Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen
Komal L Jhaveri1, Meritxell Bellet2, Nicholas C Turner3
1Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York, and Weill Cornell Medical College, New York, New York.
Purpose:
Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797).
Patients And Methods:
Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy.
Results:
As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors.
Conclusions:
Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.
Insights
Giredestrant, a novel oral treatment, showed good tolerability and clinical activity in patients with advanced ER+ breast cancer who had prior endocrine therapy. Further trials are recommended for this promising breast cancer therapeutic.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Estrogen receptor-positive (ER+) breast cancer remains a significant health concern, necessitating novel therapeutic strategies.
- Selective estrogen receptor antagonists and degraders represent a promising class of drugs for ER+ breast cancer treatment.
- Giredestrant is an investigational next-generation oral agent targeting the estrogen receptor pathway.
Purpose of the Study:
- To present the primary analysis results of the phase Ia/b GO39932 study evaluating giredestrant in ER+ breast cancer.
- To assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of single-agent giredestrant and giredestrant in combination with palbociclib.
Main Methods:
- Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy were enrolled.
- Treatment arms included single-agent giredestrant at various doses or giredestrant combined with palbociclib and/or an LHRH agonist.
- Safety, pharmacokinetics, pharmacodynamics, and efficacy endpoints were evaluated, with detailed cardiovascular assessments for giredestrant 100 mg.
Main Results:
- No dose-limiting toxicity was observed, and the maximum tolerated dose (MTD) was not reached in 175 enrolled patients.
- Giredestrant was generally well tolerated, with dose-dependent asymptomatic bradycardia noted but no clinically significant cardiac events.
- Clinical benefit was observed across all treatment cohorts, including in patients with ESR1-mutated tumors.
Conclusions:
- Giredestrant demonstrated favorable tolerability and clinical activity in patients with ER+ breast cancer who had progressed on prior endocrine therapy.
- The observed safety and efficacy profile supports further investigation of giredestrant in randomized clinical trials.
- Giredestrant holds potential as a valuable therapeutic option for both early- and late-stage ER+ breast cancer.
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