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Review
. 2022 Sep 2:16:2933-2948.
doi: 10.2147/DDDT.S380925. eCollection 2022.

Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status

Teesha Downton  1   2 , Fiona Zhou  1   2 , Davendra Segara  1 , Rinath Jeselsohn #  3 , Elgene Lim #  1   2
Affiliations
Review

Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status

Teesha Downton et al. Drug Des Devel Ther. .

Abstract

Several endocrine therapies are currently available for the treatment of estrogen receptor (ER) positive breast cancer, but the clinical benefit of these agents is limited by endocrine therapy drug resistance. A common mechanism of endocrine therapy resistance is ESR1 mutations. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has activity against ESR1 mutant tumors but requires intramuscular injection and has poor bioavailability that precludes optimal drug dosing. This led to the development of second-generation SERDs which are potent and have improved oral bioavailability and pharmacokinetics. Several of these oral SERDs are now in phase III trials in both the early and advanced ER positive breast cancer settings. This review summarizes the background of oral SERD development, the current status and future perspectives.

Keywords: breast cancer; estrogen receptor; selective estrogen receptor degraders.

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Conflict of interest statement

R.J. received research funding from Pfizer and Lilly and is a consultant for Carrick Therapeutics and Luminex. E.L. is on the advisory board for AstraZeneca, Lilly, Pfizer, Roche, Novartis and Gilead Australia, and has received research funding from Pfizer, Novartis and Bayer. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Chemical structures of SERDs. GW5638 and its metabolite GW7604 are tamoxifen analogs which, with raloxifene, became templates for the next generation of oral SERDs. ICI 164,384 and fulvestrant are estradiol analogs and first-generation SERDs, and were templates for oral SERD ZB716. Oral SERDs highlighted in purple are in active clinical development. Chemical structures are from PubChem https://pubchem.ncbi.nlm.nih.gov (Ref. Kim S, Chen J, Cheng T, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49(D1):1388–1395).
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