Roche Announces Positive Phase III evERA Trial Results for Oral SERD Giredestrant in ER+ Advanced Breast Cancer

Sep 23, 2025 07:31 CST Updated 07:31

Roche

Oncology Drug Research, Development, and Manufacturing

Roche announced positive results from its Phase 3 evERA study today. The study compared the efficacy and safety of the investigational therapy giredestrant (GDC-9545) in combination with everolimus versus standard treatment plus everolimus in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had previously received CDK4/6 inhibitors and endocrine therapy.According to the press release, this is the first head-to-head Phase III trial in which an all-oral regimen containing a selective estrogen receptor degrader (SERD) has shown positive results compared to standard combination therapy.

The results of the evERA study show,Compared with standard endocrine therapy combined with everolimus, the combination in the intent-to-treat (ITT) population andESR1The mutation population showed significant and clinically meaningful improvement in progression-free survival (PFS) for both co-primary endpoints.Overall Survival (OS) data are not yet mature, but a clear positive trend has been observed. In terms of safety, giredestrant in combination withPlanWell tolerated, adverse events consistent with the known safety profile of each monotherapy, no new safety signals observed.

Giredestrant is an oral, investigational, potential "best-in-class"Next-generation SERD with full antagonistic effect.It is designed to block the binding of estrogen to estrogen receptors, induce receptor degradation, thereby inhibiting or slowing down the growth of tumor cells.

The R&D team of Genentech, a subsidiary of Roche, onceJournal of Medicinal ChemistryPublished the development process of giredestrant.WuXi AppTec provided assistance for this study.

The researchers pointed out that although the first SERD fulvestrant was approved in 2002, its limitations in drug-like properties allow it to be administered only through intramuscular injection, which restricts its binding to the target and its potency. Therefore,The development of oral SERDs, as well as the improvement of their efficacy, safety, and oral bioavailability, has become a research focus for multiple companies.

First, the research team identified a candidate compound 12 that exhibited high activity in in vitro antagonism, degradation, and proliferation inhibition assays, and demonstrated good oral bioavailability. However, due to its high lipophilicity, this candidate compound showed suboptimal drug-like properties. Based on this candidate compound, the research team conducted a series of chemical modifications. While maintaining its activity, they reduced the molecule's lipophilicity.The final candidate compound 26 showed a 10-fold increase in solubility compared to 12, while also demonstrating 2-5 times higher activity in antagonism, degradation, and proliferation inhibition assays.

Further optimization generated candidate compounds 33 and 35, which exhibited the strongest degradation efficiency while achieving a good balance in activity and drug-likeness.

Image source: Reference [2]

Based on the crystal structures of 35 and ERα, the researchers fine-tuned 35 and developed more candidate compounds. After evaluation through multiple in vitro assays,Confirm 35Not only does it have good degradation efficiency, but it can also effectively inhibit the activity of ERα before degrading it, possessing a dual function of preventing ERα from activating target genes.

In the detection of multiple animal models, 35 not only showed good activity but also in vitro and in vivo studiesShowing goodSafety. Moreover,When used in combination with CDK4/6 inhibitors, it not only showed no adverse drug interactions but also demonstrated enhanced anti-cancer effects in different mouse models.This candidate compound was eventually selected to enter clinical development, namely giredestrant, which is currently being tested in clinical trials.

With the announcement of the positive results from today's Phase 3 clinical trial of giredestrant, this therapy is one step closer to being approved for marketing. Let us look forward to the smooth progress of the drug in subsequent development processes, benefiting breast cancer patients as soon as possible.

References:

[1] Positive phase III results show Roche’s giredestrant significantly improved progression-free survival in ER-positive advanced breast cancer. Retrieved September 22, 2025 from https://www.roche.com/media/releases/med-cor-2025-09-22

[2] Liang et al., (2021). GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer. Journal of Medicinal Chemistry, https://doi.org/10.1021/acs.jmedchem.1c00847

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