Giredestrant for Estrogen Receptor–Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study
Authors: Martín Miguel , Lim Elgene , Chavez-MacGregor Mariana , Bardia Aditya , Wu Jiong , Zhang Qingyuan , Nowecki Zbigniew , Cruz Felipe Melo , Safin Rustem , Kim Sung-Bae , Schem Christian , Montero Alberto J. , Khan Sarah , Bandyopadhyay Reeti , Moore Heather M. , Shivhare Mahesh , Patre Monika , Martinalbo Jorge , Roncoroni Laura , Pérez-Moreno Pablo Diego , Sohn Joohyuk ,   for the acelERA Breast Cancer Study Investigators, Aguil G. , Alfie M. , Caceres V. , Lerzo G. , Ostoich S. , Boyle F. , Lim E. , Martin H. , Oakman C. , Cruz F.M. , Franke F.A. , Mattar A. , Silva E.H. , Tiscoski K. , Chen W. , Li W. , Tong Z. , Wang J. , Wang S. , Wang X. , Wu J. , Wu X. , Yang J. , Zhang Q. , Emde T.-O. , Gaffunder G. , Hielscher C. , Lux M. , Schem C. , Welslau M. , Schumacher C. , Kuchuk I. , Peretz T. , Ryvo L. , Yerushalmi R. , Chae H. , Chae Y. S. , Im S.-A. , Kim H. J. , Kim J. H. , Kim S.-B. , Lee J. E. , Park Y. H. , Sohn J. , Jarząb M. , Nowaczyk M. , Nowecki Z. , Pienkowski T. , Wojtukiewicz M. , Wysocki P. , Fomin E. , Ganshina I. , Kislov N. , Kopp M. , Kovalenko N. , Makarova Y. , Matrosova M. , Orlova R. , Poltoratsky A. , Safin R. , Zukov R. , Wong A. , Yap Y.S. , Coccia-Portugal M. , Fourie N. , Khanyile R. , Schoeman L. , Chao T.-C. , Chen S.-T. , Chung W.-P. , Feng Y.-H. , Lin Y.-C. , Dejthevaporn T. , Parinyanitikul N. , Sathitruangsak C. , Somwangprasert A. , Tienchaianada P. , Alacacioglu A. , Algin E. , Cabuk D. , Demir C. , Demirci U. , Erdem D. , Gündüz Ş. , Yildirim M.E. , Khan S. , Schmid P. , Sandri I. , Oikonomidou O. , Ansari T. , Konstantis A. , Hrybach S. , Krochkin A. , Lipetska O. , Osinskii D. , Hrybach S. , Krochkin A. , Lipetska O. , Osinskii D. , Andersen J.C. , Cairo M. , Cobb P. , Konala V. , McCune S.L. , Montero A.J. , Patt D.A. , Sanchez-Rivera I. , Strain S. , Wendell K. 
Published: March 2024

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.