Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer.

<i>ESR1</i> (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor-positive (ER⁺) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, <i>ESR1</i> mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated <i>Esr1</i> mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the <i>ESR1</i> mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, <i>Esr1</i> mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of <i>ESR1</i> mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized <i>ESR1</i> mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.