Novel oral selective estrogen receptor degraders (SERDs) to target hormone receptor positive breast cancer: elacestrant as the poster-child

ABSTRACT

Introduction

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer subtype, and therapeutic management relies primarily on inhibiting ER signaling. In the metastatic setting, ER signaling is typically targeted by selective estrogen receptor degraders (SERDs) or aromatase inhibitors (AIs), the latter of which prevent estrogen production. Activating ESR1 mutations are among the most common emergent breast cancer mutations and confer resistance to AIs.

Areas Covered

Until 2023, fulvestrant was the only approved SERD; fulvestrant is administered intramuscularly, and in some cases may also have limited efficacy in the setting of certain ESR1 mutations. In 2023, the first oral SERD, elacestrant, was approved for use in ESR1-mutated, ER+/HER2- advanced breast cancer and represents a new class of therapeutic options. While the initial approval was as monotherapy, ongoing studies are evaluating elacestrant (as well as other oral SERDs) in combination with other therapies including CDK4/6 inhibitors and PI3K inhibitors, which parallels the current combination uses of fulvestrant.

Expert Opinion

Elacestrant’s recent approval sheds light on the use of biomarkers such as ESR1 to gauge a tumor’s endocrine sensitivity. Ongoing therapeutic and correlative biomarker studies will offer new insight and expanding treatment options for patients with advanced breast cancer.

KEYWORDS:

• Elacestrant
• HR+ breast cancer
• targeted therapies
• SERDs
• endocrine therapies

Article highlights

• Estrogen receptor-positive (ER+) breast cancer comprises 60-75% of all breast cancers and is generally associated with a favorable prognosis when treated with endocrine therapy, but there remains no cure in the advanced and metastatic settings.

• Fulvestrant, the only FDA-approved selective estrogen receptor degrader (SERD) for twenty years, has proven clinical benefit in treating advanced and metastatic ER+ breast cancer as monotherapy and in combination with novel endocrine agents or targeted therapies, yet it faces limitations such as its intramuscular route of administration and its limited activity in the setting of activating ESR1 mutations.

• Although ESR1 mutations confer resistance, they demonstrate the ER+ tumor’s continued reliance on the estrogen receptor pathway for proliferation, despite the presence of alternative pathways, and have thus prompted the development of next-generation, orally bioavailable SERDs, such as elacestrant.

• Preclinical studies of elacestrant as monotherapy and combination therapy with other agents demonstrated inhibition of tumor growth to a greater degree than both fulvestrant and tamoxifen and ultimately provided rationale for clinical trial testing in advanced and metastatic ER+ breast cancer.

• The phase I RAD1901-005 study validated the safety of elacestrant in humans and noted toxicities such as nausea, increased blood triglycerides, and decreased blood phosphorous, while the phase III randomized EMERALD trial earned elacestrant FDA approval by demonstrating its superior progression-free survival (PFS) when directly compared to standard-of-care monotherapy in treating ER+, ESR1-mutated advanced breast cancer in postmenopausal women and adult men.

• Ongoing clinical trials are evaluating elacestrant as combination therapy and are also investigating several other novel oral SERDs including amcenestrant, giredestrant, imlunestrant, rintodestrant, and camizestrant for the treatment of ER+ breast cancer in both the early-stage and metastatic settings.

Declaration of interest

A Bardia has disclosed consultant/advisory board for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/Astra Zeneca, Phillips, Eli Lilly, and Foundation Medicine; institutional contracted research fees/grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/Astra Zeneca, and Eli Lilly. AJ Medford has disclosed consultant/advisory board for Guardant Health, Illumina, and Natter. SA Wander has disclosed consultant/advisory board for Foundation Medicine, Veracyte, Eli Lilly, Pfizer, Biovica, Hologic, Puma Biotechnology, Novartis, and AstraZeneca; education/speaking for Eli Lilly, Guardant Health, and 2ndMD; Institutional Research Support from Genetech, Eli Lilly, Pfizer, Nuvation Bio, and Regor Therapeutics. LM Spring has disclosed consultant/advisory board for Novartis, Puma Biotechnology, GI therapeutics, Daiichi Pharma, AstraZeneca, and Eli Lilly; institutional research support from Merck, Genentech, Gilead, and Eli Lilly. 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 paper was not funded.