Giredestrant

Giredestrant (also known as GDC-9545, RG6171, or RO7197597) is an investigational oral selective estrogen receptor degrader (SERD) developed by Genentech, a member of the Roche Group, for the treatment of estrogen receptor-positive (ER+), 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 (FDA) for ER+, HER2-negative second- and third-line metastatic breast cancer.

Mechanism of action

Giredestrant is a nonsteroidal SERD that binds the estrogen receptor (ER), including wild-type and mutant forms (e.g., ESR1 mutation), 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 (SERMs) 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 (NCT04576455): A Phase II study compared giredestrant (30 mg oral daily) to physician’s choice of endocrine therapy (e.g., fulvestrant, aromatase inhibitors) in patients with 1–2 prior lines of systemic therapy for ER+, HER2-negative advanced breast cancer. At the clinical cutoff (February 18, 2022), the hazard ratio (HR) for progression-free survival (PFS) was 0.81 (95% CI, 0.60–1.10; P = 0.1757), showing no statistically significant improvement. A stronger PFS trend was observed in ESR1-mutated tumors (HR 0.60, 95% CI, 0.35–1.03).
* pionERA (NCT04478266): A Phase III, randomized, open-label study evaluating giredestrant versus fulvestrant, both combined with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib), in patients with ER+, HER2-negative advanced breast cancer resistant to prior adjuvant endocrine therapy.
* lidERA (NCT04546002): A Phase III study comparing adjuvant giredestrant to physician’s choice of endocrine monotherapy in ER+, HER2-negative early breast cancer.
* persevERA (NCT04687236): 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 (NCT05306340): A Phase III trial evaluating giredestrant with everolimus in ER+, HER2-negative advanced breast cancer post-CDK4/6 inhibitors.
* morpheus (NCT04802759): 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.

Safety and adverse effects

Giredestrant is generally well-tolerated, with a safety profile similar to endocrine therapies like fulvestrant. Common adverse events from the acelERA study and other trials include fatigue, nausea, arthralgia, diarrhea, hot flashes, headache, and musculoskeletal pain. ematologic effects (e.g., thrombocytopenia, anemia), liver enzyme elevations, and ovarian cysts (a class effect of SERDs) have been reported. Bradycardia was observed at higher doses but mitigated at the 30 mg dose used in pivotal trials.

References

Further reading

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Selective estrogen receptor degraders
Antineoplastic drugs
Anilines
Azetidines
Beta-Carbolines
Organofluorides
Fluorobenzene derivatives