Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study

Abstract

Purpose: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455).

Methods: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS).

Results: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms.

Conclusion: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

FIG 1.

CONSORT diagram. ^aOne patient was randomly assigned to the giredestrant arm but received fulvestrant. ^bFulvestrant (n = 114), letrozole (n = 15), exemestane (n = 20), or anastrozole (n = 2). ^cPatients who discontinued treatment for reasons other than progressive disease. ^dPatients who discontinued treatment because of progressive disease. AE, adverse event; CT, computed tomography; MRI, magnetic resonance imaging; PCET, physician's choice of endocrine therapy.

FIG 2.

INV-PFS, CBR, and ORR in (A) the FAS (primary end point) and in (B) patients with ESR1m tumors; (C) INV-PFS in subgroups of the FAS. aBC, advanced breast cancer; CBR, clinical benefit rate (complete or partial response, or stable disease for ≥6 months, calculated in the FAS); CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; ESR1m, ESR1 mutation; ET, endocrine therapy; FAS, full analysis set; HR, hazard ratio (stratified); INV-PFS, investigator-assessed progression-free survival; mPFS, median progression-free survival; mBC, metastatic breast cancer; NE, not evaluable; ORR, objective response rate (confirmed complete or partial response, calculated in the FAS); PCET, physician's choice of endocrine therapy; PgR, progesterone receptor.