Sponsor: Hoffmann-La Roche (industry)
Phase: 3
Start date: Dec. 11, 2023
Planned enrollment: 1050
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)
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)
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
Goal: To determine whether the oral selective estrogen receptor degrader (SERD) giredestrant, combined with a CDK4/6 inhibitor, improves progression-free survival compared with fulvestrant plus a CDK4/6 inhibitor in ER-positive, HER2-negative advanced breast cancer with resistance to prior adjuvant endocrine therapy, with a particular focus on the ESR1-mutated subgroup and the overall population.
Patients: Adults with locally advanced or metastatic ER-positive, HER2-negative breast adenocarcinoma not amenable to curative therapy, with documented ER/HER2 status, measurable or non-measurable disease per RECIST v1.1, ECOG 0–1, and resistance to prior adjuvant endocrine therapy. Baseline ctDNA testing centrally confirms ESR1 mutation status. No prior systemic therapy for advanced disease is allowed; prior adjuvant CDK4/6 inhibitor is permitted if relapse occurred at least 12 months after completion. Pre/perimenopausal women and men receive LHRH agonist therapy. Key exclusions include prior SERD or novel ER-targeting agents, prior systemic therapy for advanced disease, high-risk visceral crisis, significant cardiac disease, or clinically meaningful liver disease.
Design: Multicenter, randomized, open-label, active-controlled Phase III trial with approximately 1050 participants allocated to two arms. Stratification includes ESR1 mutation status based on central ctDNA. Investigator-assessed RECIST v1.1 is used for efficacy endpoints, with long-term follow-up for survival and patient-reported outcomes.
Treatments: Control arm: Fulvestrant plus investigator’s choice of CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Fulvestrant is an intramuscular SERD standard of care in endocrine-resistant ER+ disease. Experimental arm: Giredestrant plus investigator’s choice of CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Giredestrant is an investigational oral SERD that binds and degrades the estrogen receptor, inhibiting ER-driven transcription in both wild-type and ESR1-mutant tumors. In Phase II studies, giredestrant demonstrated significant suppression of proliferation markers in early disease and a numerical, non-significant improvement in progression-free survival versus physician’s choice endocrine therapy in previously treated advanced disease, with a signal of greater activity in ESR1-mutant tumors. Safety to date appears comparable to standard endocrine therapies with low rates of grade ≥3 treatment-related adverse events. All pre/perimenopausal women and men receive LHRH agonists per local guidelines.
Outcomes: Primary endpoints are progression-free survival in the ESR1-mutated subgroup and in the full analysis set. Key secondary endpoints include PFS in the ESR1 no-mutation-detected subgroup, overall survival, confirmed objective response rate, duration of response, clinical benefit rate, time to chemotherapy, and multiple patient-reported outcomes assessing time to confirmed deterioration in pain, pain interference, physical and role functioning, and global health status/quality of life. Safety endpoints include incidence and severity of adverse events per NCI CTCAE v5.0, and the frequency of vital sign and laboratory abnormalities.
Burden on patient: Overall burden is moderate and similar to standard first-line endocrine plus CDK4/6 therapy. Requirements include baseline ctDNA for ESR1 status, routine clinic visits for CDK4/6 monitoring, periodic laboratory assessments for hematologic and biochemical parameters, and imaging per RECIST at standard intervals. Patients in the fulvestrant arm undergo intramuscular injections, while giredestrant is oral. Use of LHRH agonists for pre/perimenopausal women and men adds scheduled injections. Patient-reported outcome questionnaires will be administered regularly. No intensive pharmacokinetic sampling or mandatory fresh tumor biopsies are indicated, which helps limit additional burden beyond standard-of-care monitoring for CDK4/6-based regimens.
Last updated: Oct 2025
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
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Seoul, 06273, South Korea
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Status: Recruiting
Seoul, 02841, South Korea
No email / No phone
Status: Recruiting
Daegu, 41404, South Korea
No email / No phone
Status: Recruiting
Seoul, 135-710, South Korea
No email / No phone
Status: Recruiting
Seongnam-si, 13620, South Korea
No email / No phone
Status: Recruiting
Seoul, 03080, South Korea
No email / No phone
Status: Recruiting
Seoul, 03722, South Korea
No email / No phone
Status: Recruiting
Ulsan, 44033, South Korea
No email / No phone
Status: Recruiting
Madrid, 28033, Spain
No email / No phone
Status: Recruiting
Jaén, 23007, Spain
No email / No phone
Status: Recruiting
Valencia, 46015, Spain
No email / No phone
Status: Recruiting
Huelva, 21005, Spain
No email / No phone
Status: Recruiting
Barcelona, 08028, Spain
No email / No phone
Status: Recruiting
Seville, 41009, Spain
No email / No phone
Status: Recruiting
Seville, 41013, Spain
No email / No phone
Status: Recruiting
Madrid, 28050, Spain
No email / No phone
Status: Recruiting
Valencia, 46009, Spain
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 Alarcón, 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
Taichung, 404, Taiwan
No email / No phone
Status: Recruiting
Hsinchu, 300, Taiwan
No email / No phone
Status: Recruiting
Taipei, 11259, Taiwan
No email / No phone
Status: Recruiting
Taipei, 100, Taiwan
No email / No phone
Status: Recruiting
Taipei, 00112, Taiwan
No email / No phone
Status: Recruiting
Xitun Dist., 40705, Taiwan
No email / No phone
Status: Recruiting
Lak Si, 10210, Thailand
No email / No phone
Status: Recruiting
Bangkok, 10330, Thailand
No email / No phone
Status: Recruiting
Muang Chiang MAI Delivery Branch 3, 50200, Thailand
No email / No phone
Status: Recruiting
Bangkok, 10400, Thailand
No email / No phone
Status: Recruiting
Bangkok, 10400, Thailand
No email / No phone
Status: Recruiting
Songkhla, 90110, Thailand
No email / No phone
Status: Recruiting
Ankara, 06800, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Bakirkoy / Istanbul, 34147, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Kadiköy, 34722, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Sihhiye/Ankara, 06230, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Izmir, 35360, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Samsun, 55200, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Mersin, 33240, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Adapazarı, 54290, Turkey (Türkiye)
No email / No phone
Status: Recruiting
Daphne, Alabama, 36526, United States
No email / No phone
Status: Recruiting
Harbor City, California, 90710, 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
Auburn, California, 95602, United States
No email / No phone
Status: Recruiting
Sacramento, California, 95816, 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
Newport Beach, California, 92663, United States
No email / No phone
Status: Recruiting
Los Angeles, California, 90033, United States
No email / No phone
Status: Recruiting
Littleton, Colorado, 80120-4413, United States
No email / No phone
Status: Recruiting
Washington D.C., District of Columbia, 20007, United States
No email / No phone
Status: Recruiting
Washington D.C., District of Columbia, 20010, United States
No email / No phone
Status: Recruiting
Altamonte Springs, Florida, 32701, United States
No email / No phone
Status: Recruiting
Jacksonville, Florida, 32256, United States
No email / No phone
Status: Recruiting
St. Petersburg, Florida, 33709, United States
No email / No phone
Status: Recruiting
Fort Myers, Florida, 33901, 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
Atlanta, Georgia, 30303, United States
No email / No phone
Status: Recruiting
Atlanta, Georgia, 30329, United States
No email / No phone
Status: Recruiting
Park Ridge, Illinois, 60068, United States
No email / No phone
Status: Recruiting
Springfield, Illinois, 62702, United States
No email / No phone
Status: Recruiting
Des Moines, Iowa, 50309, United States
No email / No phone
Status: Recruiting
Lexington, Kentucky, 40509, United States
No email / No phone
Status: Recruiting
Lexington, Kentucky, 40503, United States
No email / No phone
Status: Recruiting
Louisville, Kentucky, 40207, 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
East Brunswick, New Jersey, 08816, United States
No email / No phone
Status: Recruiting
Pennington, New Jersey, 08534, 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
Medford, Oregon, 97504-8332, United States
No email / No phone
Status: Recruiting
Philadelphia, Pennsylvania, 19106, 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
York, Pennsylvania, 17403, 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
Sioux Falls, South Dakota, 57105, United States
No email / No phone
Status: Recruiting
Aberdeen, South Dakota, 57401, 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
Fort Worth, Texas, 76104, 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
Fairfax, Virginia, 22031, United States
No email / No phone
Status: Recruiting
Richmond, Virginia, 23219, 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
Green Bay, Wisconsin, 54311, United States
No email / No phone
Status: Recruiting
Milwaukee, Wisconsin, 53215, United States
No email / No phone
Status: Recruiting
Montreal, Quebec, H4A 3J1, Canada
No email / No phone
Status: Withdrawn
San José, 11303, Costa Rica
No email / No phone
Status: Withdrawn
New Delhi, National Capital Territory of Delhi, 110017, India
No email / No phone
Status: Withdrawn
Trujillo, 13011, Peru
No email / No phone
Status: Withdrawn
Cape Town, 7700, South Africa
No email / No phone
Status: Withdrawn
Cincinnati, Ohio, 45242, United States
No email / No phone
Status: Withdrawn