Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102

Abstract

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.

ESR1 mutations in breast cancer

“…64 Patients treated with the combination showed a significant extension of PFS compared with fulvestrant alone (10.3 vs 5.1 months). 64 Patients treated with the combination showed a significant extension of PFS compared with fulvestrant alone (10.3 vs 5.1 months).…”

“…The combination of fulvestrant and everolimus has been tested in the PrE0102 (NCT01797120) clinical trial, where patients with ER-positive, AI-resistant MBC were treated with fulvestrant, with or without everolimus. 64 Patients treated with the combination showed a significant extension of PFS compared with fulvestrant alone (10.3 vs 5.1 months). However, there are no projected differences in overall survival.…”

Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2− Breast Cancer

“…Finally, everolimus has been studied in combination with fulvestrant in AI-resistant disease. 53 Median PFS improved from 5.1 to 10.3 months with the addition of everolimus (P=.02). Based on these data, the NCCN Guidelines note that everolimus in combination with ET (exemestane, tamoxifen, or fulvestrant) can be considered for patients who previously progressed on nonsteroidal AIs.…”

Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics

“…Renal cell carcinoma RECORD-1 trial [55] ; [56,113] HR+, HER2-breast cancer [118]; TAMRAD [119] ; BOLERO-2 [120] ; PrE0102 [121] Pancreatic neuroendocrine tumours RADIANT-1 (NCT00363051) [60] ; RADIANT-3 (NCT00510068) [61] ;…”