Abstract P5-14-04: A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis

Abstract

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.

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients

“…Clinical trials report a median progression-free survival of 12 weeks with the non-steroidal AR antagonists bicalutamide (13) and orteronel (14), but even complete responses have been observed (15). In a combination trial of the non-steroidal AR antagonist enzalutamide with the oestrogen antagonist fulvestrant, 45% of patients still remained on treatment after 24 weeks (16).…”

Potential Therapeutic Targets for Luminal Androgen Receptor Breast Cancer: What We Know so Far

“…In phase I studies enrolling subjects with advanced TNBC and AR>10%, seviteronel showed a 16-week CBR of 33% in 16 patients, while orteronel provided a disappointing 4.8% 6 CBR at 6 months and mPFS of 2 months in 26 patients. 77 , 78 Recently, results of the first randomized phase II trial in patients with LAR BC have been presented. Patients with advanced TNBC and at least 10% expression of AR were assigned to receive the anti-androgen darolutamide (n=61) or capecitabine (n=33).…”

Steroid Receptors in Breast Cancer: Understanding of Molecular Function as a Basis for Effective Therapy Development

“…However, according to ClinicalTrials.gov (accessed on 30 August 2021), there are also multiple recently completed or ongoing clinical trials investigating drugs targeting SRs other than ER for breast cancer therapy. These studies include e.g., NCT04738292 (onapristone—PR antagonist), NCT02651844 [ 7 ], NCT05016349, NCT01138553 (mifepristone—PR antagonist), NCT04947189 (seviteronel—androgen biosynthesis inhibitor), NCT01990209 (orteronel—androgen biosynthesis inhibitor) [ 8 ], NCT03383679 (darolutamide—AR antagonist), NCT00637897 (paricalcitol—vitamin D analog) [ 9 ] or NCT01708798 (eplerenone—MR antagonist; for cardiotoxicity prevention) [ 10 ]. Most likely, in the near future further drugs targeting these receptors will be tested.…”