GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an...

Area of Science:

• Oncology
• Pharmacology

Background:

• Breast cancer is a major cause of death in women, highlighting the need for new treatments.
• Selective estrogen receptor degraders (SERDs) are a key therapeutic class for hormone-dependent breast cancer.

Purpose of the Study:

• To present the discovery and preclinical profile of giredestrant (35), a novel oral SERD.
• To evaluate the efficacy and safety of giredestrant as a potential breast cancer therapeutic.

Main Methods:

• Discovery and optimization of giredestrant (35) with fine-tuned physicochemical properties for oral dosing.
• In vitro and in vivo assessment of antiproliferative activity, drug-drug interaction liability, and safety.
• Evaluation of tumor regression in preclinical models, including those with ESR1 mutations, as a single agent and in combination therapy.

Main Results:

• Giredestrant (35) demonstrated potent and efficient estrogen receptor degradation and antagonism, outperforming existing SERDs in antiproliferation assays.
• The drug allows for once-daily oral administration with favorable drug-drug interaction and safety profiles.
• Low doses of giredestrant induced significant tumor regressions in various models, including those with ESR1 mutations.

Conclusions:

• Giredestrant (35) is a promising clinical candidate for breast cancer treatment due to its potent SERD activity, oral bioavailability, and favorable safety profile.
• Its efficacy in preclinical models, including those with resistance mutations, supports its ongoing evaluation in Phase III clinical trials.