Selective Estrogen Receptor Degrader

• Selective Estrogen Receptor Degraders (SERDs) are a class of drugs that target and degrade estrogen receptors in cancer cells.
• Their primary application is in the treatment of hormone receptor-positive (HR+) breast cancer, particularly in advanced or metastatic settings.
• SERDs work by binding to the estrogen receptor, inducing a conformational change that leads to its destruction, thereby inhibiting estrogen-driven tumor growth.
• Fulvestrant was the first approved SERD, administered via injection, with newer oral SERDs like elacestrant now available and others in development.
• These therapies are vital for patients who have developed resistance to other endocrine treatments, offering an important therapeutic option.

What is a Selective Estrogen Receptor Degrader (SERD)?

A Selective Estrogen Receptor Degrader (SERD) is a type of anti-estrogen drug specifically designed to treat hormone receptor-positive cancers, most notably breast cancer. Unlike selective estrogen receptor modulators (SERMs) which block estrogen binding, SERDs go a step further by causing the degradation of the estrogen receptor (ER) itself. This action effectively reduces the overall number of ERs available within cancer cells, thereby diminishing the signaling pathways that estrogen uses to promote tumor growth.

The development of SERDs has provided a significant advancement in oncology, particularly for patients whose cancers rely on estrogen for proliferation. According to the American Cancer Society, approximately 67% of all breast cancers are hormone receptor-positive, making therapies that target the estrogen receptor pathway critically important for a large patient population.

SERD Mechanism of Action and Clinical Uses

The SERD mechanism of action involves a precise molecular interaction. Once a SERD binds to the estrogen receptor, it induces a distinct conformational change in the receptor protein. This altered conformation marks the receptor for ubiquitination, a process that tags proteins for destruction by the proteasome, the cell’s protein degradation machinery. The subsequent proteasomal degradation of the ER leads to a significant reduction in the cellular ER content, effectively shutting down estrogen-mediated gene transcription and inhibiting the growth of ER-positive cancer cells.

The primary selective estrogen receptor degrader uses are in the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. SERDs are particularly valuable in scenarios where patients have developed resistance to other endocrine therapies, such as aromatase inhibitors. By offering a distinct mechanism of action, SERDs can provide an effective treatment option for these challenging cases. Clinical applications include:

• Treatment of advanced or metastatic HR+, HER2- breast cancer.
• Management of breast cancer that has progressed after prior endocrine therapy.
• Potential use in combination with other targeted therapies to enhance efficacy.

List of Selective Estrogen Receptor Degrader (SERD) Drugs

The landscape of SERD drugs has evolved, offering patients more options for managing hormone receptor-positive breast cancer. The first approved SERD, fulvestrant (marketed as Faslodex), has been a cornerstone of treatment for many years. Fulvestrant is administered via intramuscular injection, which can be a limiting factor for some patients.

Recognizing the need for more convenient and potentially more effective options, pharmaceutical research has focused on developing oral SERDs. These newer agents aim to provide similar or improved efficacy with the added benefit of oral administration, enhancing patient convenience and adherence. A growing list of SERD drugs includes:

• Fulvestrant (Faslodex): The pioneering SERD, approved for HR+, HER2- advanced or metastatic breast cancer, typically after progression on other endocrine therapies.
• Elacestrant (Orserdu): An oral SERD recently approved by the FDA for postmenopausal women or adult men with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer, who have experienced disease progression after at least one line of endocrine therapy.
• Other Oral SERDs: Several other oral SERDs are currently undergoing clinical trials, demonstrating promising results and potentially expanding the therapeutic arsenal against ER-positive breast cancer in the near future. These investigational drugs aim to offer improved pharmacokinetic profiles and broader applicability.