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

Chen, Ya-Chi; Yu, Jiajie; Metcalfe, Ciara; Bruyn, Tom De; Gelzleichter, Thomas; Malhi, Vikram; Pérez-Moreno, Pablo; Wang, Xiaojing

doi:10.1080/13543784.2021.1983542

Cited by 52 publications

(45 citation statements)

References 90 publications

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“…We also investigated tamoxifen and fulvestrant, standard-of-care agents approved for ER + breast cancer, and mifepristone, a PR antagonist that also displays some activity against the glucocorticoid receptor (GR) and potentially the androgen receptor (AR). Tamoxifen, fulvestrant, and giredestrant were each dosed to achieve clinically relevant exposures ( 14 , 34 ).…”

Section: Resultsmentioning

confidence: 99%

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer

Liang¹,

Ingalla²,

Yao³

et al. 2022

Sci. Transl. Med.

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ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor–positive (ER + ) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant–expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.

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Section: Resultsmentioning

confidence: 99%

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer

Liang¹,

Ingalla²,

Yao³

et al. 2022

Sci. Transl. Med.

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“…showed a weak laso-like stimulation of AP1. As the side-arms from T6I-4 and T6I-29 are similar to the SERDs GDC-0927 and SAR439859, it may also be possible that the chemical composition of these molecules correlates to uterotrophic antagonism rather than their ERα degrading activities (4,40). Further studies on the roles of transcriptional coregulators in breast, uterine, and other ER+ tissues are needed to understand the relationship between antiestrogen chemical composition, ERα structure, and SERM-agonist activities.…”

Section: Discussionmentioning

confidence: 99%

“…Although targeted therapies have extended life, ER+ patients face relapse and drug resistance with current therapies due to multiple mechanisms of acquired and de novo resistance. Many of these resistant diseases retain ER-dependence and some degree of sensitivity to next generation antiestrogens with improved antagonistic potencies (4,5). While these molecules show improved progression-free survival compared to standard-of-care (6), many ER+ patients fail to respond.…”

Section: Introductionmentioning

confidence: 99%

Unconventional Isoquinoline-Based SERMs Elicit Fulvestrant-Like Transcriptional Programs in ER+ Breast Cancer Cells

Fanning

Hancock

Young

et al. 2022

Preprint

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Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we have developed a series of chemically unconventional antagonists based on the antiestrogens RAD1901 and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they show SERM-like ERα accumulation in breast cancer cells but lack uterotrophic activities in an endometrial cell line. RNA sequencing shows that the lead molecules mediate transcriptional pathways similar to fulvestrant and other SERDs in these cells. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

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“…Camizestrant is an effective oestrogen receptor degrader, which showed significant antitumour effects in several PDX models of HR+ breast cancer, including ESR1 -mutant [7 ▪ ,15 ▪ ]. Preliminary results from the ongoing phase 1 trial SERENA-1 in pretreated HR+/HER2-negative MBC showed an ORR of 10% and a CBR of 35.3%, with median PFS of 5.4 months.…”

Section: New Selective Estrogen Receptor Degrader: An Overviewmentioning

confidence: 99%

Integrating new oral selective oestrogen receptor degraders in the breast cancer treatment

Garcia-Fructuoso

Gomez-Bravo

Schettini

2022

Current Opinion in Oncology

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Purpose of reviewOral SERDs are under extensive development to overcome fulvestrant main limitations, including intramuscular-only formulation and poor performance in early-stage hormone receptor-positive (HR+)/HER2-negative breast cancer. This review summarizes the most relevant evidence published so far and envisions the potential integration of oral SERDs in the therapeutic algorithm of HR+/HER2-negative metastatic breast cancer (MBC).Recent findingsAmcenestrant and giredestrant, two of the most promising oral SERDs, recently failed to show a significant improvement in progression-free survival (PFS) in pivotal trials. Conversely, elacestrant demonstrated significant PFS superiority over standard-of-care endocrine therapy (aromatase inhibitors or fulvestrant) in MBC. Additionally, it did not show unusual side effects observed with other oral SERDs, like bradycardia, hematotoxicity and vision impairment, and proved to be effective also in case of ESR1-mutant endocrine-resistant breast cancer. Combination trials of oral SERDs with target agents, such as CDK4/6-inhibitors, are ongoing. Finally, some window-of-opportunity trials showed promising on-target activity in early-stage for this drug class.SummaryPromising results from early-phase trials are not translating into sufficient clinical benefit in pivotal trials of main oral SERDs in monotherapy, except for elacestrant. Whether oral SERDs might become the backbone for combination strategies in MBC or the preferred (neo)adjuvant endocrine agents is under evaluation.

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

Cited by 52 publications

References 90 publications

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer

Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer

Unconventional Isoquinoline-Based SERMs Elicit Fulvestrant-Like Transcriptional Programs in ER+ Breast Cancer Cells

Integrating new oral selective oestrogen receptor degraders in the breast cancer treatment

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