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Accelerating drug development in breast cancer: New frontiers for ER inhibition

      Highlights

      • New ER inhibitors show improved pharmacokinetics and pharmacodynamics compared to fulvestrant.
      • Composition of the side chain of oral SERDs affects their efficacy for efficacy.
      • Five oral SERDs are in phase III trials in the advanced setting and two in the adjuvant setting.
      • New ER inhibitors/degraders under investigation: SERCA, CERAN, PROTAC, and SERM/SERD hybrid.
      • Oral route and potency render the agents ideal endocrine backbone for combination therapies.

      Abstract

      The estrogen receptor (ER) is an important driver in the proliferation, tumorigenesis, and progression of breast cancers, and targeting ER signaling at different levels is a successful strategy in the control of hormone receptor positive (HR+) breast cancer. Endocrine therapy has been the treatment of choice for HR+ breast cancer in the early and advanced stages with multiple agents, including selective estrogen receptor modulators (SERMS), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics. Combination strategies also employ cyclin dependent kinase 4 and 6 and phosphatidylinositol 3-kinase to maximize the benefits of endocrine therapy. This paper reviews the clinical development of SERDs and other novel ER inhibitors, as well as combination strategies to overcome mechanisms of ER pathway escape. It also assesses the advantages of newer oral ER inhibitors with increased bioavailability, improved therapeutic index, better administration, and increased efficacy, as well as discussing future directions in the field.

      Keywords

      Abbreviations:

      AI: (Aromatase Inhibitor), AF-1 and AF2: (Activation Fuctions 1 and 2 regions of ER), CDK4/6: (Cyclin Dependent Kinase 4 and 6), CERAN: (Complete ER ANtagonists), cfDNA: (cell free DNA), DCIS: (Ductal Carcinoma In Situ), EMA: (European Medicine Agency), ESR1: (Estrogen Receptor 1), FDA: (Food and Drug Administration), HER2- : (Human Epidermal growth factor Receptor 2 negative), HR+ : (Hormone Receptors positive), OS: (Overall Survival), PFS: (Progression-Free Survival), PI3K: (Phosphatidylinositol 3-kinase), PK: (Pharmacokinetics), PROTAC: (PROteolysis TArgeting Chimera), SERCA: (Selective Estrogen Receptor Covalent Antagonist), SERD: (Selective Estrogen Receptor Degrader), SERM: (Selective Estrogen Receptor Modulator)

      Introduction

      Approximately two-thirds of breast cancers express the estrogen receptor (ER), a key driver of proliferation, tumorigenesis, and progression [
      • Howlader N.
      • Altekruse S.F.
      • Li C.I.
      • Chen V.W.
      • Clarke C.A.
      • Ries L.A.G.
      • et al.
      US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.
      ]. Interfering with ER signaling via endocrine therapy, a successful strategy in the control of hormone receptor positive (HR+) breast cancer, is the mainstay of treatment for HR+ breast cancer in early and advanced stages of disease. Agents used in clinical practice include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics (PKs). More recently developed combination strategies involve cyclin dependent kinase 4 and 6 (CDK4/6) and phosphatidylinositol 3-kinase (PI3K) inhibitors, which are used to maximize and prolong the benefits of endocrine therapy. When disease progression occurs on first line therapy with CDK4/6 inhibitors, there are a lack of effective treatment options in the second line setting and beyond, especially in patients whose tumors do not harbor targetable alterations, with poor expected response rates to endocrine monotherapy. Novel, orally administered endocrine agents such as oral SERDs have been developed to overcome the pharmacodynamic and pharmacokinetic limitations of standard endocrine therapies [
      • Hernando C.
      • Ortega-Morillo B.
      • Tapia M.
      • Moragón S.
      • Martínez M.T.
      • Eroles P.
      • et al.
      Oral selective estrogen receptor degraders (SERDs) as a novel breast cancer therapy: present and future from a clinical perspective.
      ].This review provides an overview of the pharmacology and clinical data of oral SERDs, along with our perspective on next-generation endocrine therapy and future directions in the field.

      Pharmacological evolution from SERM to SERD

      ER pathway and “old fashioned” endocrine agents

      The addiction of breast cancer cells to estrogen is mediated by the ER pathway, which drives their survival and progression by regulation of the transcriptional process. The classical mechanisms of action of the ER pathway involves estrogen binding to the receptors, dimerization, and subsequent binding to DNA regulator regions called estrogen response elements, located in the promoters of specific genes. ERs can also regulate gene expression without directly binding to the DNA. This secondary mechanism of action occurs through protein–protein interactions with other transcription factors. Additionally, less common membrane-associated ERs mediate nongenomic actions of estrogens, which can affect cytoplasmic protein function and lead to gene expression modulation [
      • Metcalfe C.
      • Friedman L.S.
      • Hager J.H.
      Hormone-targeted therapy and resistance.
      ].
      Endocrine therapy was developed to impair at different levels the ER pathway, one of the main players in the breast cancer cells survival and progression. The aromatization of A-cycle steroids leads to the conversion of androstenedione to estradiol in extra-ovarian tissue (e.g., adipose tissue), which is the main source of estrogen in post-menopausal women. By inhibiting this conversion, AIs reduce circulating estrogens and deprive the ER stimulus. In the adjuvant setting, AIs are the standard-of-care therapy for postmenopausal women and are often given in combination with ovarian function suppressors for premenopausal women at high risk of recurrence. AIs are approved to treat advanced breast cancer in combination with CDK4/6 inhibitors in the first-line setting and in combination with everolimus, an mTOR inhibitor, in subsequent lines of therapy [
      • Longo D.L.
      • Burstein H.J.
      Systemic therapy for estrogen receptor–positive, HER2-negative breast cancer.
      ].
      Unlike AIs, SERMs and SERDs directly inhibit the ER. The two ER isoforms, ERα and ERβ, have different structures, affinities for circulating estrogens, and tissue distributions. All therapeutic and diagnostic strategies currently target ERα [
      • Katzenellenbogen B.S.
      • Katzenellenbogen J.A.
      Estrogen receptor transcription and transactivation Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer.
      ]. Tamoxifen, an SERM, is the forerunner of ER inhibitors and an antagonist of genes relying on the AF-2 region for ER-mediated transcription. Crystallography has shown that when tamoxifen binds the ER, the repositioning of helix 12 prevents binding of co-activators, thereby preventing AF-2-mediated transcription and inhibiting AF-2 activation. However, tamoxifen also functions as an agonist of genes whose transcription is driven by the AF-1 domain [
      • Shiau A.K.
      • Barstad D.
      • Loria P.M.
      • Cheng L.
      • Kushner P.J.
      • Agard D.A.
      • et al.
      The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen.
      ]. Tamoxifen has tissue selectivity because of the predominance of AF-1- or AF-2-activated genes in specific tissues (e.g., uterine and breast, respectively) and has thus been reclassified as a modulator of ERα rather than a pure ER antagonist. Tamoxifen competes with estrogens in ER binding and inhibits transcription in breast tissue, but acts as an ER agonist in other tissues, including endometrial tissue, resulting in a 2- to 3-fold increased risk of endometrial cancer (higher in post-menopausal patients), and an increased risk of venous thromboembolic disease. This toxicity profile combined with the inferior efficacy compared to AI, makes tamoxifen a second choice therapy for post-menopausal patients in both early and metastatic setting [
      Breast International Group (BIG) 1-98 Collaborative Group
      A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.
      ,
      • Mouridsen H.
      • Gershanovich M.
      • Sun Y.
      • Pérez-Carrión R.
      • Boni C.
      • Monnier A.
      • et al.
      Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.
      ]. The US Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved indications for tamoxifen include treatment of advanced HR+ breast cancer, adjuvant treatment of other HR+ tumors, and risk reduction in patients with ductal carcinoma in situ (DCIS).
      Fulvestrant, a SERD, is a pure ER antagonist that, when bound to the ER, reduces dimerization and transcriptional activation while accelerating degradation through a proteasome-dependent system. The proportion of ER-fulvestrant complex that migrates into the nucleus is transcriptionally inactive, with both AF-1 and AF-2 functions disabled. Fulvestrant has shown efficacy in patients who previously progressed on tamoxifen [
      • Howell A.
      • DeFriend D.J.
      • Blamey R.W.
      • Robertson J.F.
      • Walton P.
      Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer.
      ,
      • Howell A.
      • Robertson J.F.R.
      • Quaresma Albano J.
      • Aschermannova A.
      • Mauriac L.
      • Kleeberg U.R.
      • et al.
      Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.
      ,
      • Robertson J.F.R.
      • Osborne C.K.
      • Howell A.
      • Jones S.E.
      • Mauriac L.
      • Ellis M.
      • et al.
      Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials.
      ] and is the only FDA/EMA approved SERD for the treatment of metastatic HR+ breast cancer [
      • Soleja M.
      • Raj G.V.
      • Unni N.
      An evaluation of fulvestrant for the treatment of metastatic breast cancer.
      ]. Fulvestrant monotherapy is approved as a 500 mg monthly intramuscular injection in treatment-naive patients based on the FALCON trial [
      • Robertson J.F.R.
      • Bondarenko I.M.
      • Trishkina E.
      • Dvorkin M.
      • Panasci L.
      • Manikhas A.
      • et al.
      Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.
      ] and as second-line therapy after progression on tamoxifen or AI [
      • Howell A.
      • Robertson J.F.R.
      • Quaresma Albano J.
      • Aschermannova A.
      • Mauriac L.
      • Kleeberg U.R.
      • et al.
      Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.
      ]. Fulvestrant is also approved in combination with the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib in the first- or second-line setting, and in combination with the PIK3CA inhibitor alpelisib in PIK3CA-mutant advanced breast cancer after progression on first-line therapy. However, the lack of oral bioavailability of fulvestrant, and its modest clinical activity as monotherapy after disease progression on CDK4/6 inhibitors and alpelisib limits its clinical use in later lines.
      CDK4/6 inhibitors in combination with endocrine therapies were established as first-line therapy for the treatment of metastatic HR+ disease after several studies demonstrated good rates of progression-free survival (PFS) and overall survival (OS). However, there are limited non-chemotherapy options after patients receive CDK4/6 inhibitors. Recent data suggests that in patients who progress on first line therapy with CDK4/6 inhibitors, a PFS of <2 months is observed with single agent fulvestrant [
      • Lindeman G.J.
      • Bowen R.
      • Jerzak K.J.
      • Song X.
      • Decker T.
      • Boyle F.M.
      • et al.
      Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC).
      ,
      • Bardia A.
      • Neven P.
      • Streich G.
      • Montero A.J.
      • Forget F.
      • Mouret-Reynier M.-A.
      • et al.
      Abstract GS2-02: elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial.
      ,
      • André F.
      • Ciruelos E.
      • Rubovszky G.
      • Campone M.
      • Loibl S.
      • Rugo H.S.
      • et al.
      Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.
      ]. Therefore, there is an unmet need to understand the mechanisms of resistance to endocrine therapy and find newer optimal endocrine agents that can overcome the pharmacologic liabilities and toxicity issues of currently approvents endocrine therapies. This in turn could facilitate sequential lines of endocrine therapy and delay time to chemotherapy administration.

      Mechanisms of resistance to endocrine therapy

      Endocrine therapy resistance is a complex phenomenon from both the clinical and molecular perspectives. The phenotype of a resistant cell can include mechanisms of ER reactivation or ER escape. Mechanisms of resistance to tamoxifen are commonly related to ER reactivation [
      • Ring A.
      • Dowsett M.
      Mechanisms of tamoxifen resistance.
      ]. Prolonged exposure to tamoxifen can select for cancer cell subclones that express coregulators able to bind the otherwise inactive tamoxifen-ERα complex, resulting in ER agonism and resistance. Mutations in ESR1, the gene encoding ERα, are a well-established driver of resistance to endocrine treatment, through ER reactivation [
      • Jeselsohn R.
      • Buchwalter G.
      • De Angelis C.
      • Brown M.
      • Schiff R.
      ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer.
      ]. ESR1 mutations are rare in primary breast cancers but prevalent in metastatic cancers, occurring in 25% to 40% of patients previously treated with AIs, implying that these mutations are acquired [
      • Chandarlapaty S.
      • Chen D.
      • He W.
      • Sung P.
      • Samoila A.
      • You D.
      • et al.
      Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial.
      ,
      • Reinert T.
      • Gonçalves R.
      • Bines J.
      Implications of ESR1 mutations in hormone receptor-positive breast cancer.
      ]. ESR1 mutations induce a conformational change that confers ligand independent aberrant ER transcriptional activity and decreases proteolytic degradation, thereby rendering AIs ineffective, with more variable effects on SERMs and SERDs [
      • Robinson D.R.
      • Wu Y.-M.
      • Vats P.
      • Su F.
      • Lonigro R.J.
      • Cao X.
      • et al.
      Activating ESR1 mutations in hormone-resistant metastatic breast cancer.
      ,

      Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 2014;20:1757–67.

      ]. A combined analysis of the SoFEA and EFECT trials revealed that patients with ESR1 mutations detected on cell free DNA (cfDNA), in 30% of the overall study population, had improved PFS and OS when treated with fulvestrant versus exemestane, suggesting that unlike AIs, SERDs have activity in patients harboring ESR1 mutations [

      Turner NC, Swift C, Kilburn L, Fribbens C, Beaney M, Garcia-Murillas I, et al. ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor–positive breast cancer: a combined analysis of the phase III SoFEA and EFECT trials. Clin Cancer Res 2020;26:5172–7.

      ]. The ESR1 mutations Y537S (14%) and D538G (36%) are the most prevalent mutations causing resistance to AIs. These mutations fall within the encoded ligand-binding domain of ESR1, and also reduce binding to tamoxifen and fulvestrant, thereby promoting potential resistance [
      • Jeselsohn R.
      • Buchwalter G.
      • De Angelis C.
      • Brown M.
      • Schiff R.
      ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer.
      ,
      • Robinson D.R.
      • Wu Y.-M.
      • Vats P.
      • Su F.
      • Lonigro R.J.
      • Cao X.
      • et al.
      Activating ESR1 mutations in hormone-resistant metastatic breast cancer.
      ,

      Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, et al. D538G mutation in estrogen receptor-α: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 2013;73:6856–64.

      ,
      • Li S.
      • Shen D.
      • Shao J.
      • Crowder R.
      • Liu W.
      • Prat A.
      • et al.
      Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts.
      ,
      • Toy W.
      • Shen Y.
      • Won H.
      • Green B.
      • Sakr R.A.
      • Will M.
      • et al.
      ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.
      ]. In clinical studies, while fulvestrant has been shown to be effective in patients whose tumors progressed on AI [
      • Johnston S.RD.
      • Kilburn L.S.
      • Ellis P.
      • Dodwell D.
      • Cameron D.
      • Hayward L.
      • et al.
      Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial.
      ,
      • Fribbens C.
      • O’Leary B.
      • Kilburn L.
      • Hrebien S.
      • Garcia-Murillas I.
      • Beaney M.
      • et al.
      Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer.
      ,
      • Cristofanilli M.
      • Rugo H.S.
      • Im S.-A.
      • Slamon D.J.
      • Harbeck N.
      • Bondarenko I.
      • et al.
      Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): updated analyses from PALOMA-3.
      ], data suggests that the development of an ESR1 Y537S mutation is a mechanism of acquired resistance to fulvestrant, thereby resulting in limited therapeutic activity [

      O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Disc 2018;8:1390–403.

      ]. Pre-clinically, Toy et al [

      Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, et al. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov. 2017;7:277–87.

      ] have demonstrated that Y537S-mutant cells are less sensitive to fulvestrant and require higher drug levels to achieve antitumor activity compared to other ESR1 mutations. In cohort A of plasmaMATCH trial, higher dose fulvestrant did not confirm an increased response in patients with HR+/HER2- metastatic breast cancer carrying ESR1 mutations detected by cfDNA[
      • Turner N.C.
      • Kingston B.
      • Kilburn L.S.
      • Kernaghan S.
      • Wardley A.M.
      • Macpherson I.R.
      • et al.
      Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.
      ]. Recent updates presented at ASCO 2022 Annual Meeting identified a specific mutation, ESR1 F404, as a mechanism of acquired resistance to fulvestrant in patients with prior ESR1 activating alterations [
      • Kingston B.
      • Pearson A.
      • Herrera-Abreu M.T.
      • Cutts R.
      • Moretti L.
      • Kilburn L.
      • et al.
      ESR1 F404 mutations and acquired resistance to fulvestrant in the plasmaMATCH study.
      ]. The in vitro modelling suggests that the presence of an ESR1 F404 interferes with fulvestrant-ER binding, whereas sensitivity to tamoxifen and novel SERDs appeared to be preserved. Overall, data suggests that the ESR1 mutation-based phenotype of resistance to AI or fulvestrant is variable and appears to depend on the type of mutation, the function of the involved domain, clonality, variant allele frequency in cfDNA and the presence of co-mutations in other driver pathways [

      Andreano KJ, Baker JG, Park S, Safi R, Artham S, Oesterreich S, et al. The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor. Mol Cancer Therapeut 2020;19:1395–405.

      ,
      • Brett J.O.
      • Spring L.M.
      • Bardia A.
      • Wander S.A.
      ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer.
      ,
      • Li Z.
      • McGinn O.
      • Wu Y.
      • Bahreini A.
      • Priedigkeit N.M.
      • Ding K.
      • et al.
      ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation.
      ]. Given the limitations of currently approved endocrine therapies, a primary research focus is the development of oral SERDs with higher bioavailability and greater ER targeting and degradation capabilities [
      • Nardone A.
      • Weir H.
      • Delpuech O.
      • Brown H.
      • De Angelis C.
      • Cataldo M.L.
      • et al.
      The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.
      ].
      New therapeutic strategies combine endocrine therapies with inhibitors of other prominent pathways associated with endocrine resistance and escape of ER-dependent cancer cells, including pathways involved in cell growth and cell cycle progression such as CDK4/6 and PI3K/Akt/mTOR. For instance, tumors with mutations in PIK3CA, reported in >40% of metastatic HR+ breast cancers, are vulnerable to PI3K inhibitors. Combination therapy is more effective than PI3K inhibitor monotherapy because inhibition of the PI3K pathway leads to a rebound of ER-dependent transcriptional activity [
      • Bosch A.
      • Li Z.
      • Bergamaschi A.
      • Ellis H.
      • Toska E.
      • Prat A.
      • et al.
      PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer.
      ]. Recently, new resistance of mechanisms have been identified, including activating ERBB2 mutations, NF1 loss-of-function mutations, and alterations in MAPK pathway genes (EGFR, KRAS) and in ER transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) [
      • Croessmann S.
      • Formisano L.
      • Kinch L.N.
      • Gonzalez-Ericsson P.I.
      • Sudhan D.R.
      • Nagy R.J.
      • et al.
      Combined blockade of activating ERBB2 mutations and ER results in synthetic lethality of ER+/HER2 mutant breast cancer.
      ,
      • Zehir A.
      • Benayed R.
      • Shah R.H.
      • Syed A.
      • Middha S.
      • Kim H.R.
      • et al.
      Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
      ,
      • Bertucci F.
      • Ng C.K.Y.
      • Patsouris A.
      • Droin N.
      • Piscuoglio S.
      • Carbuccia N.
      • et al.
      Genomic characterization of metastatic breast cancers.
      ,
      • Fu X.
      • Pereira R.
      • De Angelis C.
      • Veeraraghavan J.
      • Nanda S.
      • Qin L.
      • et al.
      FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer.
      ,
      • Hanker A.B.
      • Sudhan D.R.
      • Arteaga C.L.
      Overcoming endocrine resistance in breast cancer.
      ]. In a cohort of 692 pretreated breast tumors, Razavi et al. [
      • Razavi P.
      • Chang M.T.
      • Xu G.
      • Bandlamudi C.
      • Ross D.S.
      • Vasan N.
      • et al.
      The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers.
      ] reported that 22% of tumors had ER pathway escape alterations, which were mutually exclusive with ESR1 mutations and were associated with a shorter duration of response to subsequent hormonal therapies. These findings support the investigation of oral SERDs not only as monotherapy but also in combination strategies in early drug development.

      New oral SERDs: Mechanisms of action and clinical development

      The development of oral SERDs has been challenging and the hope of improving efficacy with a more favorable mode of administration has largely fallen short. Challenges with earlier agents were due to the lack of competitive bioavailability and unacceptable toxicity profiles. Nonetheless, many oral SERDs and new ER inhibitors are under development, with several ongoing phase III trials. Metcalfe et al., demonstrated that ER degradation is the primary mechanism of action of both fulvestrant and oral SERDs; ER inhibition slows nuclear ER translocation and immobilizes ER in the nucleus, thereby inhibiting transcription and accelerating ER degradation [
      • Guan J.
      • Zhou W.
      • Hafner M.
      • Blake R.A.
      • Chalouni C.
      • Chen I.P.
      • et al.
      Therapeutic ligands antagonize estrogen receptor function by impairing its mobility.
      ].
      The molecular interaction with ER differs across SERDs such that oral SERDs can be categorized based on their structure and mechanism of action (Fig. 1). Some SERDs are non-steroidal molecules with an ER-binding site and a side chain of an acrylic acid, while others have an amino base side chain, inducing different conformational changes in ER that affect transcriptional activity and the vulnerability of the ER to degradation.
      Figure thumbnail gr1
      Fig. 1Interaction of new or traditional ER inhibitors with a breast cancer cell. Estrogen receptors binds to estrogens, dimerize, and translocate to the nucleus. In the nucleus, the dimers bind to estrogen response element (ERE) of several genes and induce transcription, promoting cancer survival and proliferation. SERMs including tamoxifen, bazedoxifene, and lasofoxifene bind the ER, working as antagonists of the transcription process in the breast cancer cell and as agonists in other tissues (bone and endometrium). Fulvestrant works by inhibiting dimerization and translocation in the nucleus as well as by proteasomal degradation. In the nucleus, the transcription is not active in the absence of ER stimulus. Fulvestrant is partially active also on ESR1-mutant receptor (dotted line). ESR1, if not inhibited, is able to enhance the transcription in a ligand-independent fashion. Oral SERD, SERCA, and CERAN have the same effect as fulvestrant on ER, resulting in the inhibition of transcription, but they are more potent on ER as well as ESR1, with a higher rate of degradation of the receptors. The elements that confer more potency to these agents compared to fulvestrant is reported in the figure. PROTAC is composed of a ligand that binds to the E3 ubiquitin ligase and a ligand that binds to the target protein through a linker, which can induce the polyubiquitination and proteasomal degradation of ER in the cancer cells.

      SERDs with acrylic acid side chains

      SERDs with an acrylic acid side chain, including GW5638 (etacstil), with its active metabolites GW7604, GDC0810, AZD9496, G1T48, and LSZ102, were the first potent antiestrogen agents developed without cross-resistance to tamoxifen (Table 1). The crystallographic analysis of the ERα-GW7604 complex showed that the interaction of a carboxylic acid with the peptide backbone of ER induced a conformational change that exposed a hydrophobic surface of the receptor that targeted it for proteolytic degradation [
      • Wu Y.-L.
      • Yang X.
      • Ren Z.
      • McDonnell D.P.
      • Norris J.D.
      • Willson T.M.
      • et al.
      Structural basis for an unexpected mode of SERM-mediated ER antagonism.
      ]. As monotherapy, these agents have antitumor activity in both endocrine-sensitive and resistant preclinical models and in ESR1-mutated tumors [

      Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, et al. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov. 2017;7:277–87.

      ,
      • Nardone A.
      • Weir H.
      • Delpuech O.
      • Brown H.
      • De Angelis C.
      • Cataldo M.L.
      • et al.
      The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.
      ,
      • McDonnell D.P.
      • Wardell S.E.
      • Norris J.D.
      Oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer.
      ,
      • Lu Y.
      • Liu W.
      Selective estrogen receptor degraders (SERDs): a promising strategy for estrogen receptor positive endocrine-resistant breast cancer.
      ,
      • Joseph J.D.
      • Darimont B.
      • Zhou W.
      • Arrazate A.
      • Young A.
      • Ingalla E.
      • et al.
      The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.
      ]. Further preclinical studies demonstrated potent antitumor activity of these agents when combined with CDK4/6 inhibitors. For example, G1T48 (rintodestrant), in combination with the novel CDK4/6 inhibitor G1T38 (lerociclib), has greater tumor growth inhibition compared to either agent as monotherapy [
      • Andreano K.J.
      • Wardell S.E.
      • Baker J.G.
      • Desautels T.K.
      • Baldi R.
      • Chao C.A.
      • et al.
      G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.
      ,

      Wardell SE, Yllanes AP, Baker JG, Baldi RM, Krebs TK, Sorrentino J, et al. Abstract 5641: Effects of G1T48, a novel orally bioavailable selective estrogen receptor degrader (SERD), and the CDK4/6 inhibitor, G1T38, on tumor growth in animal models of endocrine resistant breast cancer. Cancer Res. 2017;77:5641.

      ].
      Table 1Pertinent clinical data from phase I/II trials of oral SERDs and other novel compounds.
      Investigational drug +/- other agentsType of inhibitorPhaseNESR1 mut (%)Prior CDK4/6i (%)Prior SERD (%)ORR (%)CBR (%)Median PFS*Any grade TEAE (%)Grade ≥ 3 TEAE or DLT (%)Reference
      Acrylic Acid Side Chains
      AZD9496SERDI45NA15.655.628NADiarrhea (35.6), Fatigue (31.1)15Hamilton, CCR 2018
      Rintodestrant (G1T48)SERDI (part A and B)674570645302.6–3.6Hot flush (24), Fatigue (21)NAAftimos, SABCS 2020
      Rintodestrant (G1T48) + palbociclibSERD + CDK4/6iI (part C)40NR015561NRNeutropenia (88)Neutropenia (43)Maglakelidze, ASCO 2021
      LSZ102SERDI: Arm A774258601.39.11.8Nausea (61),Diarrhea

      (55)
      NAJhaveri, CCR 2021
      LSZ102 + ribociclibSERD + CDK4/6iI: Arm B783934.660.316.935.16.2Nausea (50),Diarrhea

      (39)
      NAJhaveri, CCR 2021
      LSZ102 + alpelisibSERD + PIK3CAiI-Arm C43256546720.93.5Nausea (60),Diarrhea

      (70)
      NAJhaveri, CCR 2021
      Basic Side Chain
      Elacestrant (RAD1907)SERM/SERDI5050525219.442.64.5Nausea (50),Dyspepsia

      (32)
      41.7Bardia et al., JCO 2021
      Giredestrant (GD-9545)SERDI111NR642115507.2Fatigue (21),Arthralgia

      (17)
      5Jhaveri et al., ASCO 2021
      Giredestrant (GDC9545) + palbociclibSERDI48NR073381NRNeutropenia (50)50Lim et al., ASCO 2020
      Amcenestrant (SAR439859)SERDI (part A + B)59286346.88.533.9NRHot Flush (16), Constipation (9.7), Arthralgia (9.7)NALinden, SABCS 2020; Campone et al., ASCO2020
      Amcenestrant (SAR439859) + palbociclibSERD + CDK4/6iI (part C + D)39NR5.17.732.473.5Not reachedNausea (17.9), Fatigue (17.9%)46.2Chandarlapaty et al.,

      ASCO 2021 and SABCS 2021
      Camizestrant (AZD9833)SERDI984650531035.3NRVisual disturbances, Bradycardia, Asthenia, Anemia, QTcF prolongationDLT: QTcF, vomiting); visual disturbanceHamilton et al., ASCO 2021

      Baird et al., SABCS 2021
      Camizestrant (AZD9833) + palbociclibSERDI251117205.928NAInfections, NeutropeniaNAOliveira et al., ASCO 2022
      Imlunestrant (LY3484356)SERDI14138925112554.3Nausea (35), Fatigue (25),NAJhaveri, ASCO 2021 and 2022
      Others
      D0502SERDI16NRNRNR1050NANANAOsborne, SABCS 2020
      ZN-c5SERDI564170465383.8Nausea, Fatigue, ArthralgiaNo DLTKalinsky, SABCS 2021
      OP1250CERANI/II321692.567.9921NANausea(59), Fatigue(35), Constipation (24)No DLTPatel, SABCS 2021
      HB36545SERCAII9462877316.740.33.8Sinus bradicardia (35), Anemia(19), Fatigue(16), Diahrraea (12)Sinus bradicardia G2 (5) and QT prolungation G2/3Hamilton ASCO 2021 and SABCS 2021
      ARV471PROTACI60NA10050641NANausea (24), Fatigue (12), Vomiting (10)No grade 3 AEHamilton et al., SABCS 2021
      *TEAE: the two most common TEAE occurring in ≥ 15% of all patients.
      ASCO: American Society of Clinical Oncology; CBR: clinical benefit rate; CCR: Clinical Cancer Research; CDK4/6i: CDK4/6 inhibitor; CERAN: Complete ER Antagonists; DLT: dose limiting toxicity; eBC: early breast cancer; JCO: Journal of Clinical Oncology; mutn: mutation; NA: not applicable; NR: not reported; ORR: overall response rate; PROTAC: PROteolysis TArgeting Chimeras; PFS: progression free survival; SABCS: San Antonio Breast Cancer Symposium; SERCA: Selective Estrogen Receptor Covalent Antagonists; SERD: selective estrogen receptor downregulator; TEAE: treatment emergent adverse event.
      Early-phase clinical trials of oral SERDs with acrylic acid side chains showed less promising efficacy and tolerability results, so most of these compounds have not been further developed beyond phase I. For instance, GDC0810, a direct successor of GW5638, was less active than fulvestrant in a phase II study that was terminated early (NCT02569801). In a phase I/Ib trial of patients who had progressed on prior endocrine therapy, the majority of whom had received prior fulvestrant, CDK4/6 inhibitor, and chemotherapy, LSZ102 monotherapy resulted in an overall response rate (ORR) of only 1%, which increased to 17% and 7% when LSZ102 was given in combination with ribociclib or the PI3K inhibitor alpelisib, respectively [
      • Jhaveri K.
      • Juric D.
      • Yap Y.-S.
      • Cresta S.
      • Layman R.
      • Duhoux F.
      • et al.
      LBA1 Interim results of a phase I/Ib study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib (RIB) or alpelisib (ALP) in patients with ER+ breast cancer (BC) who had progressed after endocrine therapy (ET).
      ]. LSZ102 monotherapy was associated with high rates of gastrointestinal (GI) toxicities experienced: any grade nausea (61%) and diarrhea (55%). Notably, the toxicity profile did not significantly differ in the combination arms [
      • Jhaveri K.
      • Juric D.
      • Yap Y.-S.
      • Cresta S.
      • Layman R.M.
      • Duhoux F.P.
      • et al.
      A phase I study of LSZ102, an oral selective estrogen receptor degrader, with or without ribociclib or alpelisib, in patients with estrogen receptor–positive breast cancer.
      ].
      Rintodestrant was evaluated in a phase I trial as monotherapy and in combination with palbociclib (NCT03455270). Preliminary results from 14 patients treated with G1T48 alone demonstrated reductions in 18F-fluoroestradiol positron emission tomography uptake ranging from 70% to 98% after 4 weeks of treatment. However, among a larger group of 67 patients treated with monotherapy, 20 patients were on study >24 weeks but only 3 patients experienced partial response (PR), with a median PFS of 2 months. Similar response rates were observed when G1T48 was combined with palbociclib [
      • Aftimos P.
      • Maglakelidze M.
      • Glaudemans A.W.
      • Hamilton E.
      • Chap L.
      • de Vries E.
      • et al.
      Abstract PD8-07: Pharmacodynamic analysis from a phase 1 study of rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer.
      ,
      • Maglakelidze M.
      • Bulat I.
      • Ryspayeva D.
      • Krastev B.M.
      • Gogiladze M.
      • Crijanovschi A.
      • et al.
      Rintodestrant (G1T48), an oral selective estrogen receptor degrader, in combination with palbociclib for ER+/HER2– advanced breast cancer: phase 1 results.
      ]. The toxicity profile appears to be favorable, with <10% of patients experiencing grade 1–2 nausea, vomiting, and neutropenia. Results from the other combination cohorts are awaited.
      AZD9496 was designed with a novel binding motif of substituted aryl indole to improve affinity for either wild-type or mutant ER, but showed low response rates and some toxicity. Approximately 90% of patients experienced drug-related adverse events, including 40% with any grade diarrhea or other GI toxicity [

      Hamilton EP, Patel MR, Armstrong AC, Baird RD, Jhaveri K, Hoch M, et al. A first-in-human study of the new oral selective estrogen receptor degrader AZD9496 for ER+/HER2− advanced breast cancer. Clin Cancer Res. 2018;24:3510–8.

      ]. In February 2021, AZD9496 development was halted in favor of its more potent and tolerable successor AZD9833 (camizestrant), developed with an amino side chain instead of an acrylic acid side chain. Camizestrant rapidly progressed through phase I testing and is currently under investigation in phase II and phase III clinical trials, as discussed below.

      SERDs with basic amino side chains

      In addition to unfavorable toxicity profiles, SERDs with acrylic acid side chains were found to inconsistently inhibit ER. To overcome these challenges, SERDs with basic amino side chains were developed in an attempt to maximally and consistently degrade ER [
      • Hernando C.
      • Ortega-Morillo B.
      • Tapia M.
      • Moragón S.
      • Martínez M.T.
      • Eroles P.
      • et al.
      Oral selective estrogen receptor degraders (SERDs) as a novel breast cancer therapy: present and future from a clinical perspective.
      ], including RAD1901 (elacestrant), GDC9545 (giredestrant), SAR439859 (amcenestrant), AZD9833 (camizestrant) and LY3484356 (imlunestrant) (Table 1). These agents have demonstrated good oral bioavailability and significant antitumor activity in both treatment-naive and endocrine-resistant preclinical models, including those with ESR1 mutations and those resistant to CDK4/6 inhibition, demonstrating growth inhibition comparable to fulvestrant [
      • Guan J.
      • Zhou W.
      • Hafner M.
      • Blake R.A.
      • Chalouni C.
      • Chen I.P.
      • et al.
      Therapeutic ligands antagonize estrogen receptor function by impairing its mobility.
      ,
      • Garner F.
      • Shomali M.
      • Paquin D.
      • Lyttle C.R.
      • Hattersley G.
      RAD1901: A novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models.
      ,

      Dubash TD, Bardia A, Reeves BA, Chirn B, Szabolcs A, Wittner BS, et al. Abstract P4-01-06: Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations. Cancer Res. 2020;80:P4-01–6.

      ,

      Bihani T, Patel HK, Arlt H, Tao N, Jiang H, Brown JL, et al. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER+ breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23:4793-804.

      ,
      • Wardell S.E.
      • Nelson E.R.
      • Chao C.A.
      • Alley H.M.
      • McDonnell D.P.
      Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.
      ,
      • Stenoien D.L.
      • Patel K.
      • Mancini M.G.
      • Dutertre M.
      • Smith C.L.
      • O'Malley B.W.
      • et al.
      FRAP reveals that mobility of oestrogen receptor-α is ligand- and proteasome-dependent.
      ,
      • Fanning S.W.
      • Greene G.L.
      Next-generation ERα inhibitors for endocrine-resistant ER+ breast cancer.
      ,

      Bouaboula M, Shomali M, Cheng J, Malkova N, Sun F, Koundinya M, et al. Abstract 943: SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer. Cancer Res. 2018;78:943.

      ,
      • Patel H.K.
      • Tao N.
      • Lee K.-M.
      • Huerta M.
      • Arlt H.
      • Mullarkey T.
      • et al.
      Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors.
      ,

      Wang X, Wang X. Abstract DDT02-04: GDC-9545: Discovery of an oral estrogen receptor antagonist, degrader, and immobilizer for the treatment of ER+ breast cancer patients. Cancer Res. 2020;80:DDT02–4.

      ]. Notably, these agents may treat brain metastases from HR+/HER2- breast cancers, as evidence suggests that elacestrant crosses the blood–brain barrier. While it is unclear whether ER inhibition is as effective in the central nervous system (CNS) as in other disease sites [
      • Conlan M.G.
      • de Vries E.F.J.
      • Glaudemans AWJM
      • Wang Y.
      • Troy S.
      Pharmacokinetic and pharmacodynamic studies of elacestrant, a novel oral selective estrogen receptor degrader, in healthy post-menopausal women.
      ], a phase Ib/II trial of elacestrant plus abemaciclib in patients with active CNS metastases is ongoing (NCT04791384).
      The maximum tolerated dose (MTD) was not achieved in any trial of novel oral SERDs with basic amino side chains, resulting in the recommended phase II dose (RP2D) being chosen from efficacy, PK, pharmacodynamic, and safety data from phase I studies. Ongoing phase III trials will determine if these agents can replace traditional endocrine therapies in both early-stage and advanced disease (Table 2).
      Table 2Ongoing trials in breast cancer.
      DrugClinical Trials IdentifierPhaseExperimental armControl armPopulation characteristics
      First-line metastatic disease
      Amcenestrant (SAR439859)NCT04478266 (AMEERA-5)IIISAR439859 + palbociclibLetrozole + palbociclibNo previous treatment for metastatic disease; no previous SERDs
      Camizestrant (AZD9833)NCT04964934 (SERENA-6)IIIAZD9833 + palbociclib/ abemaciclibAI + palbociclib/ abemaciclibMBC ER+/HER2- on AI + palbo/abema with detectable ESR1 mutation without radiological POD on imaging
      NCT04711252 (SERENA-4)IIIAZD9833 + palbociclibLetrozole + palbociclibDe novo Stage IV or relapse after 24 mo of adjuvant AI and/or within 12 mo after discontinuation
      Giredestrant (GDC9545)NCT04546009 (persevERA)IIIGDC9545 + palbociclibLetrozole + palbociclibDe novo Stage IV or relapse after 24 mo of adjuvant AI and/or within 12 mo after discontinuation
      Imlunestrant (LY3484356)NCT04188548 (EMBER-1)Ia/IbLY3484356 + abemaciclib +/- AI or LY3484356 + everolimus or LY3484356 + alpelisib or LY3484356 + trastuzumab +/- abemaciclibMBC ER+/HER2- or ER+/HER2+
      ZN-c5NCT04514159IZN-c5 + abemaciclibNo prior CDK4/6 I
      NCT03560531I/IIZN-c5 +/-palboMBC ER+/HER2-
      Beyond first-line metastatic disease
      Elacestrant (RAD1901)NCT04791384Ib/IIElacestrant + abemaciclibProgressing brain mets in patients pretreated with ET and maximum 2L chemo
      Rintodestrant (G1T48)NCT03455270IRintodestrant +/- palbociclib
      Amcenestrant (SAR439859)NCT04059484 (AMEERA-3)**IIAmcenestrantET monotherapy (any AI, fulv or Tam)post CDK4/6i, secondary endocrine resistance*
      NCT03284957 (AMEERA-1)I/IISAR439859 + /-everolimus or palbociclib or abemaciclib or alpelisibsecondary endocrine resistance*
      Camizestrant (AZD9833)NCT03616587 (SERENA-1)IAZD9833 +/- everolimus or palbociclib or abemaciclib or alpelisib or capivasertibPreexposure to 1 line ET (different from SERD), only 1 line of chemo allowed,
      NCT04214288 (SERENA-2)IIAZD9833FulvestrantPreexposure to ET, no limits of lines; only 1 line of chemo allowed
      Giredestrant (GDC9545)NCT04576455 (acelERA BC)**IIGDC9545ET monotherapy

      (any AI or fulv)
      Progression after 1–2 L of ET
      NCT04802759Ib/IIGDC9545 + inavolisib (PIK3CAi), ipatasertib (CDK7i), abemaciclib, ribociclib, everolimusMBC ER+/HER2 progression after 1-3L of ET including CDK4/6i
      Imlunestrant

      (LY3484356)
      NCT04188548 (EMBER)Ia/IbLY3484356 +/- AI or everolimus or abemaciclib or alpelisib or capivasertib or trastuzumab or pertuzumabMBC ER+/HER2- or ER+/HER2 + and metastatic endometrial cancer
      NCT04975308 (EMBER-3)IIILY3484356AI or fulvestrantPOD after AI +/- CDK4/6 I
      D-0502NCT03471663Ia/IbD-0502 +/- palbociclibMBC ER+/HER2-
      Zn-c5NCT04176757IZn-c5MBC ER+/HER2-
      Zb-716NCT046695871/IIZB716 + palbociclibMBC ER+/HER2-
      Neoadjuvant setting
      Camizestrant (AZD9833)NCT04588298 (SERENA-3)IIAZD9833FulvestranteBC ER+/HER2-, palpable tumor of any size, or T ≥ 1.0 cm
      Elacestrant (RAD1901)NCT04797728 (ELIPSE)IIElacestranteBC ER+/HER2-, T ≥ 1.5 cm (cT1c-3), N0
      Imlunestrant (LY3484356)NCT04647487 (EMBER-2)IILY3484356eBC ER+/HER2-, stage I-III
      Giredestrant (GDC9545)NCT03916744IIGDC9545 +/- palbociclibAnastrozole + /-palbociclibeBC ER+/HER2-, stage I-III
      Amcenestrant (SAR439859)NCT01042379 (I-SPY)IISAR439859 alone

      SAR439859 + AI

      SAR439859 + abemaciclib
      Standard therapyeBC ER+/HER2-, stage I-III
      Adjuvant setting
      Giredestrant (GDC9545)NCT04961996 (lidERA)IIIGiredestrant alonePhysician choice endocrine treatmenteBC ER+/HER2- after definitive surgery
      Amcenestrant (SAR439859)NCT05128773 (AMEERA-6)IIIAmcenestrant aloneTamoxifeneBC who have discontinued adjuvant AI due to treatment-related toxicity
      New ER targeting agents
      H3B6545 (SERCA)NCT04288089IH3B6545 + palbociclibMBC ER+/HER2-after 1L
      ARV471 (PROTAC)NCT04072952I/IIARV-471 (PROTAC) +/- palboMBC ER+/HER2-
      OP1250 (CERAN)NCT04505826I/IIOP-1250MBC ER+/HER2-
      Bazedoxifene (SERM/SERD)NCT02448771I/IIBazedoxifene + palbociclibMBC ER+/HER2-after 1L
      LasofoxifeneNCT03781063 (ELAINE)IILasofoxifeneFulvestrantMBC ER+/HER2- with ESR1 mutn after POD to CDK4/6i + AI
      NCT04432454 (ELAINE-2)IILasofoxifene + abemaciclibMBC ER+/HER2-with ESR1 mutn after POD to CDK4/6i + AI in 1st or 2nd line
      *Secondary endocrine resistance: progression while on ET after at least 6 months of treatment for MBC, or relapse while on adjuvant endocrine therapy but after the first 2 years, or with a relapse within 12 months after completing adjuvant ET.
      AI: aromatase inhibitor; eBC: early breast cancer; ET: endocrine therapy; fulv: fulvestrant; L: lines; MBC: metastatic breast cancer; mo: months; mutn: mutation; N: nodal status; POD: progression of disease; T: tumor size; Tam: tamoxifen; WoO: window of opportunity.
      ** Active, not recruiting. Press release on primary enpoint is available. See reference

      Baird R, Oliveira M, Gil EMC, Patel MR, Bermejo de las Heras B, Ruiz-Borrego M, et al. Abstract PS11-05: Updated data from SERENA-1: A phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. Cancer Res. 2021;81:PS11-05.

      for acelERA trial and
      • Hamilton E.P.
      • Wang J.S.
      • Pluard T.J.
      • Johnston S.R.D.
      • Morikawa A.
      • Dees E.C.
      • et al.
      Phase I/II study of H3B–6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
      for AMEERA-3 trial, respectively.
      Elacestrant is the agent furthest along in development, with early clinical trials demonstrating its safety, tolerability, good oral bioavailability, and ability to penetrate the blood–brain barrier [
      • Conlan M.G.
      • de Vries E.F.J.
      • Glaudemans AWJM
      • Wang Y.
      • Troy S.
      Pharmacokinetic and pharmacodynamic studies of elacestrant, a novel oral selective estrogen receptor degrader, in healthy post-menopausal women.
      ,
      • Jager A.
      • de Vries E.G.E.
      • der Houven van Oordt C.-V.
      • Neven P.
      • Venema C.M.
      • Glaudemans A.W.J.M.
      • et al.
      A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using (18)F-FES PET/CT imaging.
      ]. In a phase I study of 57 heavily pretreated patients by Bardia et al., the ORR was 19%, and response rates were 15% in those treated with prior SERD, 17% in those treated with prior CDK4/6 inhibitors, and 33% in those with an ESR1 mutation. The clinical benefit rate (CBR) at 24 weeks was 43%, including 57% in those with an ESR1 mutation and 30% in those treated with prior CDK4/6 inhibition [
      • Bardia A.
      • Kaklamani V.
      • Wilks S.
      • Weise A.
      • Richards D.
      • Harb W.
      • et al.
      Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer.
      ,

      Bihani T, Jung J, Patel HK, Bardia A, Kabos P, Kaklamani V, et al. Abstract P5-01-05: genomic alterations detected by circulating tumor DNA and correlation with response to treatment with elacestrant, an oral selective estrogen receptor degrader, in phase 1 trials in postmenopausal women with ER+/HER2- advanced/metastatic breast cancer. Cancer Res 2020;80:P5-01–5.

      ]. The reported toxicities were predominantly GI (nausea [50%], dyspepsia [32%], and vomiting [20%]), the overwhelming majority of which were grades 1–2. The selected RP2D was 400 mg daily.
      The randomized EMERALD study was the first phase III of an oral SERD; 477 patients previously treated with CDK4/6 inhibitors for HR+ metastatic breast cancer, were randomized to elacestrant versus endocrine monotherapy (fulvestrant or an AI). One prior chemotherapy line was permitted. The primary endpoints were PFS in the overall population and PFS in patients with tumors harboring ESR1 mutations. Both primary endpoints were met. In the intention-to-treat analysis, there was a 30% reduction in the risk of progression or death versus fulvestrant or AI and a 45% reduction in the risk of progression or death in patients harboring ESR1 mutations [
      • Bardia A.
      • Neven P.
      • Streich G.
      • Montero A.J.
      • Forget F.
      • Mouret-Reynier M.-A.
      • et al.
      Abstract GS2-02: elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial.
      ]. The 12-month PFS was 22.3% in the elacestrant arm versus 9.4% in the control arm with a HR of 0.7 (0.55–0.88). A greater magnitude of benefit was shown in the subgroup of patients with tumors harboring an ESR1 mutation (12-month PFS: 26.6% versus 8.2% for ESR1 mutated and wildtype respectively). Although the absolute PFS benefit was small in this study, (2.8 versus 1.9 months in the overall population and 3.8 versus 1.9 months in the ESR1-mutant population), the PFS curves between these populations significantly diverge at 6 months and 12 months after an initial dramatic drop in both treatment arms [
      • Bardia A.
      • Neven P.
      • Streich G.
      • Montero A.J.
      • Forget F.
      • Mouret-Reynier M.-A.
      • et al.
      Abstract GS2-02: elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial.
      ]. Similar outcomes were reported in the subgroup analysis of patients who received prior endocrine therapy only [
      • Kaklamani V.G.
      • Bardia A.
      • Aftimos P.G.
      • Cortes J.
      • Lu J.M.
      • Neven P.
      • et al.
      Subgroup analysis of patients with no prior chemotherapy in EMERALD: A phase 3 trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), versus investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC).
      ]. One limitation of the EMERALD study was that 20–25% of the patients had received prior chemotherapy. In addition, approximately 30% of the study population had received prior fulvestrant and 80% had received prior AI, which may account for the initial dramatic drop seen in the PFS curves and the short PFS observed in both arms. These findings suggest that elacestrant benefit may be driven by a group of patients with endocrine sensitive tumors. The most common any grade adverse effects observed in ≥15% of patients treated with elacestrant were nausea (35%), vomiting (19%), and fatigue (19%). This study represents the first positive phase III trial of an oral SERD, and approval of elacestrant is currently under review by the FDA. Additional data on the elacestrant efficacy will be provided by the ongoing phase Ib/II trial evaluating elacestrant in combination with CDK4/6 inhibitor in patients with progressing brain metastasis (NCT04791384).
      Giredestrant has been shown to be active as monotherapy and in combination with CDK4/6 inhibitors. In a phase I trial, 111 patients, >60% of whom had previously been treated with CDK4/6 inhibitors, received monotherapy, and 48 patients naive to CDK4/6 inhibitors were treated with giredestrant plus palbociclib. The CBR was 50% with monotherapy (PR, 13%) and 81% with combination therapy (PR, 33%) [
      • Lim E.
      • Jhaveri K.L.
      • Perez-Fidalgo J.A.
      • Bellet M.
      • Boni V.
      • Perez Garcia J.M.
      • et al.
      A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2-negative breast cancer.
      ,
      • Jhaveri K.L.
      • Boni V.
      • Sohn J.
      • Villanueva-Vásquez R.
      • Bardia A.
      • Schmid P.
      • et al.
      Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC).
      ]. Grade ≥3 toxicities were observed infrequently (neutropenia [33%], fatigue [2%], and diarrhea [2%]). The phase II acelERA breast cancer trial evaluating giredestrant versus endocrine monotherapy in patients previously treated with 1–2 prior lines of systemic therapy for metastatic disease (NCT04576455) failed to demonstrate superiority of giredestrant over standard of care (Hoffmann-La Roche press release, April 2022 [

      Roche H-L. <https://www.roche.com/media/releases/med-cor-2022-04-25>.

      ]). The persevERA study is an ongoing phase III trial evaluating the efficacy of giredestrant combined with palbociclib in the first-line metastatic setting (NCT04188548).
      Giredestrant has also been studied in early-stage breast cancer with encouraging results. The first trial of predominantly luminal A breast cancers, evaluated by PAM50 criteria, studied single agent neoadjuvant giredestrant with an interim analysis, showing that giredestrant reduced Ki67 in 78% of tumors and caused complete cell cycle arrest in 55% of tumors (NCT03916744) [
      • Moore H.M.
      • Boni V.
      • Bellet M.
      • Bermejo De Las Heras B.
      • Gión Cortés M.
      • Oakman C.
      • et al.
      Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant (GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2–) operable breast cancer (BC).
      ]. The coopERA trial is a randomized, phase II neoadjuvant trial of giredestrant versus anastrozole, with the addition of palbociclib in both arms after 14 days of treatment. The final analysis on 201 evaluable patients on the lead-in phase of the study (without palbociclib) has shown a statistically significant reduction in Ki67 after 14 days of treatment with giredestrant compared to AI (relative reduction in geometric Ki67 of −75% vs −67%, respectively) [
      • Fasching P.A.
      • Bardia A.
      • Quiroga V.
      • Park Y.H.
      • Blancas I.
      • Alonso J.L.
      • et al.
      Neoadjuvant giredestrant (GDC-9545) plus palbociclib (P) versus anastrozole (A) plus P in postmenopausal women with estrogen receptor–positive, HER2-negative, untreated early breast cancer (ER+/HER2– eBC): Final analysis of the randomized, open-label, international phase 2 coopERA BC study.
      ]. However, giredestrant combined with palbociclib did not show an improvement in terms of pCR rate compared to the control arm. The lidERA randomized phase III trial is currently investigating the benefits of giredestrant compared to standard-of-care endocrine therapy in early-stage HR+, human epidermal growth factor receptor 2 negative (HER2-) breast cancer after definitive surgery (NCT04961996).
      In the ongoing phase I SERENA-1 study (NCT03616587), camizestrant is being studied as monotherapy and in combination with palbociclib or abemaciclib (CDK4/6 inhibitors), everolimus (mTOR inhibitor), or capivasertib (AKT inhibitor). Among 98 patients treated with camizestrant monotherapy, in those previously treated with fulvestrant (53%) and CDK4/6 inhibitors (50%), the ORR and CBR were 10% and 35%, respectively. In the CDK4/6 inhibitor-naive cohort including 25 patients receiving camizestrant (RP2D:75 mg) plus palbociclib, the ORR and CBR were 5.9% and 28%, respectively. Of the patients treated with camizestrant monotherapy, 46% had baseline cfDNA-detected ESR1 mutations, of whom 50% achieved PR or stable disease at 24 weeks and 85% had reductions or loss of mutant ESR1 with treatment [
      • Oliveira M.
      • Hamilton E.P.
      • Incorvati J.
      • Bermejo de la Heras B.
      • Calvo E.
      • García-Corbacho J.
      • et al.
      Serena-1: updated analyses from a phase 1 study (parts C/D) of the next-generation oral SERD camizestrant (AZD9833) in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer.
      ]. Efficacy data from the other combination arms are awaited. Any grade toxicities reported in >15% of patients were visual disturbances (53%), bradycardia (45%), and nausea (18%) [
      • Hamilton E.P.
      • Oliveira M.
      • Banerji U.
      • Hernando C.
      • Garcia-Corbacho J.
      • Armstrong A.
      • et al.
      A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer.
      ,

      Baird R, Oliveira M, Gil EMC, Patel MR, Bermejo de las Heras B, Ruiz-Borrego M, et al. Abstract PS11-05: Updated data from SERENA-1: A phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. Cancer Res. 2021;81:PS11-05.

      ]. The RP2D of 75 mg has been brought forward to the phase II setting, with the ongoing SERENA-2 study (NCT04214288) evaluating camizestrant versus fulvestrant, and to the phase III setting, with the SERENA-4 and SERENA-6 studies (NCT04711252; NCT04214288) evaluating camizestrant plus CDK4/6 inhibitor in the first-line metastatic setting.
      Amcenestrant is another new molecule under investigation as monotherapy and in combination with targeted therapies. In the phase I/II AMEERA-1 study, among 59 evaluable patients treated with monotherapy, the ORR was 9% and the CBR was 34%, increasing to 64% among patients without prior SERD, CDK4/6 inhibitors, or mTOR inhibitors [

      Linden HM, Campone M, Bardia A, Ulaner GA, Gosselin A, Doroumian S, et al. Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. Cancer Res 2021;81:PD8–08.

      ]. Among 39 patients treated with amcenestrant plus palbociclib, the ORR was 32% and CBR at 24 weeks was 73%, with a median PFS of 15 months (range 11–22.3) [
      • Chandarlapaty S.
      • Linden H.M.
      • Neven P.
      • Petrakova K.
      • Bardia A.
      • Kabos P.
      • et al.
      AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).
      ,
      • Chandarlapaty S.
      • Linden H.M.
      • Neven P.
      • Petrakova K.
      • Bardia A.
      • Kabos P.
      • et al.
      Abstract P1–17-11: Updated data from AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), combined with palbociclib in postmenopausal women with ER+/HER2- advanced breast cancer.
      ]. The most frequent any-grade toxicities occurring in ≥ 15% of patients were fatigue and nausea; 13% of patients experienced grade ≥ 3 toxicities with amcenestrant alone [

      Linden HM, Campone M, Bardia A, Ulaner GA, Gosselin A, Doroumian S, et al. Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. Cancer Res 2021;81:PD8–08.

      ,
      • Campone M.
      • Bardia A.
      • Ulaner G.A.
      • Chandarlapaty S.
      • Gosselin A.
      • Doroumian S.
      • et al.
      Phase I/II study of SAR439859, an oral selective estrogen receptor degrader (SERD), in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).
      ]. The RP2D of 400 mg daily is now being investigated in the first-line setting in combination with CDK4/6 inhibitors (NCT04478266). A recent press release reported that the phase II AMEERA-3 trial (NCT04059484) which studied patients progressing on endocrine therapy +/- CDK4/6 inhibitors (mandatory for 80% of the population) did not met its primary endpoint of PFS superiority favoring amcenestrant over the control arm (Sanofi press release, March 2022) [

      Sanofi. <https://www.sanofi.com/en/media-room/press-releases/2022/2022-03-14-06-00-00-2402216>.

      ]. Similarly, the AMEERA-4, a window of opportunity trial for patients with I-III early breast cancer showed antiproliferative activity of amcenestrant, measured as changes in Ki67 from baseline to day 14, but there were no differences conmpared to the control arm of AI [
      • Campone M.
      • Dong Y.
      • Ling B.
      • Wang L.
      • Herold C.I.
      AMEERA-4: A preoperative window-of-opportunity (WOO) study to assess the pharmacodynamic (PD) activity of amcenestrant or letrozole in postmenopausal patients with ER+/HER2− primary breast cancer.
      ]. More recently, the phase III AMEERA-6 trial evaluating amcenestrant versus tamoxifen as adjuvant treatment for patients intolerant to AI is open to enrollment (NCT05128773).
      The EMBER study, the first-in-human trial of imlunestrant, showed encouraging results in 114 heavily pretreated patients with metastatic HR+/HER2- breast cancer with a median PFS of 4.3 months (range 3.6–7.1 months). Interestingly, in 45 patients who received imlunestrant as second line therapy after CDK4/6 inhibitors, the median PFS was 6.5 months (range 3.6–8.3 months), longer than the expected PFS with currently available standard endocrine therapy[
      • Lindeman G.J.
      • Bowen R.
      • Jerzak K.J.
      • Song X.
      • Decker T.
      • Boyle F.M.
      • et al.
      Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC).
      ,
      • Bardia A.
      • Neven P.
      • Streich G.
      • Montero A.J.
      • Forget F.
      • Mouret-Reynier M.-A.
      • et al.
      Abstract GS2-02: elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial.
      ,
      • André F.
      • Ciruelos E.
      • Rubovszky G.
      • Campone M.
      • Loibl S.
      • Rugo H.S.
      • et al.
      Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.
      ]. Predominantly grade 1–2 adverse events were reported, with nausea and diarrhea being the most frequently reported toxicities [
      • Jhaveri K.L.
      • Lim E.
      • Hamilton E.P.
      • Saura C.
      • Meniawy T.
      • Jeselsohn R.
      • et al.
      A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD) in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): results from the EMBER study.
      ,
      • Jhaveri K.L.
      • Jeselsohn R.
      • Lim E.
      • Hamilton E.P.
      • Yonemori K.
      • Beck J.T.
      • et al.
      A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): monotherapy results from EMBER.
      ]. Results of the other combination arms with everolimus, abemaciclib, trastuzumab and pertuzumab are awaited. The dose of 400 mg daily is the RP2D and has been used in the design of phase I-III trials. The EMBER-3 phase III trial has been designed to evaluate the efficacy of imlunestrant alone versus imlunestrant with abemaciclib versus AI/fulvestrant in the second line setting (NCT04975308). Prior chemotherapy and fulvestrant are not permitted. Other ongoing trials are investigating the activity of imlunestrant in early-stage disease given in neoadjuvant (EMBER-2, NCT0464748) and adjuvant setting (upcoming EMBER-4). Several other molecules, including D-0502, Zb-716, ZN-c5, and SHR9549, demonstrated promising preclinical data and are under investigation in phase I and II clinical trials (Table 2).

      Innovation in ER inhibition: Next steps beyond SERDs

      Other strategies aimed at targeting ER inhibition include PROteolysis Targeting Chimeras (PROTACs), selective estrogen receptor covalent antagonists (SERCAs), complete ER Antagonists (CERANs), and new oral SERM/SERD hybrids that are direct successors of tamoxifen. These new molecules were developed with the hope of increasing the potency of ER inhibition/degradation. SERCAs inactivate both wild-type and mutant ER receptors by targeting a cysteine residue (C530), thereby enforcing a unique antagonist conformation [
      • Hernando C.
      • Ortega-Morillo B.
      • Tapia M.
      • Moragón S.
      • Martínez M.T.
      • Eroles P.
      • et al.
      Oral selective estrogen receptor degraders (SERDs) as a novel breast cancer therapy: present and future from a clinical perspective.
      ]. H3B6545, a SERCA, showed anti-tumor activity both as monotherapy and in combination with CDK4/6 and mTOR inhibitors in the preclinical setting [

      Puyang X, Furman C, Zheng GZ, Wu ZJ, Banka D, Aithal K, et al. Discovery of selective estrogen receptor covalent antagonists for the treatment of ERα(WT) and ERα(MUT) breast cancer. Cancer Discov 2018;8:1176–93.

      ]. H3B6545 is now being investigated in phase I/II trials both as monotherapy (NCT03250676; NCT04568902) and in combination with palbociclib (NCT04288089). Preliminary results demonstrated that H3B6545 monotherapy resulted in an ORR of 30% among patients with tumors harboring clonal ESR1 Y537S mutations, compared to 17% in the overall population, with CBR of 70% and 40%, respectively. Cardiovascular toxicities included grade 1 asymptomatic bradycardia (36%), grade 2 symptomatic bradycardia (5%), and grade 2/3 QT prolongation (3%) [
      • Hamilton E.P.
      • Wang J.S.
      • Pluard T.J.
      • Johnston S.R.D.
      • Morikawa A.
      • Dees E.C.
      • et al.
      Phase I/II study of H3B–6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
      ].
      Unlike partial agonists, CERANs bind the ligand binding pocket, thereby blocking ER transcriptional activity mediated by both AF1 and AF2 to achieve complete antagonism. OP1250 is a first-in-class CERAN that showed an ORR of 9% when given as monotherapy in a phase I trial. Low-grade nausea was reported in 60% of the population, but there were no dose-limiting toxicities observed (NCT04505826) [
      • Patel M.
      • Alemany C.
      • Mitri Z.
      • Makower D.
      • Borges V.
      • Sparano J.
      • et al.
      Abstract P1–17-12: Preliminary data from a phase I/II, multicenter, dose escalation study of OP-1250, an oral CERAN/SERD, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer.
      ].
      PROTACs are bifunctional small molecules that link an ER binding ligand with an E3 ligase to induce polyubiquitination and degradation of the ER complex. ARV471 is a first-in-class PROTAC targeting the ERα receptor and showed promising results when compared to fulvestrant, and in combination with palbociclib in the preclinical setting [
      • Gao H.
      • Sun X.
      • Rao Y.u.
      PROTAC technology: opportunities and challenges.
      ,

      Flanagan J, Qian Y, Gough S, Andreoli M, Bookbinder M, Cadelina G, et al. Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer. Cancer Res 2019;79:P5-04–18.

      ]. A phase I/Ib clinical trial is currently evaluating ARV471 alone and in combination with palbociclib (NCT04072952). Preliminary results have shown favorable toxicity profile: there were no cases of bradycardia, no grade 4 toxicities, and only 2 of 50 patients experienced grade 3 adverse events. The CBR was 40% in 47 evaluable patients, with responses reported in patients previously treated with fulvestrant, CDK4/6 inhibitors, and oral SERDs [
      • Hamilton E.
      • Vahdat L.
      • Han H.S.
      • Ranciato J.
      • Gedrich R.
      • Keung C.F.
      • et al.
      Abstract PD13-08: First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer.
      ]. These results suggest intriguing activity of PROTACs after progression on oral SERDs, which may be important in the future development of this new class of drug.
      SERM/SERD hybrids have demonstrated potent Erα antagonism and degradation. Lasofoxifene is a next-generation non-steroidal SERM that was developed to treat vulvovaginal atrophy and osteoporosis. In preclinical models, lasofoxifene monotherapy was more effective than fulvestrant at inhibiting primary tumor growth and reducing disease progression. In xenograft models, the addition of a CDK4/6 inhibitor to lasofoxifene improved its activity in tumor suppression and metastases prevention [
      • Lainé M.
      • Fanning S.W.
      • Chang Y.-F.
      • Green B.
      • Greene M.E.
      • Komm B.
      • et al.
      Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer.
      ]. This strong preclinical data supports the phase II ELAINE and ELAINE2 trials that are investigating lasofoxifene alone and in combination with abemaciclib, respectively (NCT03781063, NCT04432454).
      Bazedoxifene (BZA) is another SERM/SERD hybrid with strong antagonist and SERD profiles in breast tissue and concomitant agonist properties in the bone, but without agonist properties in the endometrium [
      • Fanning S.W.
      • Greene G.L.
      Next-generation ERα inhibitors for endocrine-resistant ER+ breast cancer.
      ,

      Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res 2013;19:2420–31.

      ,
      • Komm B.S.
      • Kharode Y.P.
      • Bodine P.V.N.
      • Harris H.A.
      • Miller C.P.
      • Lyttle C.R.
      Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity.
      ,
      • Lewis-Wambi J.S.
      • Kim H.
      • Curpan R.
      • Grigg R.
      • Sarker M.A.
      • Jordan V.C.
      The selective estrogen receptor modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-regulates estrogen receptor α and cyclin D1.
      ]. With long-term safety data in thousands of patients, BZA is already approved in the US as a hormone replacement therapy and is approved in Europe for the prevention of osteoporosis [
      • Fanning S.W.
      • Greene G.L.
      Next-generation ERα inhibitors for endocrine-resistant ER+ breast cancer.
      ,

      Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res 2013;19:2420–31.

      ,
      • Lewis-Wambi J.S.
      • Kim H.
      • Curpan R.
      • Grigg R.
      • Sarker M.A.
      • Jordan V.C.
      The selective estrogen receptor modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-regulates estrogen receptor α and cyclin D1.
      ,
      • Biskobing D.M.
      Update on bazedoxifene: a novel selective estrogen receptor modulator.
      ,
      • Fanning S.W.
      • Jeselsohn R.
      • Dharmarajan V.
      • Mayne C.G.
      • Karimi M.
      • Buchwalter G.
      • et al.
      The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.
      ,
      • Tikoo D.
      • Gupta M.
      Duavee: a tissue-selective estrogen complex for menopausal symptoms and prevention of osteoporosis.
      ]. In breast cancer, BZA demonstrated good oral bioavailability and improved PK profile compared to fulvestrant, as well as potent anti-tumor activity in both AI and SERM-resistant tumors and in ESR1-mutated cells [

      Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res 2013;19:2420–31.

      ,
      • Biskobing D.M.
      Update on bazedoxifene: a novel selective estrogen receptor modulator.
      ,
      • Fanning S.W.
      • Jeselsohn R.
      • Dharmarajan V.
      • Mayne C.G.
      • Karimi M.
      • Buchwalter G.
      • et al.
      The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.
      ,

      Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res 2015;21:5121–30.

      ]. Preliminary results from a phase Ib/II study of BZA with palbociclib has shown an ORR of 8%, CBR of 36%, and PFS of 4 months in a heavily pretreated population. Final results from this study are expected towards the end of 2022 (NCT02448771) [

      Jeselsohn R, Guo H, Rees R, Barry WT, Barlett CH, Tung NM, et al. Abstract PD1-05: Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer. Cancer Res 2019;79:PD1–05.

      ]. Additionally, BZA conjugated with estrogens is under investigation as primary prophylaxis for patients at high risk of developing breast cancer and in patients with DCIS (NCT04821141; NCT02694809).

      Future directions

      The drug development platform of oral SERDs has rapidly progressed from preclinical studies to phase III trials both in late and early-stage settings. The phase III EMERALD trial has recently provided proof-of-principle for activity of oral SERDs compared to physician’s choice endocrine therapy after progression on CDK4/6 inhibitors in the metastatic setting, particularly in patients whose tumors harbor ESR1 mutations. The oral bioavailability of these agents, in addition to their favorable toxicity profiles, may be particularly pertinent when considering their role in combination with other targeted therapies, including CDK4/6 inhibitors and agents targeting the PI3K/Akt/mTOR pathways. Although GI toxicities including nausea, vomiting and diarrhea occur frequently, they are typically low grade and are rarely observed as grade 3–4 toxicities. There are no major overlapping toxicities between SERDs and targeted therapies. Diarrhea has been observed mainly for SERDs with acrylic acid side chains and therefore may present challenges when given in combination with abemaciclib. However, this combination might be still potentially manageable and tolerable with dose reductions and/or alternative schedules. Hence, multiple phase III trials are ongoing and evaluating the role of oral SERDs plus CDK4/6 inhibitors in the first-line metastatic setting. The PADA1 trial demonstrated that switching from an AI plus CDK4/6 inhibitor to fulvestrant plus CDK4/6 inhibitor in the first-line setting doubles PFS in those patients who develop a cfDNA-detected ESR1 mutation prior to radiological progression of disease [
      • Bidard F.-C.
      • Hardy-Bessard A.-C.
      • Bachelot T.
      • Pierga J.-Y.
      • Canon J.-L.
      • Clatot F.
      • et al.
      Abstract GS3-05: Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial.
      ]. This supports the idea that oral SERDs may be beneficial when used early, especially in patients refractory to currently approved endocrine therapies and in those who develop ESR1 mutations. The ongoing phase III SERENA-6 trial (NCT04964934) will evaluate if switching from standard endocrine therapy to an oral SERD at first appearance of an ESR1 mutation can prevent clinical disease progression in patients on first-line therapy with CDK4/6 inhibitors. The current challenge is how to best use these agents to optimize treatment outcomes for patients. To that end, we eagerly await results from ongoing studies of other oral SERDs to determine if these agents should be best utilized as single agents or in combination with targeted therapies post-progression on CDK4/6 inhibitor therapy or may be most effective in the first-line metastatic setting in combination with CDK4/6 inhibitors.
      Despite oral SERDs not yet obtaining regulatory approval for metastatic disease, trials in the early-stage setting are already in progress (Table 2). Given their high potency and possibility for dose reduction, they have the potential to increase patients’ adherence and tolerance of treatment both in the metastatic but more importantly in the early stage setting where non-adherence is an issue [
      • Hershman D.L.
      • Kushi L.H.
      • Shao T.
      • Buono D.
      • Kershenbaum A.
      • Tsai W.-Y.
      • et al.
      Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients.
      ]. Abemaciclib was recently FDA approved as adjuvant therapy for high-risk, early-stage ER+ breast cancers based on the results of the MonarchE trial [
      • Johnston S.R.D.
      • Harbeck N.
      • Hegg R.
      • Toi M.
      • Martin M.
      • Shao Z.M.
      • et al.
      Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE).
      ]. However, despite the significant reduction in both disease-free and relapse-free survival with 2 years of adjuvant abemaciclib, this agent is associated with high rates of GI toxicities. Given the excellent tolerability and relatively low rates of toxicities seen with newer-generation oral SERDs, these agents may be particularly promising in early-stage disease to change the landscape of adjuvant endocrine therapy. However, there are many unanswered questions, including whether oral SERD monotherapy might be sufficient treatment for high-risk disease, and whether it is necessary to combine oral SERDs with abemaciclib in the adjuvant setting. With respect to the optimal sequence in early-stage disease, questions remain about whether oral SERDs should be used as upfront therapy versus tamoxifen/AI, whether they should be used as part of a switch strategy after patients have been treated with at least 2 years of standard-of-care endocrine therapy, or whether oral SERDs may function as extended endocrine therapy.
      In conclusion, oral SERDs and other new ER inhibitors represent a promising advancement in drug development for ER+ breast cancers. There is high expectation in the scientific community that these agents may be soon included in the treatment paradigm for metastatic HR+/HER2-breast cancer. The big question ahead of us remains how best to optimally sequence these agents in order to improve outcomes for our patients. While these agents are active against ESR1 mutations, other agents are needed that will tackle the ligand binding domain mutation independent mechanisms of endocrine resistance such as ARID1A mutations and ESR1 fusion. With the currently available data, single agent SERDs have not been shown to provide a prolonged and meaningful benefit post CDK4/6 inhibitor therapy. Better results are anticipated when SERDs are used in earlier lines and/or as a backbone for combination therapies. Our hope is that the introduction of novel endocrine therapy options with increased potency and favorable toxicity profiles into clinical practice may contribute to prolonging the chemotherapy-free interval as much as possible for our patients, thereby facilitating more targeted and personalized treatment approaches, especially in the context of endocrine resistance.

      CRediT authorship contribution statement

      Emanuela Ferraro: Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Elaine M. Walsh: Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Jacqueline J. Tao: Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Sarat Chandarlapaty: Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Komal Jhaveri: Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We thank Susan D. Weil from the Design and Creative Services at MSK for her diligent assistance in creating the figure for this manuscript. We thank Reeja M. Thomas and Hannah L. Rice from the Editorial/Grant Writing Services at MSK for providing support with proof reading and editing this manuscript. E.F. thanks the American-Italian Cancer Foundation (AICF) for the 2021–2022 Post-Doctoral Fellowship for the funding support. K.J. would like to acknowledge the Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748].

      Funding

      This work was supported by the National Institutes of Health/National Cancer Institute, Cancer Center Support Grant [P30 CA008748].

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