Andrew Wardley1, Javier Cortes2,3, Louise Provencher4, Kathy Miller5, A Jo Chien6, Hope S Rugo6, Joyce Steinberg7, Jennifer Sugg7, Iulia C Tudor8, Manon Huizing9, Robyn Young10, Vandana Abramson11, Ron Bose12, Lowell Hart13, Stephen Chan14, David Cameron15, Gail S Wright16, Marie-Pascale Graas17, Patrick Neven18, Andrea Rocca19, Stefania Russo20, Ian E Krop21. 1. NIHR Manchester Clinical Research Facility at The Christie NHS Foundation Trust and Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. 2. Division of Breast Cancers and Gynecological Tumors, IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain. 3. Division of Breast Cancer and Melanoma, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 4. Department of Surgery, Centre des Maladies du Sein, CHU de Québec-Université Laval, Québec, Canada. 5. Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, USA. 6. UCSF Comprehensive Cancer Center, University of California, San Francisco, USA. 7. Astellas Pharma Inc., Northbrook, USA. 8. Pfizer Inc., San Francisco, USA. 9. Department of Oncology, Antwerp University Hospital, Edegem, Belgium. 10. Division of Breast Oncology, The Center for Cancer and Blood Disorders, Fort Worth, USA. 11. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, USA. 12. Washington University School of Medicine in St. Louis, Washington University in St. Louis, St. Louis, USA. 13. Division of Medical Oncology, Florida Cancer Specialists & Research Institute, Fort Myers, USA. 14. City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. 15. University of Edinburgh Cancer Research Centre, IGMM, The University of Edinburgh, Edinburgh, UK. 16. Division of Medical Oncology, Florida Cancer Specialists and Research Institute, New Port Richey, USA. 17. Department of Oncology, Le Centre Hospitalier Chrétien (CHC), Liège, Belgium. 18. Department of Gynaecology and Obstetrics, University Hospital Leuven, Leuven, Belgium. 19. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 20. Department of Oncology, Udine University Hospital, Udine, Italy. 21. Division of Breast Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA. ian_krop@dfci.harvard.edu.
Abstract
PURPOSE: Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. METHODS: Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. RESULTS: Overall, 103 women were enrolled [median age 60 years (range 34-83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0-3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. CONCLUSIONS: Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. CLINICALTRIALS. GOV NUMBER: NCT02091960.
PURPOSE:Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. METHODS: Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. RESULTS: Overall, 103 women were enrolled [median age 60 years (range 34-83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0-3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. CONCLUSIONS:Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. CLINICALTRIALS. GOV NUMBER: NCT02091960.
Entities:
Keywords:
Androgen receptor; Enzalutamide; HER2; Human epidermal growth factor receptor 2; Metastatic breast cancer; Trastuzumab
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