A randomized phase II study of fulvestrant with or without ganetespib in patients with endocrine-resistant metastatic breast cancer
Abstract
Background: Patients with endocrine-resistant hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) have limited effective treatment options. Heat shock protein 90 (HSP90) regulates estrogen receptor stability and function; its inhibition has been proposed as a strategy to overcome endocrine resistance. Ganetespib is a second-generation HSP90 inhibitor with demonstrated anti-tumor activity in preclinical breast cancer models.
Methods: In this randomized phase II study, 50 patients with HR+ MBC previously treated with endocrine therapy were randomized 1:2 to fulvestrant alone (n = 15) or fulvestrant with ganetespib (n = 35), respectively. Median age was 53 years. Fulvestrant was administered at standard dosing; ganetespib (200 mg/m2) was given intravenously on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and safety/tolerability.
Results: Median PFS was similar between arms (3.7 vs 3.6 months; log-rank P = .79). Toxicity was higher with ganetespib, with substantially increased diarrhea (97% vs 7%) and nausea (63% vs 40%). Exploratory genomic analysis of on-treatment biopsies (n = 13) showed ESR1 mutations were enriched among patients without clinical benefit, while all patients with clinical benefit exhibited a Luminal A transcriptional subtype. Tumors lacking clinical benefit showed enrichment of proliferative and cell cycle–associated transcriptional programs.
Conclusions: Adding ganetespib to fulvestrant did not improve clinical outcomes and increased toxicity in endocrine-resistant HR+ MBC. Our findings support the hypothesis that ESR1 alterations and proliferative transcriptional activity contribute to established endocrine resistance, limiting the therapeutic impact of HSP90 inhibition in this setting.
Clinical trial registration number: NCT01560416 (ClinicalTrials.gov)
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BibTeX
@article{grinshpun2026randomized,
title = {{A randomized phase II study of fulvestrant with or without ganetespib in patients with endocrine-resistant metastatic breast cancer}},
author = {Albert Grinshpun and Adrienne G Waks and Jingxin Fu and Patrick Kurnia and Hao Guo and Tianyu Li and McKenna Moore and Molly DiLullo and Ashka Patel and Luke Whitesell and Stefan Atanasov and Ann H Partridge and Erica L Mayer and Ian E Krop and Sandro Santagata and Myles Brown and Eric P Winer and Katherine Reeder-Hayes and Carey Anders and Rinath Jeselsohn and Nancy U Lin},
journal = {The Oncologist},
year = {2026},
month = oct,
doi = {10.1093/oncolo/oyag414},
url = {https://doi.org/10.1093/oncolo/oyag414},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - A randomized phase II study of fulvestrant with or without ganetespib in patients with endocrine-resistant metastatic breast cancer
AU - Albert Grinshpun
AU - Adrienne G Waks
AU - Jingxin Fu
AU - Patrick Kurnia
AU - Hao Guo
AU - Tianyu Li
AU - McKenna Moore
AU - Molly DiLullo
AU - Ashka Patel
AU - Luke Whitesell
AU - Stefan Atanasov
AU - Ann H Partridge
AU - Erica L Mayer
AU - Ian E Krop
AU - Sandro Santagata
AU - Myles Brown
AU - Eric P Winer
AU - Katherine Reeder-Hayes
AU - Carey Anders
AU - Rinath Jeselsohn
AU - Nancy U Lin
PY - 2026
DA - 2026/10/14
JO - The Oncologist
DO - 10.1093/oncolo/oyag414
UR - https://doi.org/10.1093/oncolo/oyag414
AB - Background: Patients with endocrine-resistant hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) have limited effective treatment options. Heat shock protein 90 (HSP90) regulates estrogen receptor stability and function; its inhibition has been proposed as a strategy to overcome endocrine resistance. Ganetespib is a second-generation HSP90 inhibitor with demonstrated anti-tumor activity in preclinical breast cancer models. Methods: In this randomized phase II study, 50 patients with HR+ MBC previously treated with endocrine therapy were randomized 1:2 to fulvestrant alone (n = 15) or fulvestrant with ganetespib (n = 35), respectively. Median age was 53 years. Fulvestrant was administered at standard dosing; ganetespib (200 mg/m2) was given intravenously on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and safety/tolerability. Results: Median PFS was similar between arms (3.7 vs 3.6 months; log-rank P = .79). Toxicity was higher with ganetespib, with substantially increased diarrhea (97% vs 7%) and nausea (63% vs 40%). Exploratory genomic analysis of on-treatment biopsies (n = 13) showed ESR1 mutations were enriched among patients without clinical benefit, while all patients with clinical benefit exhibited a Luminal A transcriptional subtype. Tumors lacking clinical benefit showed enrichment of proliferative and cell cycle–associated transcriptional programs. Conclusions: Adding ganetespib to fulvestrant did not improve clinical outcomes and increased toxicity in endocrine-resistant HR+ MBC. Our findings support the hypothesis that ESR1 alterations and proliferative transcriptional activity contribute to established endocrine resistance, limiting the therapeutic impact of HSP90 inhibition in this setting. Clinical trial registration number: NCT01560416 (ClinicalTrials.gov)
SN - 1083-7159
SN - 1549-490X
ER -