Giredestrant (SERD)

(RG6171, GDC-9545)

Breast

Phase III

A Study Evaluating the Efficacy and Safety of Adjuvant Giredestrant Compared With Physician's Choice of Adjuvant Endocrine Monotherapy in Participants With Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer (lidERA Breast Cancer)

NCT04961996

VIEW TRIAL

A Study Evaluating the Efficacy and Safety of Giredestrant Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Participants With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (persevERA Breast Cancer)

NCT04546009

VIEW TRIAL

A Study to Evaluate the Efficacy and Safety of Giredestrant in Combination With Phesgo (Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf) Versus Phesgo in Participants With Locally Advanced or Metastatic Breast Cancer (heredERA Breast Cancer)

NCT05296798

VIEW TRIAL

This compound and its use are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

A novel selective estrogen receptor degrader (SERD) (Giredestrant)

Giredestrant, an investigational molecule

The estrogen receptor (ER)

The ER is a ligand-sensitive transcription factor expressed in various tissues, including the breast, where it can drive ER+ tumor cell division.¹

The ER signaling pathway

The activating ligand estrogen enters the cell and binds to the ligand-binding domain of the ER, promoting the dynamic association of the ER with specific regions of DNA.¹ Hotspot mutations in the ER (eg, Y537S and D538G) allow for estrogen-independent activation of the ER.^2-4

The activated ER triggers the expression of numerous target genes, including cyclin D1 (CCND1), which regulates the activity of cyclin-dependent kinases 4 and 6 (CDK4/6), and the progesterone receptor (PGR).^5,6

The gene expression program activated by the ER promotes ER+ tumor growth by driving cell proliferation.¹

Giredestrant is an investigational molecule designed to inhibit the ER

Giredestrant, designed to inhibit the estrogen receptor

Giredestrant, an investigational small molecule, is a full ER antagonist belonging to the SERD class of therapeutics.^7,8

Giredestrant targets ER-induced tumor proliferation

Preclinical studies suggest that Giredestrant is orally bioavailable and competitively inhibits the binding of estrogen to the ER.^7,9

In preclinical models, Giredestrant has been shown to restrain the normally dynamic behavior of both wild-type and mutant ER, immobilizing the ER and attenuating the expression of its target genes.^7,9,10 The ER is subsequently degraded by the proteasome, which may lead to a reduction in ER protein level without completely eliminating it.^7,9

In preclinical models, Giredestrant demonstrates inhibition of the ER-induced proliferative program and suppression of tumor growth.^7,9

As with other SERDs, the addition of CDK4/6 inhibitors may potentially enhance the antiproliferative effect of Giredestrant in ER+ breast cancer cells.¹¹

- Liang J, Shang Y. Estrogen and cancer. Annu Rev Physiol. 2013;75:225-240. PMID: 23043248
  
  Liang J, Shang Y. Estrogen and cancer. Annu Rev Physiol. 2013;75:225-240. PMID: 23043248
- Metcalfe C, Friedman LS, Hager JH. Hormone-targeted therapy and resistance. Annu Rev Cancer Biol. 2018;2:291-312.
  
  Metcalfe C, Friedman LS, Hager JH. Hormone-targeted therapy and resistance. Annu Rev Cancer Biol. 2018;2:291-312.
- Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439-1445. PMID: 24185512
  
  Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439-1445. PMID: 24185512
- Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446-1451. PMID: 24185510
  
  Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446-1451. PMID: 24185510
- O'Lone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol Endocrinol. 2004;18(8):1859-1875. PMID: 15031323
  
  O'Lone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol Endocrinol. 2004;18(8):1859-1875. PMID: 15031323
- Kim JK, Diehl JA. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol. 2009;220(2):292-296. PMID: 19415697
  
  Kim JK, Diehl JA. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol. 2009;220(2):292-296. PMID: 19415697
- Metcalfe C, Ingalla E, Blake RA, et al. Poster presented at the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P5-04-07.
  
  Metcalfe C, Ingalla E, Blake RA, et al. Poster presented at the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P5-04-07.
- Jhaveri K, Winer EP, Lim E, et al. Poster presented at the 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract PD7-05.
  
  Jhaveri K, Winer EP, Lim E, et al. Poster presented at the 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract PD7-05.
- Wang X. Presented at 2020 American Association for Cancer Research Virtual Annual Meeting I; April 22-27, 2020. Abstract DDT02-05.
  
  Wang X. Presented at 2020 American Association for Cancer Research Virtual Annual Meeting I; April 22-27, 2020. Abstract DDT02-05.
- Guan J, Zhou W, Hafner M, et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell. 2019;178(4):949-963.e18. PMID: 31353221
  
  Guan J, Zhou W, Hafner M, et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell. 2019;178(4):949-963.e18. PMID: 31353221
- Iorfida M, Mazza M, Munzone E. Fulvestrant in combination with CDK4/6 inhibitors for HER2- metastatic breast cancers: current perspectives. Breast Cancer (Dove Med Press). 2020;12:45-56. PMID: 32256106
  
  Iorfida M, Mazza M, Munzone E. Fulvestrant in combination with CDK4/6 inhibitors for HER2- metastatic breast cancers: current perspectives. Breast Cancer (Dove Med Press). 2020;12:45-56. PMID: 32256106