A randomized phase II study of fulvestrant with or without ganetespib in patients with endocrine resistant metastatic breast cancer

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.