Background: The frequency of AR expression varies in the different breast cancer subtypes with 88%, 59%, and 32% expression reported in ER+, HER2+, and triple negative tumors, respectively. AR expression is associated with resistance to endocrine therapy in ER+ breast cancer. Androgen levels frequently increase following treatment with aromatase inhibitors suggesting a role for androgen synthesis inhibitors in ER+ breast cancer. AR signaling and expression are seen in triple negative breast cancer (TNBC), and a distinct AR TNBC subtype can be identified by gene expression profiling. AR expression in TNBC offers a potential therapeutic target. Preclinical and clinical studies demonstrated anti-androgen agent activity in breast cancer cell lines; preliminary clinical data suggests activity in TNBC. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis that is being evaluated as endocrine therapy in various hormone-sensitive cancers. In this phase 2 study we are evaluating single agent orteronel in AR+ MBC. Methods: Pts with AR expressing MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC and Cohort 2-ER+ (HER2 could be +/- in this cohort). Pts must have been previously treated with standard therapy for MBC (1-3 chemotherapy regimens for TNBC, 1-3 hormonal therapies + 1 chemotherapy for ER+ patients, ≥2 HER2-targeted regimens for HER2+ patients). A 6 pt lead-in for safety and tolerability of orteronel in AR+ female MBC pts was followed by open enrollment to either cohort. All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment was continued until disease progression or unacceptable toxicity. The hypothesized response rate for Cohort 1 was 10% and 13% for Cohort 2. We present the results of a protocol-specified interim analysis of the ER+ MBC pts (Cohort 2). Results: From 3/2014 to 4/2015, a total of 29 pts were enrolled on cohort 2. Median age was 65 years (range, 39-79); 90% ECOG ≤1; 90% HER2-/10% HER2+; median of 7 prior therapies (range 3-11). 93% had prior chemotherapy. Pts received a median of 2 cycles of orteronel treatment (range 1-4) and 3 pts (10%) are still on treatment. Of the 26 pts (90%) pts that have discontinued, 19 (66%) discontinued due to disease progression, 4 (14%) due to pt decision, 2 (7%) due to adverse event (AE), and 1 (3%) due to non-compliance. The most common treatment-related G 3/4 AEs were increased lipase [3 pts (10%)] and hypertension [2 pts (7%)]. There were no treatment-related SAEs or deaths on study. Three pts (10%) had stable disease as their best response. Further response evaluation is underway. Conclusions: Orteronel monotherapy was well tolerated but appears to have limited single-agent activity in this heavily pre-treated ER+ MBC pt population. The full results from this interim analysis will be presented. Citation Format: Yardley DA, Peacock N, Young RR, Silber A, Chung G, Webb CD, Jones SF, Shastry M, Midha R, DeBusk LM, Hainsworth JD, Burris HA. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-04.

Background: Residual breast cancer after NAC is associated with a high risk of recurrence. Little evidence supports the use of further chemotherapy in this setting. Eribulin, an inhibitor of microtubule dynamics, demonstrated a survival advantage in patients with metastatic breast cancer who had progressed after previous anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of eribulin (2-yr disease-free survival) administered postoperatively to breast cancer pts not achieving a pCR following standard NAC. Methods: Women with invasive breast cancer (stage T1-4b, N0-2, M0 at diagnosis) and evidence of residual cancer (>5 mm) in the breast or axillary lymph nodes (LN) following ≥4 cycles of standard anthracycline and/or taxane-containing NAC were eligible. Additional eligibility criteria: age ≥18 yrs, peripheral neuropathy < 1, adequate hematologic, hepatic, and renal function. 3 groups were studied: Cohort A-triple negative (TN), Cohort B-HR+/HER2-, Cohort C-HER2+. After recovery from definitive surgery, all pts received eribulin mesylate 1.4mg/m2 IV on days 1 and 8 every 21 days for 6 cycles. Cohort C pts also received trastuzumab 6mg/kg IV day 1 every 21 days for a total of 1 yr from start of NAC. Adjuvant hormonal therapy and loco-regional radiotherapy were administered per institutional guidelines. We hypothesized post-operative eribulin would result in a 40% increase over the reported 40% 2 yr DFS for TN, and a 15% increase over the reported 80% 2 yr DFS for HR+/HER2- pts who did not achieve pCR following standard NAC. Results: 127 pts were enrolled (54, Cohort A; 42, Cohort B; 31, Cohort C). Pts on Cohort C continue with study treatment. Here, we present the results of 95 pts treated on Cohorts A and B. Median age-52 yrs (range, 27-74). 87 pts (92%) had invasive ductal adenocarcinoma, 6 (6%) invasive lobular, 1 (1%) mucinous, and 1 (1 %) unknown; 34 pts (36%) had T3 or T4 tumors and 65 (68%) had N1-2 disease at diagnosis. NAC with anthracyclines was administered to 74 pts (78%), taxanes to 88 (93%), and 72 (76%) received both. 71 pts (75%) had mastectomies, 24 (25%) had breast conserving surgery. Median residual tumor was 17.5 mm (range 0.1 to 80); 60 pts (63%) were LN+. 78 pts (81%) completed the planned 6 cycles of eribulin. Adjuvant radiation was administered in 28 pts (30%). 3 pts discontinued treatment due to toxicity (1 each with G3 neutropenia, G3 nausea, and unknown grade neuropathy). The most common treatment-related G3/4 adverse events were neutropenia [29 pts (31%)] and leukopenia [10 pts (11%)]. 3 pts (3%) had G3/4 febrile neutropenia and 2 pts (2%) had G3/4 neuropathy. Growth factors were administered to 22 pts (24%). There were no treatment-related deaths. With a median follow up of 19.2 and 14.9 months for Cohorts A and B respectively, the 2 yr DFS probabilities calculated from date of surgery were 61.1 % (95% CI-41.2-76.0) for Cohort A; 82.2% (95% CI-60.2-92.7) for Cohort B. Conclusions: The addition of eribulin is safe and feasible in pts who do not achieve pCR following anthracycline and/or taxane based NAC. At a median follow up of 19.2 months, a statistically significant improvement in the estimated 2 yr DFS was evident in the TN (Cohort A) pts. Citation Format: Yardley DA, Peacock N, Shroff S, Molthrop, Jr DC, Anz B, Daniel BR, Young RR, Weaver R, Harwin W, Webb CD, Ward P, Shastry M, DeBusk LM, Midha R, Hainsworth JD, Burris III HA. A phase 2 study of eribulin in breast cancer not achieving a pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-04.