Navigating the rapidly expanding treatment evidence base for HR+/HER− breast cancer remains a significant challenge. Previously, endocrine therapy (ET, including aromatase inhibitors, selective estrogen receptor degraders, and selective estrogen receptor modulators) was the preferred frontline treatment approach for HR+/HER2− metastatic disease until patients developed endocrine resistance.1 Recent advances have been in the incorporation of targeted therapy, including cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; ie, palbociclib, ribociclib, and abemaciclib) in the management of this type of cancer. Ultimately, oncologists in the United States need to consider treatment expectations, patient clinical characteristics, and nonclinical factors when selecting treatments.Â
Aromatase inhibitors are one of the most common treatments for breast cancer and have been used as monotherapy in the first-line setting for many years. Exemestane is a steroidal AI, and anastrozole (the most commonly used) and letrozole are nonsteroidal, with this distinction being important when considering combination therapy.2 The CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib have all been approved in combination with aromatase inhibitors, with significant improvements in progression-free survival (PFS) and objective response rate (ORR) for patients with HR+/HER2− metastatic breast cancer, compared with AI monotherapy.3
Tamoxifen is the most commonly used SERM and has been a key part of the treatment paradigm for patients with ER+ breast cancer for over 30 years.2 Although other SERMs have been approved since the approval of tamoxifen, they are associated with significant adverse effects, such as endometrial carcinoma, hot flashes, and venous thromboembolism, so tend not to be used. Results from several clinical trials have shown that tamoxifen can be used in combination with CDK4/6 inhibitors, although combination with ribociclib is not recommended because of the cumulative impact on QT interval prolongation.4
Fulvestrant was the first SERD approved for the treatment of ER-positive metastatic breast cancer by the FDA (in 2002) after demonstrating a clinical benefit rate of 69% in patients with tamoxifen-resistant disease; it is also approved for combination therapy with CDK4/6 inhibitors.5 Fulvestrant is administered as a monthly intramuscular injection, and injection-site reactions are a common adverse event, along with vasodilation and hot flushes.
Elacestrant was approved based on data from the EMERALD study, which showed a significant PFS improvement compared with standard of care with common adverse events including nausea, fatigue, and vomiting.6,7,8 Elacestrant is now being assessed in combination with abemaciclib in the phase 1b ELECTRA study in patients with ER+/HER2− metastatic breast cancer to address treatment resistance and enable oral administration.9 Preliminary findings show the efficacy is encouraging and the safety profile is manageable.
Imlunestrant, camizestrant, and giredestrant are in development, and all are being assessed in combination with other agents, such as CDK4/6 inhibitors, to extend the benefit of endocrine therapy by circumventing treatment resistance. For example, imlunestrant has shown promising efficacy in the phase 3 EMBER-3 study.10 As monotherapy imlunestrant significantly reduced the risk of progression or death by 38% compared to standard endocrine therapy in patients with ESR1 mutations. Additionally, as combination therapy imlunestrant plus abemaciclib significantly reduced the risk of progression or death by 43%, compared to imlunestrant alone, in all patients regardless of ESR1 mutation status.
Camizestrant is an oral SERD that is currently in development.11,12 Results from the phase 2 SERENA-2 study showed that median PFS was greater with camizestrant than with fulvestrant, and it was well tolerated.11 Interim results from a phase 2 study comparing giredestrant with physician’s choice of endocrine therapy in patients with HR+/HER2− metastatic breast cancer showed no significant improvement in the overall population.13,14 However, initial findings from the MORPHEUS study have shown encouraging efficacy for giredestrant plus everolimus.15
The treatment landscape in HR+/HER2− metastatic breast cancer is changing constantly and rapidly so members of the oncology team need to be constantly vigilant on what is becoming available and how it can be used for breast cancer treatment.
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