Abstract OT3-02-05: NCI-2016-00367: A phase IIB study of neoadjuvant ZT regimen (enzalutamide therapy in combination with weekly paclitaxel) for androgen receptor (AR)-positive triple-negative breast cancer (TNBC)
Authors: Fujii T , Lim B , Helgason T , Hess KR , Gilcrease MZ , Willey JS , Tripathy D , Litton JK , Moulder S , Krishnamurthy S , Yang W , Reuben JM , Symmans WF , Ueno NT 
Published: March 2017

Abstract
BACKGROUND: Approximately 50% of TNBC expresses AR by immunohistochemical (IHC) staining. Luminal androgen receptor (LAR) subtype is heavily enriched in hormonally regulated genes, yet negative for ER by IHC. LAR is associated with low pCR rates and long survival. Preclinical data have shown that taxanes inhibit translocation of AR from the cytoplasm to the nucleus where AR is activated. Combining paclitaxel with enzalutamide may inhibit the AR pathway synergistically thereby increasing pCR rates. We hypothesized that patients with AR-positive TNBC who have chemo-insensitive disease (CID) after initial anthracycline-based chemotherapy treated with ZT would have higher RCB-0 and RCB-I rates than those who receive conventional taxane-based chemotherapy. Our team developed a clinical trial to identify patients with CID (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). In the ARTEMIS trial, treatment-naïve patients with localized TNBC undergo a pretreatment biopsy and then begin anthracycline-based chemotherapy. Molecular testing results and radiographic response assessment are used to identify CID and will guide the second phase of neoadjuvant chemotherapy (NACT) to overcome CID.
PRIMARY OBJECTIVE: To determine RCB-0 and RCB-I rates of patients with TNBC who have CID to initial anthracycline-based chemotherapy and who received ZT.
TRIAL DESIGN AND STATISTICAL METHODS: Patients with CID from the ARTEMIS trial can enroll in the 12-week ZT (paclitaxel, 80 mg/m2 intravenously per week; enzalutamide, 160 mg orally per day). We will define pCR (RCB-0) or RCB-I as a response, using a Simon optimal 2-stage design with alpha=beta=10% and then setting the threshold for an acceptable pCR or RCB-I rate at 20%. We will enroll 12 patients into the first stage. If no patients experience pCR or RCB-I, we will stop the study after the first stage. If at least 1 patient experiences pCR or RCB-I, we will enroll 25 more patients for a total of 37 patients. We would declare the treatment worthy of further study if at least 4 of the 37 patients experience pCR or RCB-I. This design has a 54% probability of early termination after the first stage if the true pCR or RCB-I probability is 5%. Because patients with CID have a very low chance (5%) of achieving pCR with additional chemotherapy, improving pCR rates to 20% in this patient population would be clinically meaningful.
BRIEF ELIGIBILITY CRITERIA: Inclusion criteria: Primary invasive TNBC patients who have CID under the ARTEMIS trial; AR+ ≥1% nuclear staining by IHC; and adequate physical, organ, bone marrow, and cardiac functions. Exclusion criteria: Pregnant or lactating patients, history of colitis or absorption abnormality, known or suspected brain metastasis or leptomeningeal disease, or history of seizure.
CORRELATIVE SCIENCE: Enumeration of circulating tumor cells (CTCs) and expression of CTC-related gene transcripts will be measured to correlate CTC characteristics and/or gene profiles related to the AR pathway and treatment response to ZT.
Citation Format: Fujii T, Lim B, Helgason T, Hess KR, Gilcrease MZ, Willey JS, Tripathy D, Litton JK, Moulder S, Krishnamurthy S, Yang W, Reuben JM, Symmans WF, Ueno NT. NCI-2016-00367: A phase IIB study of neoadjuvant ZT regimen (enzalutamide therapy in combination with weekly paclitaxel) for androgen receptor (AR)-positive triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-05.