Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A—500 mg intramuscular (i.m.) day −14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B—1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (α=0.10, β=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided χ2-test; 95% CI for difference (14.5%)=−0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs. A proteasome inhibitor likely enhances the effectiveness of the breast cancer drug fulvestrant, according to a small, randomized trial. Kerin Adelson, formerly of Mount Sinai and currently of Yale University School of Medicine, led this New York Cancer Consortium, National Cancer Institute-funded randomized phase II trial testing fulvestrant (an estrogen receptor degrader) with or without the addition of bortezomib (a drug that blocks the cellular complexes that break down proteins) in 118 postmenopausal women with a form of hormone receptor-positive metastatic breast cancer that is often treated with fulvestrant. Although the median time before tumors started to grow was similar between the two treatment arms of the study, a significantly larger fraction of patients who received bortezomib were living without tumor growth at 12 months compared to those who received fulvestrant alone. The addition of bortezomib may help delay or reverse resistance to fulvestrant.