Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer

ABSTRACT

Introduction

The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy.

Areas covered

Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant.

Expert opinion

Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.

KEYWORDS:

• Amcenestrant
• breast cancer
• camizestrant
• elacestrant
• endocrine therapy
• fulvestrant
• giredestrant
• oncology
• rintodestrant
• SERD

Article Highlights

• Despite the success of current endocrine therapies in treating hormone receptor-positive (HR-positive) breast cancer, acquired or de novo resistance limits their use.

• The clinical impact of fulvestrant, the only currently approved selective estrogen receptor degrader (SERD) for HR-positive breast cancer, has been limited by poor drug-like properties and an inconvenient method of administration (i.e. intramuscular injection).

• Property- and structure-based drug design and optimization of estrogen receptor (ER)-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic (PK) properties have recently led to the development of innovative oral SERDs.

• The unique physicochemical properties of each oral SERD are evident through their different potencies, presence or absence of ER-agonist activity, PK profiles (including nonlinear PK and food effects), requirements for higher dosing, and potential for drug–drug interactions.

• Giredestrant (GDC-9545) has displayed potency superior to other SERDs in development based on preclinical data which, combined with a high safety margin, have translated into having the lowest recommended phase 2 dose (30 mg once a day) relative to all the other investigational agents entering later-stage clinical development.

• It is hoped that, if the results of phase 3 trials confirm the preliminary safety and efficacy results of early clinical studies, these investigational agents may lead to superior efficacy in the clinic.

This box summarizes key points contained in the article.

Acknowledgments

Support for third-party writing assistance for this manuscript, furnished by Martin Cadogan, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Author Contributions

All authors were involved in conception of the work and drafting the article or revising it critically for important intellectual content. All authors approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declaration of interest

All authors are employees of Genentech, Inc., and hold stock options in F. Hoffmann-La Roche Ltd and received research support in the form of third-party medical writing assistance for this manuscript, provided by F. Hoffmann-La Roche Ltd. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by F. Hoffmann-La Roche Ltd.