Suppression of the estrogen receptor has proven to be an effective treatment for hormone receptor–positive breast cancer, but standard endocrine therapies have liabilities that are not limited to their pharmacokinetics or toxicity profiles, which allow for ligand-independent estrogen receptor signaling as a mechanism of resistance. Novel endocrine approaches to addressing treatment resistance, with a focus on oral selective estrogen receptor degraders (SERDs), were described at the 2024 Miami Breast Cancer Conference by Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center, New York.1
Dr. Jhaveri is the Patricia and James Cayne Chair for Junior Faculty, Section Head of the Endocrine Therapy Research Program, and Clinical Director of the Early Drug Development Service at Memorial Sloan Kettering and Associate Professor of Medicine at Weill Cornell Medical College, New York.
What happens to [breast cancer] tumors can be categorized based on what happens to their dependency on the estrogen receptor.— Komal Jhaveri, MD
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The treatment landscape for hormone receptor–positive, HER2-negative advanced breast cancer has broadened significantly since 2010, prior to which antiestrogens were essentially the only approach. Since then, a novel SERD, multiple targeted agents, antibody-drug conjugates, and a checkpoint inhibitor, have been incorporated. Other SERDs are in late phases of development. Questions include: When and for whom should we consider SERD monotherapy, and what is the role for combination therapies? When to consider combination therapies was the focus of Dr. Jhaveri’s presentation.
Evolution of Tumors and ESR1 Testing
“What happens to tumors can be categorized based on what happens to their dependency on the estrogen receptor,” Dr. Jhaveri said. The acquisition of the ESR1 mutation exemplifies the evolution of tumors under the selective pressure of endocrine therapies. The ESR1 mutation allows tumors to progress in an estrogen receptor–dependent—but estradiol-independent or other ligand–independent—manner. These estrogen receptor–dependent tumors are not responsive to the original antiestrogens like tamoxifen but are responsive to next-generation estrogen receptor therapies such as oral SERDs.
Tumors can also acquire alterations in other key transcription factors. It is unclear whether these retain their dependency on the estrogen receptor, in which case they might respond to next-generation estrogen receptor–targeted therapies. Other cancers lose dependency on the estrogen receptor, often driven by other signaling pathways.
Most ESR1 mutations are acquired in the metastatic setting under the selective pressure of aromatase inhibitors. They are ligand-independent but still estrogen receptor–dependent and are relatively rare in primary disease. Although biopsies reveal them in about 20% of metastatic tumors, testing in plasma reveals a prevalence of 40% to 50%, as these mutations are subclonal. “Plasma, therefore, is the ideal way of detecting ESR1 mutations,” Dr. Jhaveri said, adding that serial testing is wise, as patients progress through lines of treatment.
“We want to know this because ESR1 has prognostic implications, as tumors with ESR1 mutations have worse outcomes. More importantly, it can give predictive information,” she explained. In the combined analysis of the SoFEA and EFFECT trials, in which patients had disease progression on nonsteroidal aromatase inhibitors, those with ESR1 mutations had a 12-month overall survival of 80% on fulvestrant but 62% on exemestane.2 It is best to switch these patients to a SERD-based strategy, she said.
Oral SERDs
The first-generation intramuscularly delivered SERD, fulvestrant, has pharmacologic limitations, so there has been great interest in developing next-generation, oral SERDs. The aim has been to identify drugs that can downregulate the estrogen receptor and offer an optimal therapeutic index and good safety profile.
The first oral SERD to be approved was elacestrant. In the phase III EMERALD trial of patients with disease progression on endocrine therapy and CDK4/6 inhibitors, elacestrant significantly improved progression-free survival over standard endocrine therapy (hazard ratio [HR] = 0.70).3 Particular benefit was observed in patients with ESR1-mutant disease (HR = 0.55), whereas benefit was less pronounced in ESR1 wild-type tumors. The approved indication for this oral SERD, therefore, is restricted to patients with ESR1 mutations.
Randomized trials of other SERDs (giredestrant, imlunestrant, camizestrant) are showing “common signals,” Dr. Jhaveri said. “We are seeing activity after CDK4/6 inhibitors and after fulvestrant and seeing a slightly better signal in ESR1-mutant tumors…. But 40% of patients still have early disease progression on SERD monotherapy, and 60% get less than 6 months of benefit. To further move the needle and improve outcomes, we may need to think about combinations.”
But there do seem to be subsets of patients for whom elacestrant alone “shows respectable disease control,” she noted. In a subanalysis of EMERALD, patients with an ESR1 mutation and at least 12 months of prior CDK4/6 inhibition had a median progression-free survival of 8.6 months on elacestrant, compared to less than 2 months on standard endocrine therapy (HR = 0.41).4 “This is where monotherapy has a role, where we can expect good benefit for our patients,” she commented.
Another interesting analysis by Bardia et al showed that in patients with both ESR1 and PIK3CA mutations and at least 12 months of prior CDK4/6 inhibition, median progression-free survival was 5.5 months, compared to less than 2 months with standard therapy (HR = 0.423). Those with ESR1 mutations, wild-type PIK3CA, and ≥ 12 months of CDK4/6 inhibition had a median progression-free survival of 9.0 months (HR = 0.364).5
Data are also emerging from the EMBER trial of imlunestrant in combination with other agents, for which Dr. Jhaveri is an investigator. The phase III registrational EMBER-3 trial, which is evaluating this SERD vs physician's choice of endocrine therapy and will also evaluate this SERD plus the CDK4/6 inhibitor abemaciclib in a third cohort, should help answer additional questions about the role of oral SERDs.
Other combination trials have been either reported or are underway. Among 42 patients treated with imlunestrant plus everolimus in the phase 1a/b EMBER trial, median progession-free survival was 15.9 months ( 95% confidence interval [CI] = 11.3–19.1). Of the 21 patients treated with imlunestrant with alpelisib, median progession-free survival was 9.2 months (95% CI = 3.7–11.1). The phase III ELEVATE trial is evaluating elacestrant plus the available CDK4/6 inhibitors, as well as with the PI3K inhibitor alpelisib and the mTOR inhibitor everolimus. The phase III pionERA Breast Cancer trial will compare giredestrant plus a CDK4/6 inhibitor vs fulvestrant plus a CDK4/6 inhibitor. And the phase III registrational evERA Breast Cancer trial is evaluating giredestrant plus everolimus compared vs physician's choice of endocrine therapy plus everolimus (ClinicalTrials.gov identifier NCT05306340).
Additional Questions
Another important question being asked is whether oral SERDs, in combination with CDK4/6 inhibitors, can be brought into the first-line metastatic setting. Two phase III trials are directed at this possibility: persevERA Breast Cancer (with giredestrant, palbociclib, and letrozole) and SERENA-4 (with camizestrant, palbociclib, and anastrozole).
Yet another question is whether circulating tumor DNA can be applied serially to identify ESR1 mutations before radiologic disease progression is observed. Can we switch therapies and use SERDs in that context? This is the aim of SERENA-6, which is recruiting patients with mutations detected during first-line aromatase inhibitor therapy, who will be switched to camizestrant or continued on the aromatase inhibitor, both with CDK4/6 inhibition.
Can SERDs be moved into the early-stage setting? The coopERA Breast Cancer trial enrolled 221 postmenopausal patients with untreated cT1c to cT4a-c tumors and baseline Ki67 scores ≥ 5%. Patients were randomly assigned to giredestrant or anastrozole for 2 weeks, biopsied, and then continued on the same neoadjuvant regimen with the addition of palbociclib for 16 weeks. The primary endpoint—week 2 decrease in Ki67—was met, with superior Ki67 reduction achieved with giredestrant.6
Large adjuvant studies are now underway in patients with medium- to high-risk estrogen receptor–positive, HER2-negative disease. The lidERA Breast Cancer study is evaluating an upfront strategy with giredestrant vs standard endocrine therapy. EMBER-4 and CAMBRIA-1 are randomizing patients after 2 to 5 years of endocrine therapy to imlunestrant or camizestrant, respectively, vs continued standard-of-care endocrine monotherapy. And CAMBRIA-2 is evaluating camizestrant vs endocrine therapy, with or without abemaciclib. “These studies are exciting and might change our treatment paradigm for early-stage estrogen receptor–positive breast cancer,” Dr. Jhaveri commented.
DISCLOSURE: Dr. Jhaveri has consulted for AbbVie, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Genentech/Roche, Jounce Therapeutics, Lilly, Menarini/Stemline Therapeutics, Novartis, Pfizer, Scorpion Therapeutics, Seagen, Sun Pharma Advanced Research Company, and Taiho Oncology.
REFERENCES
1. Jhaveri K: Novel endocrine therapies and oral SERDs for hormone receptor-positive metastatic breast cancer. 2024 Miami Breast Cancer Conference. Presented March 8, 2024.
2. Turner NC, et al: ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor–positive breast cancer. Clin Cancer Res 26:5172-5177, 2020.
3. Bidard FC, et al: Elacestrant versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. J Clin Oncol 40:3246-3256, 2022.
4. Kaklamani V, et al: EMERALD Phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+, HER2- metastatic breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 8, 2022.
5. Bardia A, et al: Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer with ESR1 mutation. 2023 San Antonio Breast Cancer Symposium. Abstract PS17-02. Presented December 8, 2023.
6. Hurvitz SA, et al: Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer. Lancet Oncol 24:1029-1041, 2023.
