An evaluation of fulvestrant for the treatment of metastatic breast cancer

ABSTRACT

Introduction: Fulvestrant is currently the only selective estrogen receptor degrader (SERD) that is approved for clinical use in estrogen receptor (ER) positive advanced breast cancer (ABC). The drug is approved as single-agent therapy in the first and second-line setting of metastatic ER-positive breast cancer.

Areas covered: In this review, the authors review the preclinical studies that were pivotal in the development of fulvestrant, the pharmacologic properties of the drug, and the key clinical trials that resulted in its approval for clinical use. The authors discuss mechanisms of endocrine resistance and potential targets for endocrine refractory disease while highlighting ongoing studies that assess fulvestrant use with novel agents.

Expert opinion: While fulvestrant has limited use in the first-line setting in advanced breast cancer, it is most frequently used in the second line after progression with aromatase inhibitors. The combination of fulvestrant with CDK4/6 inhibitors has shown a clear benefit over monotherapy in patients who progress on prior endocrine therapy. Further study is necessary to assess if patient outcomes can be enhanced by optimizing the sequence of endocrine therapies, targeting resistance pathways with novel agents, and development of new agents in the SERD class.

KEYWORDS:

• Fulvestrant
• hormone-receptor positive
• metastatic breast cancer
• advanced breast cancer
• endocrine resistance
• Selective Estrogen Receptor Positive (SERD)

Article Highlights

• Fulvestrant is a selective estrogen receptor degrader that inhibits tumor growth by binding to estrogen receptor-α (ERα) resulting complete anti-estrogen activity.

• Dosing schedules for fulvestrant have been modified to achieve rapid steady state concentrations that are well above the therapeutic threshold for more effective dosing.

• Fulvestrant is approved as monotherapy as first line treatment for metastatic breast cancer, but its use in this setting may be limited to situations where combination with CDK4/6 inhibitors is not available. Response to fulvestrant was particularly durable in patients with bone only metastatic disease.

• The combination of fulvestrant with CDK4/6 inhibitors has shown superior efficacy compared to monotherapy in patients with metastatic hormone receptor positive breast cancer who have progressed or relapsed on prior tamoxifen or aromatase inhibitor therapy.

• Resistance to hormonal therapy is commonly associated with PIK3CA and ESR1 mutations. Alternative hormone resistance pathways may be mediated by upregulation of PI3K/AKT, HER2, FGFR and IGF pathways.

• Fulvestrant regimens in combination with novel targeted agents are being developed to overcome endocrine resistant breast cancer. Most recently, fulvestrant with alpelisib, an α-selective PI3K inhibitor, has been recently approved a for patients who have progressed on endocrine therapy with PIK3CA mutated breast cancer.

Declaration of interest

N Unni declares that they serve on the advisory board of Eisai and have received honoraria for speaker’s training and for serving on a drug advisory board from M3 Global Research. Meanwhile, GV Raj is Part Owner of C-Diagnostics as well as owner and founder of EtiraRx and Gaudium Rx, all of which he owns stocks with. He has also received research support from Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.