Giredestrant
Giredestrant is an investigational oral selective [estrogen receptor degrader] developed by Genentech, a member of the Roche Group, for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer, as well as endometrial cancer, ovarian cancer, and other solid tumors.
It is a potent, nonsteroidal compound that antagonizes estrogen effects by competitively binding to both wild-type and mutant estrogen receptors with nanomolar potency. Giredestrant works by inducing an inactive conformation of the estrogen receptor ligand-binding domain and promoting proteasome-mediated degradation of the receptor protein.
As of May 2025, giredestrant is in clinical trials and has received Fast Track designation from the Food and Drug Administration for ER+, HER2-negative second- and third-line metastatic breast cancer.
Mechanism of action
Giredestrant is a nonsteroidal SERD that binds the estrogen receptor, including wild-type and mutant forms, inducing a conformational change in the receptor's ligand-binding domain. This promotes proteasome-mediated ER degradation, preventing ER-mediated signaling critical for tumor growth in ER+ breast cancer.Compared to selective estrogen receptor modulators or aromatase inhibitors, giredestrant's degradation mechanism better addresses resistance in ESR1-mutated tumors.
Research
In clinical trials, giredestrant has been evaluated in patients with ER+, HER2-negative breast cancer and other solid tumors, including endometrial and ovarian cancers, including those with ESR1 mutations, both as a single agent and in combination with other therapies. Its orally bioavailable.Breast Cancer
- acelERA : A Phase II study compared giredestrant to physician's choice of endocrine therapy in patients with 1–2 prior lines of systemic therapy for ER+, HER2-negative advanced breast cancer. At the clinical cutoff, the hazard ratio for progression-free survival was 0.81, showing no statistically significant improvement. A stronger PFS trend was observed in ESR1-mutated tumors.
- pionERA : A Phase III, randomized, open-label study evaluating giredestrant versus fulvestrant, both combined with a CDK4/6 inhibitor, in patients with ER+, HER2-negative advanced breast cancer resistant to prior adjuvant endocrine therapy.
- lidERA : A Phase III study comparing adjuvant giredestrant to physician's choice of endocrine monotherapy in ER+, HER2-negative early breast cancer.
- persevERA : A Phase III study comparing giredestrant plus palbociclib and placebo versus letrozole plus palbociclib and placebo in first-line metastatic ER+, HER2-negative breast cancer.
- evERA : A Phase III trial evaluating giredestrant with everolimus in ER+, HER2-negative advanced breast cancer post-CDK4/6 inhibitors.
- morpheus : A Phase I study assessing giredestrant with various combinations, including the immune checkpoint inhibitor atezolizumab, in metastatic breast cancer.
Other Indications
- Endometrial Cancer: Phase II trials are evaluating giredestrant for recurrent or persistent endometrial cancer.
- Ovarian Cancer: Phase II studies are exploring giredestrant in rare ovarian cancers.