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Giredestrant

Modality: Oral selective estrogen receptor degrader (SERD)

Disease State: ER+/HER2- breast cancer, ER+/HER2+ breast cancer

Summary

Giredestrant (RG6171, GDC-9545) is an investigational oral selective estrogen receptor degrader (SERD) that is designed to bind to the estrogen receptor (ER) and limit its function by outcompeting estrogen.[1-3] Giredestrant-bound ER was shown to remain in an inactive conformation and directed for proteasome-dependent degradation.

ER, estrogen receptor; HR, hormone receptor; mTOR, mammalian target of rapamycin; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; RTK, receptor tyrosine kinase; SERD, selective estrogen receptor degrader

Clinical Trials

ER+/HER2- Breast Cancer
Phase	Enrollment Status	Title
Phase III	Active, not recruiting	A Phase III Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Giredestrant Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Patients With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (persevERA Breast Cancer)	View Details
Phase III	Recruiting	A Phase III Randomized, Open-Label Study Evaluating Efficacy and Safety of Giredestrant Compared With Fulvestrant, Both Combined With a CDK4/6 Inhibitor, in Patients With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer With Resistance to Prior Adjuvant Endocrine Therapy (pionERA Breast Cancer)	View Details

ER+/HER2+ Breast Cancer
Phase	Enrollment Status	Title
Phase III	Active, not recruiting	A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Giredestrant in Combination With Phesgo Versus Phesgo After Induction Therapy With Phesgo + Taxane in Patients With Previously Untreated HER2-Positive, Estrogen Receptor-Positive Locally-Advanced or Metastatic Breast Cancer (heredERA Breast Cancer)	View Details

ER=-estrogen receptor; CDK=Cyclin-dependent kinase; HER2=human epidermal growth factor receptor 2

Proposed Mechanism of Action

Giredestrant (RG6171, GDC-9545) is an investigational selective estrogen receptor degrader (SERD) that is designed to bind to the estrogen receptor (ER) and limit its function by outcompeting estrogen.[1-3] It is thought that giredestrant-bound ER changes the shape of the receptor in such a way that the cell eliminates it by degradation.

ER, estrogen receptor; HR, hormone receptor; mTOR, mammalian target of rapamycin; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; RTK, receptor tyrosine kinase; SERD, selective estrogen receptor degrader

Liang J, Zbieg JR, Blake RA, et al. GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer. J Med Chem 2021;64:11841-11856. https://doi.org/10.1021/acs.jmedchem.1c00847
Metcalfe C, Zhou W, Guan J, et al. Abstract 3406: GDC-9545: A pure antiestrogen clinical candidate that immobilizes the estrogen receptor and profoundly alters chromatin accessibility in vivo. Cancer Res (2020) 80 (16_Supplement): 3406. https://doi.org/10.1158/1538-7445.AM2020-3406
Jhaveri K, Winer EP, Lim E, et al. Cancer Res. 2020;80 (4 Suppl):Abstract PD7-05. https://doi.org/10.1158/1538-7445.SABCS19-PD7-05

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