The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options

Abstract

Hormonal therapy plays a vital part in the treatment of estrogen receptor-positive (ER +) breast cancer. ER can be activated in a ligand-dependent and independent manner. Currently available ER-targeting agents include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or AIs. These tumors remain sensitive to SERDs such as fulvestrant. Fulvestrant is limited in clinical utilization by its intramuscular formulation and once-monthly injection in large volumes. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Elacestrant is the first oral SERD that went through a randomized phase III trial showing increased efficacy, especially in tumors bearing ESR1 mutation, and good tolerability. Two other oral SERDs recently failed to achieve the primary endpoints of longer progression-free survival (PFS). They targeted tumors previously treated with several lines of prior therapies untested for ESR1 mutation. Initial clinical trial data demonstrated that tumors without the ESR1 mutation are less likely to benefit from the SERDs and may still respond to SERMs or AIs, including tumors previously exposed to hormonal therapy. Testing for ESR1 mutation in ongoing clinical trials and in hormonal therapy for breast cancer is highly recommended. Novel protein degradation technologies such as proteolysis-targeting chimera (PROTACS), molecular glue degrader (MGD), and lysosome-targeting chimeras (LYTACS) may result in more efficient ER degradation, while ribonuclease-targeting chimeras (RIBOTAC) and small interfering RNA (siRNA) may inhibit the production of ER protein.

Keywords: Aptamers; Clinical trials; LYTAC; Oral SERDs; PROTC; Protein degradation; RIBOTAC; Selective estrogen receptor degraders.

Fig. 1

Structure of estrogen receptor isoforms/variants and their interaction with SERM/ SERD. A Structure of estrogen receptor (ER) isoforms and their variants. A/B–F: Structural regions. The A/B region contains the amino-terminal domain and the ligand-independent AF-1 (activation function-1) domain; the C region is the binding domain of DNA (DBD); the D region is the hinge region. The D region also encompasses part of the ligand-dependent activation function (AF) domain and the nuclear localization signal. The E and F regions contain the C-terminus region; they encompass the ligand-binding domain (LBD) and ligand-dependent AF-2. The difference of the main isoforms of ERα can be found in region F of ERα36. The ERβ presents variations in the F domain of each isoform. DBD, binding domain of DNA; ER, estrogen receptors; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; ERα-66, estrogen receptor alpha with molecular weight of 66 kDa; ERβ1-59, estrogen receptor beta with molecular weight of 59 kDa; LBD, ligand-binding domain. B Interaction of ER with SERM/SERD. Tamoxifen blocks ERAF1 only as a partial agonist. Fulvestrant blocks both AF1 and AF2 domains as pure antagonist. AF, activation function; ER, estrogen receptor; ERE, estrogen response element; F, fulvestrant; RNA-poly, RNA-polymerase; T, tamoxifen

Fig. 2

Estrogen receptor signaling pathways: genomic or NISS pathways and the non-genomic or MISS pathway. AKT, protein kinase B; CoA, co-activator; CoR, co-activator receptor; CDK4/6, cyclin-dependent kinase 4/6; ER, estrogen receptor; ERE, estrogen responsive element; FGFR, fibroblast growth factor receptor; HER2, epidermal growth factor receptor 2; IGF1, insulin growth factor 1; MISS, membrane-initiated steroid signaling; mTORi, mammalian target of rapamycin inhibitors; MAPK, mitogen-activated protein kinase; NISS, nuclear-initiated steroid signaling; PI3Ki, phosphoinositide 3-kinase inhibitor; TFs, transcription factors

Fig. 3

Mechanism of action for estradiol, SERMs, and SERDs. CoA, co-activator; CoR, co-activator receptor; ER, estrogen receptor; ESR1, estrogen receptor 1; ERE, estrogen response element; SERDs, selective estrogen receptor degrader or down-regulator; SERMs, selective estrogen modulators; TFs, transcription factors

Fig. 4

ER inhibition by ER antagonist, PROTAC, and MGDs. Target proteins possessing the binding sockets (or degrons) to which inhibitors or PROTAC linkers can bind are druggable. Otherwise, they are considered non-druggable. ER, estrogen receptor; MGDs, molecular glue degrader; POI, protein of interest; PROTAC, proteolysis-targeting chimera; SERD, selective estrogen receptor degraders; SERM, selective estrogen receptor modulator