Abstract OT2-1-07: A phase II study with orteronel as monotherapy in patients with androgen receptor (AR) expressing metastatic breast cancer (MBC)
Authors: Yardley Denise A , Jones Suzanne F , Peacock Nancy W , Shastry Mythili , Young Robyn R , Kallab Andre M , Burris III Howard A 
Published: May 2015

Abstract
Background: Androgen Receptor (AR) signaling is a new target present in and under evaluation in all breast cancer subtypes. AR expression is noted in 70%-90% of primary breast tumors, up to 75% of all breast cancer metastases and is associated with resistance to endocrine therapy. Orteronel, an oral, selective, nonsteroidal inhibitor of androgen synthesis, is being developed as an endocrine therapy for hormone-sensitive cancers. In preclinical studies, orteronel suppresses sex hormone levels in blood and hormone-dependent malignant tissue. This study will evaluate the safety and efficacy of orteronel in the treatment of AR+ MBC.
Study Objectives: This phase II trial is designed to determine the response rate and disease control rate (CR+PR+SD at 6 mo) following treatment with orteronel in pts with AR+ MBC. Two groups will be evaluated: Cohort 1 will include pts with AR+, triple negative (TN) (ER-/PR-/HER2-) MBC, and Cohort 2 will include pts with AR+, ER+ and/or PR+ MBC (may be HER2+ or HER2-). Secondary objectives include evaluation of PFS and OS, safety and tolerability, as well as evaluation of changes in serum levels of total and free testosterone, sex hormone binding globulins (SHBG), adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S), cortisol and estradiol during orteronel treatment. As an exploratory objective, archived tumor tissue will be analyzed for the presence of phosphatidylinositol 3-kinase (PIK3CA) mutations and loss of phosphatase and tensin homolog (PTEN).
Eligibility: Pts ≥18 years with AR+ (≥10% staining by immunohistochemistry) MBC, either TN or ER+ and/or PR+, are eligible. TNBC pts must have had 1-3 prior chemotherapy regimens in the advanced setting and ER+ and/or PR+ pts must have had 1-3 prior hormonal therapies and ≥1 chemotherapy regimen in the advanced setting. HER2+ pts must have received ≥2 lines of HER2-directed therapies. Additional eligibility criteria include: ECOG PS 0-2; adequate bone marrow and organ function, including left ventricular ejection fraction of ≥50%.
Trial Design: Six pts will be enrolled and treated with orteronel in the lead-in phase to confirm safety and tolerability. In the absence of any safety concerns, subsequent pts will be enrolled to either Cohort 1 or Cohort 2 (described above). Cohort 1 will contain 31 pts with AR+ TNBC and Cohort 2 will contain 55 pts with AR+ ER+ and/or PR+ MBC. All pts will receive 300 mg orteronel PO BID over a 4 week cycle. Pts will be evaluated with CT scans every 2 cycles and treatment will continue until disease progression or unacceptable toxicity. Response rate and disease control rate will be presented as the point estimate along with 95% confidence interals calculated using both asymptotic normal approximation and exact binomial methods. Simon’s two-stage design will be applied using alpha=0.10 and power=0.80 for each cohort. Blood samples will be collected at baseline, on Cycle 2 Day 1, Cycle 4 Day 1, and at the end of treatment to evaluate serum total and free testosterone, SHBG, ACTH, DHEA-S, cortisol, and estradiol levels. Archival tumor samples will be collected for exploratory PTEN and PIK3CA biomarker evaluations. This trial is currently enrolling and has a total accrual goal of 86 pts.
Citation Format: Denise A Yardley, Suzanne F Jones, Nancy W Peacock, Mythili Shastry, Robyn R Young, Andre M Kallab, Howard A Burris III. A phase II study with orteronel as monotherapy in patients with androgen receptor (AR) expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-07.