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Life sciences · Journal article
The Oncologist · October 14, 2026
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Abstract Background Patients with endocrine-resistant hormone receptor-positive (HR+), HER2-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 = 0.79). 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. ClinicalTrials.gov Registration Number NCT01560416