Sponsor: Hoffmann-La Roche (industry)
Phase: 3
Start date: Dec. 11, 2023
Planned enrollment: 1050
Giredestrant, also known as GDC-9545, is an investigational oral selective estrogen receptor degrader (SERD) developed for the treatment of estrogen receptor-positive (ER+), HER2-negative breast cancer. It is designed to degrade the estrogen receptor, thereby inhibiting ER-mediated signaling pathways critical for tumor growth in ER+ breast cancer.
Giredestrant binds to the estrogen receptor, inducing a conformational change that promotes proteasome-mediated degradation of the receptor. This degradation prevents ER-mediated transcriptional activity, effectively inhibiting the proliferation of ER+ breast cancer cells. Notably, giredestrant has demonstrated activity against both wild-type and mutant forms of the estrogen receptor, including ESR1 mutations, which are often associated with resistance to standard endocrine therapies. (pmc.ncbi.nlm.nih.gov)
Early Breast Cancer:
In the phase II coopERA Breast Cancer study, giredestrant was evaluated as a neoadjuvant treatment in postmenopausal women with untreated ER+/HER2− early breast cancer. The study met its primary endpoint, showing a statistically significant greater reduction in the proliferation marker Ki67 after two weeks of treatment compared to anastrozole (75% vs. 67%, respectively; p=0.0433). Additionally, the complete cell cycle arrest rate was higher with giredestrant (20%) compared to anastrozole (14%). (ascopubs.org)
Advanced Breast Cancer:
The phase II acelERA Breast Cancer study assessed giredestrant in patients with ER+/HER2− locally advanced or metastatic breast cancer who had received 1–2 prior lines of systemic therapy. Giredestrant provided a numerical, but not statistically significant, improvement in progression-free survival (PFS) over physician’s choice of endocrine therapy (median PFS: 5.6 months vs. 5.4 months; hazard ratio, 0.81; p=0.1757). A more pronounced effect was observed in patients with ESR1 mutations. (ascopubs.org)
Giredestrant has been generally well-tolerated across clinical trials. In the coopERA study, adverse events (AEs) were non-serious and occurred at similar rates between the giredestrant and anastrozole arms, with related Grade ≥3 AEs reported in 6% of patients in each group. (ascopubs.org) In the acelERA study, the safety profile of giredestrant was comparable to that of standard endocrine therapies, with Grade 3 or 4 treatment-related AEs occurring in 4% of patients receiving giredestrant and 3% of those receiving physician’s choice of endocrine therapy. (ascopubs.org)
Last updated: Aug 2025
As of August 3, 2025, the Phase III clinical trial NCT06065748 is ongoing and actively recruiting participants. The trial commenced on December 11, 2023, with an estimated primary completion date of July 30, 2026. The study aims to evaluate the efficacy and safety of giredestrant compared with fulvestrant, both in combination with a CDK4/6 inhibitor, in patients with estrogen receptor-positive (ER+), HER2-negative advanced breast cancer who have developed resistance to prior adjuvant endocrine therapy. (cdek.pharmacy.purdue.edu)
While specific results from NCT06065748 are not yet available, related studies provide context for giredestrant's development:
AcelERA Study: A Phase II trial comparing giredestrant to physician's choice of endocrine therapy in previously treated ER+, HER2-negative advanced breast cancer. The study did not meet its primary endpoint of progression-free survival but indicated a favorable trend in patients with ESR1 mutations. (ascopubs.org)
CoopERA Study: A Phase II trial assessing neoadjuvant giredestrant plus palbociclib versus anastrozole plus palbociclib in ER+, HER2-negative early breast cancer. Giredestrant demonstrated a stronger antiproliferative effect, as indicated by a greater reduction in Ki67 scores, compared to anastrozole. (ascopost.com)
Giredestrant has received Fast Track designation from the U.S. Food and Drug Administration (FDA) in 2022, recognizing its potential to address an unmet medical need in ER+, HER2-negative advanced breast cancer. Additionally, the European Medicines Agency (EMA) has included giredestrant in its Priority Medicines (PRIME) scheme, facilitating earlier access in Europe. (drugpatentwatch.com)
Last updated: Aug 2025
Goal: To compare the efficacy and safety of giredestrant versus fulvestrant, each combined with a CDK4/6 inhibitor, in patients with ER-positive, HER2-negative advanced breast cancer who have developed resistance to prior adjuvant endocrine therapy.
Patients: Adult patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer, with resistance to prior adjuvant endocrine therapy, measurable or non-measurable (including bone-only) disease, ECOG performance status 0-1, and known ESR1 mutation status. No prior systemic therapy for advanced disease or prior SERD/novel ER-targeting agents allowed. Both male and female patients are eligible, with LHRH agonist required for pre/perimenopausal women and men.
Design: Randomized, open-label, multicenter phase III trial with two parallel arms. Patients are stratified by ESR1 mutation status and receive investigator's choice of CDK4/6 inhibitor with either fulvestrant or giredestrant.
Treatments: The control arm receives fulvestrant, a standard intramuscular SERD, plus the investigator's choice of a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). The experimental arm receives giredestrant, an oral selective estrogen receptor degrader (SERD) that targets and degrades both wild-type and mutant estrogen receptors, including those with ESR1 mutations implicated in endocrine resistance. Prior trials of giredestrant have shown promising activity, particularly in patients with ESR1 mutations, and a generally favorable safety profile. Both arms also require LHRH agonist for hormone suppression in pre/perimenopausal women and men.
Outcomes: Primary endpoints are progression-free survival (PFS) in the ESR1 mutation subset and the full analysis set. Key secondary endpoints include PFS in the ESR1 no-mutation-detected subset, overall survival, objective response rate, duration of response, clinical benefit rate, time to chemotherapy, and several patient-reported outcomes related to pain, physical and role functioning, and quality of life. Safety endpoints include incidence and severity of adverse events, vital sign abnormalities, and laboratory test abnormalities. All time frames extend up to five years.
Burden on patient: Burden on patients is estimated to be low to moderate. The trial involves standard procedures for advanced breast cancer such as regular imaging (per RECIST criteria), laboratory monitoring, and safety assessments. There is a baseline ctDNA sample for ESR1 mutation testing, which may require one additional blood draw, but no mandatory extra biopsies. Treatments are either standard of care oral or intramuscular agents combined with standard oral CDK4/6 inhibitors. Patients will require site visits for drug administration and assessments, but the visit frequency and monitoring reflect current practice standards, keeping the trial burden similar to routine care.
Inclusion Criteria:
* Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
* Documented estrogen receptor-positive (ER+), HER2-negative (HER2-) tumor assessed locally on the most recent tumor biopsy (or an archived tumor sample if a recent tumor sample is not available for testing)
* Confirmed ESR1 mutation status (ESR1m versus ESR1nmd) in baseline circulating tumor DNA (ctDNA) through central laboratory testing
* Resistance to prior adjuvant endocrine therapy (ET), which is defined as having relapsed with prior standard adjuvant ET, on-treatment after \>/=12 months or off-treatment within 12 months of completion. Prior use of adjuvant CDK4/6i is allowed (if relapse occurred \>/=12 months since completion).
* No prior systemic anti-cancer therapy for advanced disease
* Measurable disease as defined per RECIST v.1.1 or non-measurable (including bone-only) disease
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
* For pre/perimenopausal women and for men: willing to undergo and maintain treatment with approved LHRH agonist therapy (as per local guidelines) for the duration of study treatment
Exclusion Criteria:
* Prior systemic therapy (e.g., prior chemotherapy, immunotherapy, or biologic therapy) for locally advanced unresectable or metastatic breast cancer
* Prior treatment with another SERD (e.g., fulvestrant, oral SERDs) or novel ER-targeting agents
* Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
* Active cardiac disease or history of cardiac dysfunction
* Clinically significant history of liver disease
San Juan, J5400, Argentina
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Status: Recruiting
Singapore, 119228, Singapore
No email / No phone
Status: Recruiting
Ljubljana, 1000, Slovenia
No email / No phone
Status: Recruiting
Cape Town, 7700, South Africa
No email / No phone
Status: Recruiting
Port Elizabeth, 6045, South Africa
No email / No phone
Status: Recruiting
Badalona, Barcelona, 08916, Spain
No email / No phone
Status: Recruiting
Sant Andreu de La Barca, Barcelona, 08740, Spain
No email / No phone
Status: Recruiting
Jerez de La Frontera, Cadiz, 11407, Spain
No email / No phone
Status: Recruiting
Pozuelo de Alarcon, Madrid, 28223, Spain
No email / No phone
Status: Recruiting
EL Palmar (EL Palmar), Murcia, 30120, Spain
No email / No phone
Status: Recruiting
Vigo, Pontevedra, 36213, Spain
No email / No phone
Status: Recruiting
Jaen, 23007, Spain
No email / No phone
Status: Recruiting
Barcelona, 08028, Spain
No email / No phone
Status: Recruiting
Huelva, 21005, Spain
No email / No phone
Status: Recruiting
Madrid, 28033, Spain
No email / No phone
Status: Recruiting
Madrid, 28050, Spain
No email / No phone
Status: Recruiting
Sevilla, 41009, Spain
No email / No phone
Status: Recruiting
Sevilla, 41013, Spain
No email / No phone
Status: Recruiting
Valencia, 46009, Spain
No email / No phone
Status: Recruiting
Valencia, 46015, Spain
No email / No phone
Status: Recruiting
Taipei City, 11259, Taiwan
No email / No phone
Status: Recruiting
Taipei, 00112, Taiwan
No email / No phone
Status: Recruiting
Taipei, 100, Taiwan
No email / No phone
Status: Recruiting
Hsinchu City, 300, Taiwan
No email / No phone
Status: Recruiting
Xitun Dist., 40705, Taiwan
No email / No phone
Status: Recruiting
Taichung, 404, Taiwan
No email / No phone
Status: Recruiting
Bangkok, 10400, Thailand
No email / No phone
Status: Recruiting
Bangkok, 10400, Thailand
No email / No phone
Status: Recruiting
Bangkok, 10330, Thailand
No email / No phone
Status: Recruiting
Songkhla, 90110, Thailand
No email / No phone
Status: Recruiting
Muang Chiang MAI Delivery Branch 3, 50200, Thailand
No email / No phone
Status: Recruiting
Lak Si, 10210, Thailand
No email / No phone
Status: Recruiting
Sihhiye/Ankara, 06230, Turkey
No email / No phone
Status: Recruiting
Mersin, 33240, Turkey
No email / No phone
Status: Recruiting
Kadiköy, 34722, Turkey
No email / No phone
Status: Recruiting
Izmir, 35360, Turkey
No email / No phone
Status: Recruiting
Bakirkoy / Istanbul, 34147, Turkey
No email / No phone
Status: Recruiting
Ankara, 06800, Turkey
No email / No phone
Status: Recruiting
Adapazar?, 54290, Turkey
No email / No phone
Status: Recruiting
Samsun, 55200, Turkey
No email / No phone
Status: Recruiting
Daphne, Alabama, 36526, United States
No email / No phone
Status: Recruiting
Sacramento, California, 95816, United States
No email / No phone
Status: Recruiting
Auburn, California, 95602, United States
No email / No phone
Status: Recruiting
Glendale, California, 91260, United States
No email / No phone
Status: Recruiting
Greenbrae, California, 94904, United States
No email / No phone
Status: Recruiting
Harbor City, California, 90710, United States
No email / No phone
Status: Recruiting
Los Angeles, California, 90033, United States
No email / No phone
Status: Recruiting
Newport Beach, California, 92663, United States
No email / No phone
Status: Recruiting
Roseville, California, 95661, United States
No email / No phone
Status: Recruiting
Torrance, California, 90502, United States
No email / No phone
Status: Recruiting
Littleton, Colorado, 80120-4413, United States
No email / No phone
Status: Recruiting
Washington, District of Columbia, 20010, United States
No email / No phone
Status: Recruiting
Washington, District of Columbia, 20007, United States
No email / No phone
Status: Recruiting
Jacksonville, Florida, 32256, United States
No email / No phone
Status: Recruiting
Saint Petersburg, Florida, 33709, United States
No email / No phone
Status: Recruiting
West Palm Beach, Florida, 33401-3406, United States
No email / No phone
Status: Recruiting
Tampa, Florida, 33603, United States
No email / No phone
Status: Recruiting
Altamonte Springs, Florida, 32701, United States
No email / No phone
Status: Recruiting
Fort Myers, Florida, 33908, United States
No email / No phone
Status: Recruiting
Atlanta, Georgia, 30303, United States
No email / No phone
Status: Recruiting
Atlanta, Georgia, 30329, United States
No email / No phone
Status: Recruiting
Springfield, Illinois, 62702, United States
No email / No phone
Status: Recruiting
Park Ridge, Illinois, 60068, United States
No email / No phone
Status: Recruiting
Des Moines, Iowa, 50309, United States
No email / No phone
Status: Recruiting
Louisville, Kentucky, 40207, United States
No email / No phone
Status: Recruiting
Lexington, Kentucky, 40503, United States
No email / No phone
Status: Recruiting
Lexington, Kentucky, 40509, United States
No email / No phone
Status: Recruiting
Scarborough, Maine, 04074, United States
No email / No phone
Status: Recruiting
Frederick, Maryland, 21702, United States
No email / No phone
Status: Recruiting
Annapolis, Maryland, 21401, United States
No email / No phone
Status: Recruiting
Boston, Massachusetts, 02215, United States
No email / No phone
Status: Recruiting
Detroit, Michigan, 48202, United States
No email / No phone
Status: Recruiting
O'Fallon, Missouri, 62269, United States
No email / No phone
Status: Recruiting
Kansas City, Missouri, 64132, United States
No email / No phone
Status: Recruiting
Omaha, Nebraska, 68130-2042, United States
No email / No phone
Status: Recruiting
Pennington, New Jersey, 08534, United States
No email / No phone
Status: Recruiting
East Brunswick, New Jersey, 08816, United States
No email / No phone
Status: Recruiting
Jamaica, New York, 11432, United States
No email / No phone
Status: Recruiting
Raleigh, North Carolina, 27607, United States
No email / No phone
Status: Recruiting
Cincinnati, Ohio, 45242, United States
No email / No phone
Status: Recruiting
Medford, Oregon, 97504-8332, United States
No email / No phone
Status: Recruiting
Philadelphia, Pennsylvania, 19106, United States
No email / No phone
Status: Recruiting
York, Pennsylvania, 17403, United States
No email / No phone
Status: Recruiting
Bensalem, Pennsylvania, 19020, United States
No email / No phone
Status: Recruiting
Lancaster, Pennsylvania, 17604, United States
No email / No phone
Status: Recruiting
Providence, Rhode Island, 02905, United States
No email / No phone
Status: Recruiting
Charleston, South Carolina, 29425, United States
No email / No phone
Status: Recruiting
Aberdeen, South Dakota, 57401, United States
No email / No phone
Status: Recruiting
Sioux Falls, South Dakota, 57105, United States
No email / No phone
Status: Recruiting
Nashville, Tennessee, 37203, United States
No email / No phone
Status: Recruiting
Germantown, Tennessee, 38138, United States
No email / No phone
Status: Recruiting
Irving, Texas, 75063, United States
No email / No phone
Status: Recruiting
Austin, Texas, 78731, United States
No email / No phone
Status: Recruiting
Fort Worth, Texas, 76104, United States
No email / No phone
Status: Recruiting
Richmond, Virginia, 23219, United States
No email / No phone
Status: Recruiting
Fairfax, Virginia, 22031, United States
No email / No phone
Status: Recruiting
Tacoma, Washington, 98405, United States
No email / No phone
Status: Recruiting
Morgantown, West Virginia, 26056, United States
No email / No phone
Status: Recruiting
Milwaukee, Wisconsin, 53215, United States
No email / No phone
Status: Recruiting
Green Bay, Wisconsin, 54311, United States
No email / No phone
Status: Recruiting