Emerging Data With Oral SERDs Reframe Frontline and Post–CDK4/6 Decisions in ER+ Breast Cancer

Oral selective estrogen receptor degraders (SERDs) are poised to reshape therapeutic sequencing discussions following CDK4/6 inhibitors and aromatase inhibitors in estrogen receptor (ER)–positive, HER2-negative breast cancer, shifting the clinical focus from incremental efficacy toward quality-of-life–driven decision-making, according to panelists who participated in an OncLive® Scientific Interchange and Workshop.¹

The workshop, held during the 2025 San Antonio Breast Cancer Symposium (SABCS), focused on treatment strategies in patients with early-stage hormone receptor–positive, HER2-negative breast cancer, including CDK4/6 inhibitors in the early-stage and adjuvant settings. At the tail end of the discussion, experts homed in on emerging data with oral SERDs from phase 3 trials like EMBER-3 (NCT04975308) lidERA Breast Cancer (NCT04961996), and SERENA-6 (NCT04964934), and debated their effect on sequencing and treatment duration.

“As we have been trying to develop new drugs to replace fulvestrant [Faslodex], there has been this renewed interest in novel SERDs,” Christos Vaklavas, MD, moderator of the workshop and a professor of medicine in the Division of Oncology, Department of Internal Medicine at the University of Utah and Huntsman Cancer Institute in Salt Lake City, stated. “When we started realizing that we’re dealing with a beast with ESR1 mutations, that generated this idea. [Oral SERDs] are back in prime time, but…there’s only a handful in the running right now.”

What do EMBER-3 data suggest about sequencing after CDK4/6 inhibition?

During the workshop, participants began by discussing ongoing phase 3 trials evaluating oral SERDs of interest. The first of these, imlunestrant (Inluriyo), continues to show significant progression-free survival (PFS) benefit vs standard-of-care (SOC) endocrine therapy in patients with previously treated ER-positive, HER2-negative advanced breast cancer, as evidenced by data presented during the 2025 SABCS.^1,2

Updated data from EMBER-3 showed that, at a median follow-up of 27.6 months, patients with ESR1 mutations achieved a median PFS of 5.5 months (95% CI, 3.9-7.4) with imlunestrant (n = 138) vs 3.8 months (95% CI, 3.7-5.5) with the SOC (n = 118; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). Among all patients, the median PFS was 10.9 months (95% CI, 7.5-12.5) with imlunestrant plus abemaciclib (Verzenio; n = 213) vs 5.5 months (95% CI, 3.8-5.6) with imlunestrant alone (n = 213; HR, 0.59; 95% CI, 0.47-0.74; P < .0001). Notably, this PFS benefit for the combination was seen regardless of ESR1 mutation status. Among patients who had previously received a CDK4/6 inhibitor, the median PFS was 9.1 months (95% CI, 7.2-11.3) with imlunestrant plus abemaciclib (n = 139) vs 3.7 months (95% CI, 2.1-5.5) with imlunestrant alone (n = 140; HR, 0.53; 95% CI, 0.40-0.69; P < .0001).

Notably, at 50% overall survival (OS) maturity and a median follow-up of 29.5 months, patients in the ESR1 mutation group achieved a median OS of 34.5 months (95% CI, 25.4-not reached) with imlunestrant vs 23.1 months (95% CI, 18.4-28.9) with SOC endocrine therapy (HR, 0.60; 95% CI, 0.43-0.86; P = .0043). Although not statistically significant, this numerical OS benefit was considered clinically meaningful.

Based on the primary PFS analysis of EMBER-3, the FDA approved imlunestrant monotherapy in September 2025 for the treatment of patients with ER-positive, HER2-negative, ESR1-mutant advanced breast cancer with disease progression following at least 1 line of endocrine therapy.³

Next steps for the development of imlunestrant include the randomized, open-label, global, multicenter phase 3 EMBER-4 study (NCT05514054).⁴ The study is enrolling approximately 8000 patients with ER-positive, HER2-negative early breast cancer who have received 2 to 5 years of adjuvant endocrine therapy with or without a CDK4/6 inhibitor who are at increased risk of recurrence. Eligible patients will be randomly assigned 1:1 to single-agent imlunestrant or SOC endocrine therapy, including an aromatase inhibitor or tamoxifen.

Are the lidERA data ready for early-stage application?

Next, panelists expressed interest in results from the lidERA study and debated whether they could be considered practice-changing for patients with ER-positive, HER2-negative, medium- and high-risk early breast cancer.¹

Findings from lidERA, presented during the 2025 SABCS, showed that giredestrant produced a significant and clinically meaningful improvement in invasive disease-free survival (iDFS) compared with SOC endocrine therapy in the above patient population.⁵

Patients treated with giredestrant (n = 2084) experienced a 30% reduction in the risk of invasive disease recurrence or death vs the SOC (n = 2086; HR, 0.70; 95% CI, 0.57-0.87; P = .0014) after a median follow-up of 32.36 months. The respective 12-, 24-, and 36-month iDFS rates in the giredestrant arm were 97.7%, 94.6%, and 92.4%; corresponding rates in the SOC arm were 96.9%, 92.3%, and 89.6%. This iDFS benefit was consistent across all key prespecified subgroups.

Similarly to EMBER-3, interim OS data revealed a numerical improvement with giredestrant, although this result was not statistically significant (HR, 0.79; 95% CI, 0.56-1.12; P = .1863). Of note, these data were immature at the time of analysis.

Despite these encouraging data, the panelists expressed caution when interpreting these results due to an earlier data readout and potential underperformance of the control arm.¹

“This study enrolled patients that are…chemo-exposed and non–chemo-exposed,” Giancarlo Moscol, MD, a hematologist/oncologist and associate professor in the Department of Breast Medical Oncology, Division of Cancer Medicine & Department of General Oncology, at The University of Texas MD Anderson Cancer Center in Houston, stated. “The risk of relapse has not materialized, really, and we don’t know the maturity. For this to be a winner, we will need longer maturity and then prove—similarly to what has happened with CDK4/6 [inhibitors]—that the separation between the curves goes on.”

His colleague Jason Mouabbi, MD, highlighted biological inconsistencies. “What’s really puzzling is that single-agent giredestrant in the metastatic setting didn’t do much, and all other SERDs showed activity mainly in ESR1-mutant patients. Now we bring them to the early setting where [the incidence of] ESR1 is less than 5%, and now [the results are] positive.” Mouabbi is an assistant professor in the Department of Breast Medical Oncology and the Department of General Oncology in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center.

Panelists then cited the need for more information from further subgroup analyses before incorporating these findings into clinical practice, emphasizing unresolved sequencing questions.

“It’s going to be tricky because these patients didn’t get CDK4/6 inhibitors,” Jessica Sharpe, MD, PhD, an assistant professor of medicine in the Division of Hematology/Oncology at Vanderbilt University Medical Cancer in Nashville, Tennessee, asserted. “For now, that’s what I’m going to continue doing for the patients I think are truly high-risk. I’ll be curious to see the subgroup analysis for patients who got chemotherapy vs [those who] did not.”

However, Michelle Melisko, MD, noted a potential niche. “For intermediate-risk patients who may be candidates for [the phase 3] NATALEE trial [NCT03701334] but are not abemaciclib candidates and may not be compliant, this could fill a gap.” Melisko is a breast medical oncologist and clinical professor of medicine in the Division of Hematology and Oncology at the University of California San Francisco.

What is the feasibility of incorporating dynamic ctDNA assessment into routine clinical practice, as per the SERENA-6 approach?

Discussion then shifted to SERENA-6, which evaluated early switching to camizestrant plus continued CDK4/6 inhibition upon detection of emergent ESR1 mutations. Data from the SERENA-6 trial showed that switching to camizestrant plus continued CDK4/6 inhibition exhibited a clinically meaningful improvement in PFS vs continued aromatase inhibition and CDK4/6 inhibition in this patient population.⁶ Updated data presented during the 2025 SABCS showed that the median PFS was 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). Time to first subsequent therapy also favored camizestrant (HR, 0.47; 95% CI, 0.35-0.62).

Despite these positive efficacy signals, panelists questioned the real-world feasibility of this ctDNA-guided approach.¹ They noted that this strategy will require serial liquid biopsies potentially every 4 weeks or every few months, which introduces financial toxicity and patient anxiety. Experts noted that for this to succeed, a point-of-care ESR1 mutation test would likely be necessary.

“It’s an impossible trial to perform,” Moscol said. “The ask is too high. We’re using too many resources and producing background noise just to look for ESR1 mutations.”

Shivani Shinde, MD, a hematologist/oncologist at Intermountain Health in Murray, Utah, echoed some of these concerns. “Even for patients it’s a lot [to undergo]. There’s a lot of financial toxicity and anxiety associated with it. And then there’s the whole question about [time to second subsequent therapy].”

Given the availability of effective second-line SERDs and the cost of surveillance, panelists suggested that OS data would likely be required to justify regulatory approval of this approach.

“For me, the numbers do not lie,” Mouabbi said. “And the numbers are telling you it’s not ready for prime time.”

What threshold of benefit would justify moving oral SERDs into the frontline?

Looking ahead, panelists identified ongoing phase 3 trials like persevERA (NCT04546009) and SERENA-4 (NCT04711252) as pivotal for determining whether oral SERDs should replace aromatase inhibitors as the initial endocrine backbone in the frontline.¹ These studies are evaluating giredestrant or camizestrant, respectively, in combination with palbociclib (Ibrance) compared with standard aromatase inhibitor–based regimens in ER-positive, HER2-negative advanced or metastatic breast cancer.^7,8

Despite eagerness to see data read out from SERENA-4, some panelists conveyed concern regarding the delay in results and theorized that there may not be enough events to create separation.¹ Experts also questioned the magnitude of benefit required to displace current standards.

“If we see benefit, the best-case scenario is a 2-percentage point difference,” Vaklavas said. “If we see a 2-month difference and it’s statistically significant, is that practice changing?”

Moscol framed the question in practical terms. “We have 7 months with SERENA-6, then 10 months with [the phase 3] evERA study [NCT05306340] in the second line. Any new approach has to beat either of those scenarios. Otherwise, why prescribe a medication for more than 3 years in the frontline when I can use it for 10 months later?”

Collectively, panelists agreed that oral SERDs represent a meaningful advance, particularly in ESR1-mutant disease, but emphasized that sequencing decisions will increasingly hinge on durability of benefit, feasibility of molecular monitoring, and long-term tolerability.¹ As Vaklavas concluded, the field is no longer debating whether SERDs work—but rather where, when, and for whom they should be deployed.

References

1. Early-stage HR+/HER2– breast cancer: expert perspective on evolving approaches to optimize adjuvant therapy. An OncLive Scientific Interchange and Workshop. OncLive. December 9, 2025. Accessed January 20, 2026.
2. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): updated efficacy results from the phase 3 EMBER-3 trial. Presented at: San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. GS3-08.
3. FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. September 25, 2025. Accessed January 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imlunestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
4. A study of imlunestrant versus standard endocrine therapy in participants with early breast cancer (EMBER-4). Clinicaltrials.gov. Updated January 21, 2026. Accessed January 21, 2026. https://www.clinicaltrials.gov/study/NCT05514054
5. Bardia AL, 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.
6. Bidard FC, Mayer EL, Park YH, et al. Updated results and an exploratory analysis of ESR1m circulating tumor DNA dynamics from SERENA-6, a phase 3 trial of camizestrant + CDK4/6 inhibitor for emergent ESR1m during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF7-03.
7. A study evaluating the efficacy and safety of giredestrant combined with palbociclib compared with letrozole combined with palbociclib in participants with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer (persevERA Breast Cancer). Updated January 7, 2026. Accessed January 20, 2026. https://www.clinicaltrials.gov/study/NCT04546009
8. A comparative study of AZD9833 plus palbociclib versus anastrozole plus palbociclib in patients with ER-positive HER2 negative breast cancer who have not received any systemic treatment for advanced disease (SERENA-4). Clinicaltrials.gov. Updated October 14, 2025. Accessed January 20, 2026. https://www.clinicaltrials.gov/study/NCT04711252