Abstract PS11-29: A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic triple-negative breast cancer (TNBC)
Authors: Yardley Denise A , Young Robyn R , Adelson Kerin B , Silber Andrea L , Kommor Michael D , Najera Jose E , Daniel Davey B , Peacock Nancy W , Shastry Mythili , Hainsworth John D , Burris Howard A 
Published: February 2021

Background: Treatment options for TNBC are limited by the lack of estrogen and progesterone receptors as well as the absence of HER2 overexpression. AR is present in all breast cancer subtypes and up to 40% of TNBC have AR overexpression (AR+). Thus AR positivity in TNBC represents a potential targetable signaling pathway. Preclinical studies demonstrated that AR modulation inhibits cell proliferation, and clinical activity with anti-androgen monotherapy has been reported in breast cancer. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis under evaluation as a potential therapeutic strategy in hormone-sensitive cancers. In this phase 2 study, we evaluated androgen blockade with single agent orteronel in AR+ metastatic breast cancer (MBC). Methods: Male or female pts with AR+ MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC (AR+/ER-/PR-/HER2-) and Cohort 2-ER+ (AR+/ER+/HER2 +/-). Results in Cohort 2 (ER+) have been previously reported; here we report results in the AR+ TNBC cohort. TNBC pts must have been previously treated with standard therapy (1-3 chemotherapy regimens for MBC). All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment continued until disease progression or unacceptable toxicity. The hypothesized response rate for pts with previously treated metastatic AR+ TNBC was 11%. Results: From 7/2014 to 2/2019 a total of 26 AR+ TNBC pts were enrolled on cohort 1. The trial closed early due to slow accrual. Median age was 57 years (range, 33-92); 96% ECOG 0-1; all pts had ≥ 1 prior chemotherapy; 42% prior targeted therapy; 8% prior immunotherapy. All tumors were ER and PR negative per institutional standards. PI3K was mutated in 16% (3/19) tumors tested and 65% (13/20) were PTEN-negative. Median duration of treatment was 8 weeks (range 0.7-35.7) with 15% of pts on treatment ≥ 6 months (mo). All pts have discontinued treatment, 85% due to disease progression, and 15% due to AEs. Nausea and fatigue [8 pts each (31%)] were the most common AEs noted. G 3/4 AEs included hypertension, increased amylase and lipase [2 pts each (8%)] with 4 patients reporting SAEs (G2 pneumonitis, G2 chest pain and G2 peripheral edema, G4 prolonged QT and G4 hypokalemia). The ORR was 4% and DCR was 15%. Median PFS was 2.0 mo and median OS was 10.2 mo. Conclusions: Orteronel monotherapy was well tolerated but demonstrated limited clinical activity in this heavily pre-treated metastatic AR+ TNBC patient population. As novel AR targeting agents are being developed, future studies are needed to identify AR+ breast cancer patients most likely to benefit from AR inhibition.

Citation Format: Denise A Yardley, Robyn R Young, Kerin B Adelson, Andrea L Silber, Michael D Kommor, Jose E Najera, Davey B Daniel, Nancy W Peacock, Mythili Shastry, John D Hainsworth, Howard A Burris, III. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-29.