3 Things You Should Know About Using Selective Estrogen Receptor Degraders in Hormone Receptor–Positive, HER2-Negative Advanced Breast Cancer

Release Date: May 6, 2026

Expiration Date: May 6, 2027

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Implement best practices for molecular testing in hormone receptor-positive/HER2-negative metastatic breast cancer, including selection of tissue vs liquid biopsy and indications for repeat testing at progression.
• Apply clinical trial and real-world evidence to select and sequence oral SERDs after progression on CDK4/6 inhibitor plus endocrine therapy.
• Develop treatment strategies for dual resistance, integrating evidence for targeting the PI3K/AKT pathway in patients with co-occurring ESR1 and PIK3CA pathway alterations.

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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Educational Grant Support

This activity is supported by an educational grant from Stemline Therapeutics, Inc.

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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

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Activity

Approximately 70% to 80% of breast cancers (BCs) overexpress the estrogen receptor (ER),¹ and mutations in the ESR1 ligand binding domain can lead to constitutive, estradiol-independent activation resulting in endocrine therapy (ET) resistance.^2,3 While some genomic alterations remain relatively constant throughout BC treatment (eg, PIK3CA), others, like ESR1 mutations, commonly arise in response to selective therapeutic pressure.^2,3 Reassessing the genomic signature of hormone receptor–positive/HER2-negative advanced BC (aBC) at the time of each progression using circulating tumor DNA (ctDNA) blood-based testing can facilitate optimal subsequent ET selection.⁴ Here are 3 things you should know about using selective ER degraders (SERDs) to treat hormone receptor-positive/HER2-negative aBC.

1. SERD monotherapy is an option for patients with ESR1-mutated, ER+/HER2-negative aBC progressing on prior ET, including those who have received multiple prior therapies or who have a concomitant PIK3CA mutation.

There are multiple FDA-approved SERDs available for patients with hormone receptor-positive/HER2-negative aBC harboring a targetable alteration, as shown in the Table.^5-9 Activating ESR1 mutations, which are rarely detected in primary breast tumors,³ occur in about 11% to 55% of metastatic BCs previously treated with aromatase inhibitors (AIs).^10-12 Investigators for the open-label phase 3 EMERALD study (NCT03778931) randomly assigned 477 patients with ER+/HER2-negative aBC after progression on 1 to 2 prior lines of ET with a CDK4/6 inhibitor (CDK4/6i) to receive elacestrant monotherapy vs standard of care (SOC) endocrine monotherapy.¹³ Elacestrant prolonged progression-free survival (PFS) vs SOC in patients with an ESR1 mutation (6-month PFS rates, 40.8% vs 19.1%; HR, 0.55; 95% CI, 0.39-0.77; P = .0005). In a post hoc analysis of patients with ESR1-mutated disease, prior ET plus CDK4/6i use for 12 months or longer was associated with a significant improvement in median PFS for elacestrant vs SOC (8.6 vs 1.9 months; HR, 0.41; 95% CI, 0.26-0.63).¹⁴ Two studies evaluating real-world outcomes in patients with ESR1-mutated ER+/HER2-negative aBC demonstrated a durable benefit in time to next therapy for elacestrant monotherapy, including for patients with 3 or more lines of prior therapy or concomitant PIK3CA mutations.^15,16

Investigators for the open-label phase 3 EMBER-3 trial (NCT04975308) randomly assigned 874 patients with ER+/HER2-negative aBC that had recurred or progressed on an AI with or without a CDK4/6i to receive SOC or imlunestrant with or without abemaciclib.¹⁷ For patients with ESR1-mutated disease, the median PFS was 5.5 months vs 3.8 months for imlunestrant monotherapy vs SOC (HR, 0.62; 95% CI, 0.47-0.82; nominal P = .0007).¹⁸ With a maturity of 50% in the ESR1-mutated cohort, the data also demonstrated improved overall survival with imlunestrant monotherapy vs SOC (median OS, 34.5 months vs 23.1 months; HR, 0.60; 95% CI, 0.43-0.86; P = .0043).

2. SERD-based combinations improve outcomes for patients with ER+/HER2-negative aBC with biochemical or clinical disease progression.

Investigators for the double-blind, placebo-controlled phase 3 SERENA-6 trial (NCT04964934) screened 3256 patients for ESR1 mutations using blood-based ctDNA testing every 2 to 3 months.¹⁹ Upon detection of a new ESR1 mutation, 315 patients with ER+/HER2-negative aBC but no radiologic progression after receiving at least 6 months of first-line AI plus CDK4/6i were randomly assigned to continue their original CDK4/6i plus AI vs switching the AI to camizestrant and continuing the CDK4/6i. At the second data cutoff, the median PFS was significantly improved with camizestrant vs continuing original therapy (median PFS, 16.6 vs 9.2 months; HR, 0.46; 95% CI, 0.34-0.62; P < .00001).²⁰

Phase 2 and 3 studies have also demonstrated benefit with SERD-based combinations upon clinical disease progression on first-line treatment for ER+/HER2-negative aBC. In the EMBER-3 trial, the addition of abemaciclib to imlunestrant improved PFS (median PFS, 10.9 vs 5.5 months; HR, 0.59; 95% CI, 0.47-0.74; nominal P < .0001),²¹ a benefit that was observed regardless of ESR1 and PI3Kpathway mutational status.

Activation of the PI3K/AKT/mTOR pathway, which can be targeted with mTOR inhibitors such as everolimus, is associated with the development of endocrine resistance in hormone receptor-positive BCs, as illustrated in Figure 1.^22-27 Investigators for the phase 2 ELEVATE trial (NCT05563220) are evaluating elacestrant in combination with different agents, including everolimus, for patients with ER+/HER2-negative aBC following 1 to 2 lines of ET with or without a CDK4/6i.²⁸ The median PFS was 8.3 months with elacestrant plus everolimus and 14.3 months with elacestrant plus abemaciclib. Investigators for the double-blind, phase 3 ADELA trial (NCT06382948) are evaluating the addition of everolimus to elacestrant for patients with ER+/HER2-negative, ESR1-mutated aBC progressing on ET plus a CDK4/6i.²⁹

Investigators for the phase 3 evERA trial (NCT05306340) compared everolimus in combination with either giredestrant or SOC ET in 373 patients with ER+/HER2-negative aBC progressed on or after ET plus a CDK4/6i.³⁰ The evERA population, which included 55% of patients having ESR1 mutations, had improved PFS in both the intention-to-treat (ITT; median PFS, 8.77 vs 5.49 months; HR, 0.56; 95% CI, 0.44-0.71; P < .0001) and ESR1-mutated (9.99 vs 5.45 months; HR, 0.38; 95% CI, 0.27-0.54; P < .0001) groups with the giredestrant-everolimus vs SOC ET-everolimus. A subgroup analysis of evERA demonstrated significant improvements in PFS for both the ESR1-mutated and ITT populations regardless of PIK3CA mutations and PIK3CA/AKT1/PTEN alterations.³¹

3. The addition of PI3K pathway inhibitors to SERDs improves outcomes for patients with hormone receptor-positive/HER2-negative aBC that has progressed on prior ET.

An estimated 55% of hormone receptor-positive/HER2-negative aBCs have at least 1 PIK3CA/AKT1/PTEN alteration,³² which are typically present at baseline.³³ Alpelisib and capivasertib, both oral inhibitors of the PI3K pathway (Figure 2), are FDA approved for use with fulvestrant to treat PI3K pathway–altered hormone receptor-positive/HER2-negative aBC after progression on prior ET based on PFS data from the phase 3 SOLAR-1 (NCT02437318) and CAPItello-291 (NCT04305496) studies.^8,9,34-36

Gedatolisib is an intravenous drug that targets all class I PI3K isoforms and mTOR complexes 1 and 2 as demonstrated in Figure 2.^36,37 Investigators for study 1 of the open-label phase 3 VIKTORIA-1 trial (NCT05501886) randomly assigned patients with hormone receptor-positive/HER2-negative, PIK3CA-wildtype aBC progressed on prior AI plus CDK4/6i therapy to receive fulvestrant plus gedatolisib plus palbociclib (arm A), fulvestrant plus gedatolisib (arm B), or fulvestrant alone (arm C), with crossover permitted upon disease progression.³⁸ Improved PFS was demonstrated for arm A vs arm C (9.3 vs 2.0 months; HR, 0.24; 95% CI, 0.17-0.35; P < .001) and arm B vs arm C (7.4 vs 2.0 months; HR, 0.33; 95% CI, 0.24-0.48; P < .001).³⁹

Key References

13. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) vs standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase 3 EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/jco.22.00338

30. Mayer E, Tolaney S, Martin M, et al. LBA16 Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+/HER2- aBC) previously treated with a CDK4/6 inhibitor (i): primary results of the phase 3 evERA BC trial. Ann Oncol. 2025;36:S1561-S1562. doi:10.1016/j.annonc.2025.09.026

39. Hurvitz SA, Layman RM, Curigliano G, et al. VIKTORIA-1 trial of gedatolisib plus fulvestrant with or without palbociclib in hormone receptor-positive/HER2-/PIK3CA wild-type advanced breast cancer. J Clin Oncol. Published online March 9, 2026. doi:10.1200/jco-25-02643

For a full list of references go to https://www.gotoper.com/mbcc26smtdserds-postref

CME POSTTEST QUESTIONS

Outcomes Questions

A 63-year-old postmenopausal woman was diagnosed with metastatic breast cancer (ER+; HER2 IHC 1+, FISH negative; PIK3CA/AKT/PTEN wildtype, ESR1 wildtype). She received an aromatase inhibitor plus a CDK4/6 inhibitor as first-line therapy for 18 months but is now progressing in bone and lung. She is very eager to start treatment. Which of the following is the best guideline-concordant next step?

1. Obtain blood-based circulating tumor DNA to repeat next-generation sequencing (NGS)
2. Obtain a new tissue sample to repeat NGS
3. Start everolimus plus exemestane
4. Start fulvestrant plus a different CDK4/6 inhibitor

A 57-year-old postmenopausal woman presented with de novo ER+/HER2-negative (IHC 1+) metastatic breast cancer to the bone in 2019. She was started on letrozole plus palbociclib and after 5 years presents with progression in the bones and 2 new liver metastases. An NGS panel shows ESR1D538G, ESR1Y537S, and PIK3CA1047R mutations. Her LFTs are normal, and she is asymptomatic. Significant comorbidities include well-controlled diabetes and migraines. You are discussing treatment with elacestrant.

Which of the following would be most appropriate to share with the patient?

1. Efficacy may be enhanced given the long prior duration of CDK4/6 inhibitor
2. Efficacy may be enhanced given the coexisting PIK3CA mutation
3. Endocrinology follow-up is needed to mitigate potential hyperglycemia
4. Neurology follow-up is needed to mitigate potential headaches

In updated findings from the EMBER-3 trial, addition of imlunestrant to abemaciclib demonstrated which of the following compared with imlunestrant alone for advanced, hormone receptor-positive, HER2-negative breast cancer?

1. Improved PFS only in the subgroup with a PI3K pathway mutation
2. Improved PFS only in the subgroup with no PI3K pathway mutation
3. Improved PFS in all patients
4. Similar PFS in all patients

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To learn more about this topic, including information on selecting therapies for patients with hormone receptor-positive/HER2-negative aBC harboring both PI3K pathway alterations and ESR1 mutations, go to https://www.gotoper.com/mbcc26smtdserds-activity

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