HR+, HER2- Metastatic Breast Cancer: ET Advancements

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HR+, HER2- Metastatic Breast Cancer

Scientific Advancements in ET

Scientific advancements in endocrine therapy (ET) seek to maximize antagonizing the estrogen receptor (ER) pathway in ER-positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer.^1-3

ER pathway and novel therapies that target the ER pathway. — AIs block estrogen production by inhibiting aromatase. SERMs block ER transcription by competitively inhibiting the binding of estrogen to ER. SERDs block ER translocation to the nucleus, and upon binding to ER, results in degradation of the SERD-ER complex. PROTACs bind to both ER and the E3 ubiquitin ligase, resulting in ubiquitination and degradation. CERANs block both transcriptional activation domains of ER. SERCAs inhibit ER gene transcription by binding to the C530 cysteine residue on ER.³

Next-Generation Oral ETs

Research and development into next-generation oral ETs are enabling more potent endocrine pathway antagonism while conferring alternative properties, including exposure, binding, and degradation.^1-3

Exposure

Sustained high, dose-dependent exposure supporting oral options^1-3

Binding

Potent and highly specific binding to both wildtype and mutated ER^1,3
Maintain activity in aromatase inhibitor (AI)-resistant and ESR1-mutant models^1-3

Degradation

Selective estrogen receptor degraders (SERDs) and proteolysis targeting chimeras (PROTACs) have potent ER degradation and suppression of ER-dependent signaling^1-3

Doctor discussing treatment advancements with a patient.

Scientific advancements in ETs seek to maximize antagonizing the ER pathway.

As healthcare providers, it is important to stay updated on next-generation oral ETs and how they may be used as monotherapy or in combination with targeted therapies. For more information on advancements in novel ETs and ongoing clinical trials, please see additional resources below.

Related Resources

Downloadable PDFs

INFOGRAPHIC: Scientific Advancements: Next-Generation ETs in ER+, HER2-, ABC

This infographic provides an overview of the approved and investigational ET classes in ER+, HER2-, ABC; highlights the potential benefits of next-generation ETs, resulting in more potent endocrine pathway antagonism.

DECK: Overview of ER+, HER2-, ABC including ER-Targeted Therapies

This slide deck provides an overview of the ER+, HER2- advanced breast cancer landscape, including information on ER targeted therapies, mechanisms of resistance to ET +/- CDK4/6 inhibitors, & scientific advancements in the form of next-generation ETs.

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Endocrine therapies (ETs) either block the estrogen receptor (ER) or deprive the tumor of endogenous estrogen. And this class of drugs can be really used in various lines of treatment, as long as the tumors are endocrine sensitive. Selective ER down regulators or degraders (SERDs) are a type of ET that bind to the ER to suppress its transcriptional activity and trigger its degradation. The very first SERD, fulvestrant, was developed nearly 20 years ago and was described as a pure ER antagonist. It demonstrated efficacy in patients exposed previously to aromatase inhibitors (AIs). It is widely used as monotherapy and in combination with targeted agents in pre- and postmenopausal patients with hormone receptor–positive (HR+), HER2–negative (HER2-) metastatic breast cancer (MBC).

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Fulvestrant, while providing benefit to our patients, certainly has its limitations, including toxicity and pharmacologic limitations. For instance, the poor solubility of fulvestrant requires intramuscular (IM) administration by a healthcare professional at a medical office. Over the years, we've learned that fulvestrant's efficacy is dose dependent. The currently approved dose of 500 mg IM injection was superior than 250 mg, but we’re not able to go any higher. Fulvestrant is also historically used after progression on an AI monotherapy in the metastatic setting. Now that [a] majority of our patients, if not all, are receiving AI with CDK4/6 inhibitors (CDK4/6i) in the first-line (1L) metastatic setting, we have now begun to notice that fulvestrant offers a very modest efficacy in patients who are exposed to CDK4/6i, and this is in the order of a median progression-free survival (PFS) of only 2 to 3 months. Forty to 50 percent of our patients develop ESR1 mutations [due] to prior AI therapy, and fulvestrant is not very effective for certain ESR1 mutations including Y537S.

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We're starting to see a rise in the research of novel endocrine agents, with oral SERDs being the furthest in clinical development. And as of 2023, we already have regulatory approval for the very first oral SERD, which is indicated for postmenopausal women and adult men with HR+, HER2-, ESR1-mutant MBC, following progression on 1L standard-of-care (SOC) therapy. Clinical data from the first approved oral SERD suggests an improved PFS compared to SOC ET. An increased benefit was seen in patients with ESR1 mutations, suggesting that ESR1 mutations are a surrogate for endocrine sensitivity and continuing to target this pathway remains relevant despite progression on prior ET.

SERDs: Relevance and Role in Current & Future Treatments for HR+, HER2- MBC

In this video, Dr. Komal Jhaveri shares her expertise on SERDs for the treatment of HR+, HER2- MBC, including the evolving role of novel oral SERDs.

References

Llyod MR, et al. Ther Adv Med Oncol. 2022;14:17588359221113694.
Mittal A, et al. Cancers (Basel). 2023;15(7):2015.
Patel R, et al. NPJ Breast Cancer. 2023;9(20). doi: 10.1038/s41523-023-00523-4

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