3K/AKT/mTOR signaling. These processes, alongside alterations in RB1 integrity, FGFR pathway activation, and FAT1 loss, have been extensively described as central components of CDK4/6 inhibitor resistance. Recent comprehensive reviews on the clinical and molecular mechanisms of CDK4/6 resistance further support the concept that deeper ER suppression may restore cell cycle vulnerability and provide a rationale for therapeutic re-sensitization strategies using optimized endocrine partners, including our recently published narrative review on resistance mechanisms and re-sensitization strategies (11).

Nevertheless, several limitations of the EMBER-3 study should be acknowledged. The open-label design introduces potential bias, particularly in progression assessments. The use of investigator-assessed PFS as the primary endpoint, without blinded independent central review as the principal analysis, further compounds this concern. Additionally, the control arm predominantly consisted of fulvestrant, a drug with known limitations, including intramuscular administration, suboptimal bioavailability, and reduced efficacy in ESR1-mutant tumors. These factors may have contributed to a relative overestimation of the benefit observed with imlunestrant. From a clinical standpoint, it is unlikely that imlunestrant monotherapy will meaningfully alter current practice, given the modest efficacy and the growing availability of more effective agents. Conversely, the data from the combination arm provide a strong rationale for further development of oral SERDs in conjunction with CDK4/6 inhibitors, and potentially other targeted therapies.

The EMBER-3 trial reinforces the growing importance of biomarker-driven strategies in the management of ER+/HER2 advanced breast cancer. The consistent benefit observed in patients harboring ESR1m supports the routine incorporation of molecular profiling—particularly liquid biopsy-based assays—in clinical decision-making. Beyond ESR1, the integration of additional biomarkers may help refine treatment selection and optimize sequencing strategies. On the other hand, the efficacy of the optimized combination of imlunestrant and abemaciclib, observed in the mutated and non-mutated cohorts, clearly supports the need for combinations to address the evolving complex biology of HR-positive disease. As the field evolves, the use of oral SERDs will likely be shaped not by their standalone efficacy but by their role within rational combination regimens, especially alongside CDK4/6 inhibitors and potentially PI3K, AKT, or mTOR inhibitors. Furthermore, their oral route of administration offers meaningful advantages in terms of convenience and patient adherence, particularly in settings where prolonged therapy is required.

Furthermore, the increasing availability of different treatment alternatives for HR-positive patients raises the need to study rational sequencing strategies. This will require a more detailed and systematic approach to further understand resistance mechanisms that will be as diverse and heterogeneous as the molecular changes we are learning to identify as these tumors progress. Looking ahead, clinical research should focus on better defining the optimal endocrine backbone across different lines of therapy, ideally through biomarker-enriched trials that reflect real-world treatment scenarios. The comparative effectiveness of endocrine-based combinations versus emerging strategies—including antibody-drug conjugates—also warrants further exploration. Ultimately, the goal is to personalize ET beyond receptor status, using molecular signatures to tailor treatment intensity, improve outcomes, and delay the need for cytotoxic chemotherapy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-98/coif). C.H.B. reports grants/research support from Amgen, Astra Zeneca, Aveo Oncology, BioNTech, BMS, Daiichi Sankyo, Dizal Pharma, Exelixis, Fortrea, Gilead Sciences, GSK, ICON, IQVIA, Janssen, Labcorp, Lilly, Medpace, MSD, Novartis, Novocure, Nuvisan, OBI Pharma, Parexel, Pfizer, PharmaMar, PPD, PSI, Regeneron, Roche/Genentech, Samsung, Sandoz, Sanofi, Seagen, Servier, Stemline Therapeutics, Syneos Health, Taiho, Takeda, Tolmar, and TRIO Worldwide; academic research projects with CPO, PUCRS, LACOG, and GBECAM; stocks ownership in Tummi, MEDSir, and CPO; and participation in advisory boards, consulting, and receipt of travel and presentation honoraria from Adium, Novartis, Pfizer, Roche/Genentech, MSD, Astra Zeneca, Lilly, Daiichi, and Gilead. T.R. reports grants/research support from AstraZeneca; and participation in advisory boards, consulting, and receipt of travel and presentation honoraria from Novartis, Pfizer, MSD, Astra Zeneca, Lilly, Daiichi, Gilead, and Libbs. The authors have no other conflicts of interest to declare.

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