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

Abstract

ESR1 (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, ESR1 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 Esr1 mutant–expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 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 ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 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.

Giredestrant for Estrogen Receptor–Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study

“…In acelERA BC, giredestrant trended toward a favorable benefit among patients with ESR1 m tumors, consistent with findings in EMERALD 21 and SERENA-2, 22 indicating that giredestrant, a potent antagonist of mutant ER-reversing progesterone hypersensitivity, 25 can target this mechanism of endocrine resistance more effectively than an AI or fulvestrant. In later lines, particularly in patients without ESR1 m tumors, additional mechanisms of resistance emerge that progressively decrease the dependence on the ER pathway, 26,27 as evidenced by the limited efficacy of single-agent ET in the aforementioned studies in patients without ESR1 m tumors.…”

Targeting Breast Cancer: An Overlook on Current Strategies

“…GDC-9545 (giredestrant) was identified as an oral SERD with an exceptional preclinical profile [ 71 ]. It is now in phase III clinical trials as monotheraphy [ 72 , 73 ], and in association with palcociclib [ 74 , 75 , 76 , 77 ] and its use was suggested in order to overcome acquired resistance, since it was observed that BCs with mutant ERα remain sensitive to giredestrant and reversed progesterone hypersensitivity driven by this mutation [ 78 ]. Rintodestrant (G1T48) is an orally bioavailable, nonsteroidal SERD that was developed through structure-guided investigations driven by activity in BC cell lines.…”

Tailoring therapies to counter the divergent immune landscapes of breast cancer

“…Activating mutations in the gene encoding the ER (ESR1) have been identified in the context of metastatic breast cancer previously treated with tamoxifen and aromatase inhibitors (Turner et al, 2020;Zundelevich et al, 2020). Mutations in the ER are associated with reduced progression free survival and overall survival (Turner et al, 2020;Zundelevich et al, 2020) as well as resistance to the HR+ breast cancer standard of care (Herzog and Fuqua, 2021;Liang et al, 2022). Interestingly, it was recently demonstrated that tumors harbouring mutations in the ER had elevated levels of inflammatory cytokines S100A8 and S100A9, T regs and PDL1 positive macrophages in addition to expression of the immunosuppressive cytokine, chitinase-3-like 1 (CHI3L1) (Zhao et al, 2020b;Williams et al, 2021;Li et al, 2022).…”