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Giredestrant

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Giredestrant
Clinical data
Other namesGDC-9545, RG6171, RO7197597
Identifiers
  • 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol
CAS Number
PubChem CID
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC27H31F5N4O
Molar mass522.564 g·mol−1
3D model (JSmol)
  • C[C@@H]1CC2=C([C@H](N1CC(CO)(F)F)C3=C(C=C(C=C3F)NC4CN(C4)CCCF)F)NC5=CC=CC=C25
  • InChI=InChI=1S/C27H31F5N4O/c1-16-9-20-19-5-2-3-6-23(19)34-25(20)26(36(16)14-27(31,32)15-37)24-21(29)10-17(11-22(24)30)33-18-12-35(13-18)8-4-7-28/h2-3,5-6,10-11,16,18,26,33-34,37H,4,7-9,12-15H2,1H3/t16-,26-/m1/s1
  • Key:GQCXHIKRWBIQMD-AKJBCIBTSA-N

Giredestrant (also known as GDC-9545, RG6171, or RO7197597) is an investigational oral selective estrogen receptor degrader (SERD) developed by Genentech, a member of the Roche Group, for the treatment of estrogen receptor-positive (ER+), HER2-negative advanced breast cancer, as well as endometrial cancer, ovarian cancer, and other solid tumors.[1][2]

It is a potent, nonsteroidal compound that antagonizes estrogen effects by competitively binding to both wild-type and mutant estrogen receptors with nanomolar potency.[1][3] Giredestrant works by inducing an inactive conformation of the estrogen receptor ligand-binding domain and promoting proteasome-mediated degradation of the receptor protein.[1][4][5]

As of May 2025, giredestrant is in clinical trials and has received Fast Track designation from the Food and Drug Administration (FDA) for ER+, HER2-negative second- and third-line metastatic breast cancer.[6][7]

Mechanism of action

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Giredestrant is a nonsteroidal SERD that binds the estrogen receptor (ER), including wild-type and mutant forms (e.g., ESR1 mutation), inducing a conformational change in the receptor’s ligand-binding domain. This promotes proteasome-mediated ER degradation, preventing ER-mediated signaling critical for tumor growth in ER+ breast cancer.[8][9]

Compared to selective estrogen receptor modulators (SERMs) or aromatase inhibitors, giredestrant’s degradation mechanism better addresses resistance in ESR1-mutated tumors.[10]

Research

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In clinical trials, giredestrant has been evaluated in patients with ER+, HER2-negative breast cancer and other solid tumors, including endometrial and ovarian cancers, including those with ESR1 mutations, both as a single agent and in combination with other therapies.[2][11] Its orally bioavailable.[3][4]

Breast Cancer

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  • acelERA (NCT04576455): A Phase II study compared giredestrant (30 mg oral daily) to physician’s choice of endocrine therapy (e.g., fulvestrant, aromatase inhibitors) in patients with 1–2 prior lines of systemic therapy for ER+, HER2-negative advanced breast cancer. At the clinical cutoff (February 18, 2022), the hazard ratio (HR) for progression-free survival (PFS) was 0.81 (95% CI, 0.60–1.10; P = 0.1757), showing no statistically significant improvement. A stronger PFS trend was observed in ESR1-mutated tumors (HR 0.60, 95% CI, 0.35–1.03).[6]
  • pionERA (NCT04478266): A Phase III, randomized, open-label study evaluating giredestrant versus fulvestrant, both combined with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib), in patients with ER+, HER2-negative advanced breast cancer resistant to prior adjuvant endocrine therapy.[3]
  • lidERA (NCT04546002): A Phase III study comparing adjuvant giredestrant to physician’s choice of endocrine monotherapy in ER+, HER2-negative early breast cancer.[12]
  • persevERA (NCT04687236): A Phase III study comparing giredestrant plus palbociclib and placebo versus letrozole plus palbociclib and placebo in first-line metastatic ER+, HER2-negative breast cancer.[13]
  • evERA (NCT05306340): A Phase III trial evaluating giredestrant with everolimus in ER+, HER2-negative advanced breast cancer post-CDK4/6 inhibitors.[14]
  • morpheus (NCT04802759): A Phase I study assessing giredestrant with various combinations, including the immune checkpoint inhibitor atezolizumab, in metastatic breast cancer.[15]

Other Indications

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  • Endometrial Cancer: Phase II trials are evaluating giredestrant for recurrent or persistent endometrial cancer.[12]
  • Ovarian Cancer: Phase II studies are exploring giredestrant in rare ovarian cancers.[1]

Safety and adverse effects

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Giredestrant is generally well-tolerated, with a safety profile similar to endocrine therapies like fulvestrant. Common adverse events from the acelERA study and other trials include fatigue, nausea, arthralgia, diarrhea, hot flashes, headache, and musculoskeletal pain. ematologic effects (e.g., thrombocytopenia, anemia), liver enzyme elevations, and ovarian cysts (a class effect of SERDs) have been reported. Bradycardia was observed at higher doses but mitigated at the 30 mg dose used in pivotal trials.[6][14]

References

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  1. ^ a b c d "Giredestrant (GDC-9545)". NCI Formulatry. U.S. National Cancer Institute.
  2. ^ a b Malhi V, Agarwal P, Gates MR, Liu L, Wang J, De Bruyn T, et al. (December 2023). "Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer". Cancer Research Communications. 3 (12): 2551–2559. doi:10.1158/2767-9764.CRC-23-0324. PMC 10722959. PMID 38019116.
  3. ^ a b c "A clinical study to compare giredestrant with fulvestrant, both combined with a targeted therapy (CDK4/6 inhibitor) in people with ER‑positive, HER2-negative breast cancer that has come back after adjuvant hormone therapy". Roche.
  4. ^ a b Jhaveri KL, Bellet M, Turner NC, Loi S, Bardia A, Boni V, et al. (February 2024). "Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer". Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 30 (4): 754–766. doi:10.1158/1078-0432.CCR-23-1796. PMC 10870118. PMID 37921755.
  5. ^ Liang J, Zbieg JR, Blake RA, Chang JH, Daly S, DiPasquale AG, et al. (August 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. 64 (16): 11841–11856. doi:10.1021/acs.jmedchem.1c00847. PMID 34251202.
  6. ^ a b c Kalinsky K, Oliveira M, Traina T (Jan 2023). "Giredestrant and Physician's Choice of Endocrine Monotherapy for ER+, HER2-Negative Advanced Breast Cancer: Results From the Phase II acelERA Study". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 41 (2): 198–205. doi:10.1200/JCO.22.01209 (inactive 30 May 2025). PMC 9839304. PMID 36332179.{{cite journal}}: CS1 maint: DOI inactive as of May 2025 (link)
  7. ^ "Giredestrant: A Promising New Treatment for Breast Cancer". ClinicalTrials.eu. Retrieved 2025-05-30.
  8. ^ Jeselsohn R, Dalton A, Bardia A (May 2024). "Next-Generation Selective Estrogen Receptor Degraders for the Treatment of Breast Cancer". Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 56 (3): 75–79. doi:10.1158/1078-0432.CCR-23-2390. PMID 38416409.
  9. ^ Martin L, Ribbons A, Patel A (2023). "Targeting ESR1-Mutant Breast Cancer with Giredestrant". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 41 (16_suppl): 1016. doi:10.1200/JCO.2023.41.16_suppl.1016.
  10. ^ Hurvitz S, Chia S, Turner N (2023). "Novel Selective Estrogen Receptor Degraders: A Review of Preclinical and Clinical Advances". Endocrinology. 164 (4): bqad027. doi:10.1210/endocr/bqad027. PMID 36762961.
  11. ^ Lawrence L (25 July 2024). "Giredestrant Bests Anastrozole in ER+, HER2- Early Breast Cancer".
  12. ^ a b "Clinical Trials Using Giredestrant". National Cancer Institute. Retrieved 2025-05-30.
  13. ^ "A trial of giredestrant (GDC-9545) for breast cancer (persevERA Breast Cancer)". Cancer Research UK. 25 May 2021. Retrieved 2025-05-30.
  14. ^ a b "Health Technology Briefing March 2025" (PDF). NIHR Innovation Observatory. Retrieved 2025-05-30.
  15. ^ "A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic Breast Cancer (Morpheus)". ClinicalTrials.gov. 8 May 2025. Retrieved 2025-05-30.

Further reading

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