Investigational Drug
Giredestrant
TrialFetch AI Analysis
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Overview
Giredestrant (GDC‑9545) is an investigational, oral selective estrogen receptor degrader (SERD) and full ER antagonist being developed for ER‑positive/HER2‑negative breast cancer across early and advanced disease settings. It has shown antiproliferative activity in neoadjuvant early breast cancer and has mixed results in metastatic disease to date, including one negative phase II trial versus physician’s‑choice endocrine therapy and a positive phase III combination trial reported by press release in the post‑CDK4/6 inhibitor setting. (pubs.acs.org)
Mechanism of action
- Potent, non‑steroidal oral SERD that competitively binds ERα, induces receptor degradation via the proteasome, and fully antagonizes ER signaling, leading to suppression of ER‑dependent transcription and tumor cell proliferation. Preclinical studies showed activity in both ESR1 wild‑type and ESR1‑mutant models. (pubs.acs.org)
Efficacy
Early breast cancer (neoadjuvant, coopERA BC; phase II) - In a randomized neoadjuvant study (n=221), giredestrant produced a greater relative geometric mean reduction in Ki‑67 at 2 weeks than anastrozole (−75% vs −67%; p=0.043). With added palbociclib for 16 weeks, Ki‑67 suppression at surgery remained greater (−81% vs −74%), while objective response rates were similar (50% vs 49%); pathologic complete response was ~4–5% in both arms. (thelancet.com)
Previously treated advanced/metastatic disease (acelERA BC; phase II) - Randomized, open‑label study (n=303) comparing giredestrant vs physician’s‑choice endocrine therapy (mostly fulvestrant) did not meet the primary endpoint: investigator‑assessed PFS HR 0.81 (95% CI, 0.60–1.10; P=0.176); median PFS 5.6 vs 5.4 months. Prespecified subgroup analysis suggested a larger, non‑significant effect in ESR1‑mutated tumors (HR 0.60; 95% CI, 0.35–1.03). (ascopubs.org)
Post‑CDK4/6 inhibitor advanced/metastatic disease (evERA BC; phase III, combination with everolimus) - Company press release (Sept 22, 2025) reported evERA met both co‑primary endpoints, with statistically significant and clinically meaningful PFS improvement for giredestrant + everolimus vs standard endocrine therapy + everolimus in the intention‑to‑treat and ESR1‑mutated populations; OS data immature. Full peer‑reviewed results are pending. (globenewswire.com)
Other ongoing phase III programs - First‑line metastatic with palbociclib (persevERA; NCT04546009) and adjuvant early disease (lidERA; NCT04961996) are ongoing; results not yet published in peer‑reviewed venues as of October 7, 2025. (inclinicaltrials.com)
Safety
- Across studies to date, giredestrant has been generally well tolerated with a safety profile comparable to endocrine therapy controls.
- In acelERA BC (phase II), treatment‑related grade 3–4 AEs occurred in 4.0% with giredestrant vs 2.6% with control; treatment‑related serious AEs 2.0% vs 0.7%; discontinuations due to AEs 1.3% vs 2.0%. (ascopost.com)
- In coopERA BC, endocrine therapy–related AEs and grade ≥3 events were similar between giredestrant and anastrozole arms (both 6% grade ≥3 in final analysis). Patient‑reported outcomes showed manageable symptom burden. (ascopubs.org)
- Phase Ib experience (monotherapy and with palbociclib) described giredestrant as well‑tolerated; common AEs (≥10%) with monotherapy included fatigue, cough, back pain, pain in extremity, and arthralgia. (ascopubs.org)
- Press release for evERA reported the combination with everolimus was well tolerated with no new safety signals; detailed rates await full presentation/publication. (globenewswire.com)
Further reading
- Journal of Medicinal Chemistry paper describing discovery and preclinical profile of giredestrant. (pubs.acs.org)
- Lancet Oncology publication of coopERA BC neoadjuvant trial. (thelancet.com)
- Journal of Clinical Oncology publication of the phase II acelERA BC trial. (ascopubs.org)
- ASCO Meeting Abstracts for coopERA BC final analysis and PROs. (ascopubs.org)
- Phase Ib combination/monotherapy experience (ASCO abstract). (ascopubs.org)
- Company press release summarizing positive phase III evERA results (pending peer‑reviewed presentation). (globenewswire.com)
Notes: Giredestrant remains investigational; no regulatory approvals are documented as of October 7, 2025. Where only press releases are available (evERA), conclusions should be considered preliminary until peer‑reviewed data are published. (globenewswire.com)
Last updated: Oct 2025
Active trials using Giredestrant
Found 4 active trials using this drug:
TrialFetch AI summary: Adults with ER-positive, HER2-negative locally advanced/metastatic breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy (ECOG 0–1) are enrolled to receive GDC-4198—an oral next-generation cyclin-dependent kinase inhibitor with potent CDK4 and additional CDK2 activity—alone or with the oral SERD giredestrant, and in Phase II are randomized to GDC-4198 + giredestrant (two dose levels) versus abemaciclib + giredestrant. Excludes visceral crisis requiring chemotherapy and prior chemotherapy for metastatic disease.
ClinicalTrials.gov ID: NCT07100106
TrialFetch AI summary: This trial enrolls adult patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who have developed resistance to prior adjuvant endocrine therapy, with no prior systemic treatment for advanced disease. Patients are randomized to receive either fulvestrant (IM SERD) or giredestrant (oral selective estrogen receptor degrader targeting both wild-type and mutant ER), each combined with a CDK4/6 inhibitor of the investigator's choice.
ClinicalTrials.gov ID: NCT06065748
TrialFetch AI summary: Biomarker-driven platform for adults with recurrent/persistent endometrial carcinoma after 1–2 prior lines, assigning patients by FoundationOne CDx to targeted doublets with or without the PD‑L1 inhibitor atezolizumab. Active cohorts include atezolizumab plus talazoparib for high genomic LOH, atezolizumab plus anti‑TIGIT tiragolumab for MSI‑H/high TMB tumors, inavolisib (PI3Kα inhibitor) plus letrozole for PIK3CA‑mutant tumors without PTEN/AKT1 alterations, and giredestrant (oral SERD) plus abemaciclib for ER‑positive, RB1‑intact disease.
ClinicalTrials.gov ID: NCT04486352
TrialFetch AI summary: This trial enrolls postmenopausal women with advanced ER+ and/or HER2+ breast cancer who have progressed after standard therapies into multiple cohorts based on subtype, randomizing them to investigational combinations featuring the oral SERD giredestrant (estrogen receptor degrader), CDK7 inhibitor samuraciclib, pan-AKT inhibitor ipatasertib, PI3K inhibitor inavolisib, HER2-targeted agents, immune checkpoint blockade (atezolizumab), and/or standard partners. Patients must have good performance status and meet strict eligibility criteria, with adaptive assignment to novel regimens as new data emerge.
ClinicalTrials.gov ID: NCT04802759
