A Phase II Study Evaluating Orteronel, an Inhibitor of Androgen Biosynthesis, in Patients With Androgen Receptor (AR)-Expressing Metastatic Breast Cancer (MBC)

• Published in: Clinical breast cancer Vol. 22; no. 3; pp. 269 - 278
• Main Authors: Yardley, Denise A., Young, Robyn R., Adelson, Kerin B., Silber, Andrea L., Najera, Jose E., Daniel, Davey B., Peacock, Nancy, Finney, Lindsey, Hoekstra, Susan J., Shastry, Mythili, Hainsworth, John D., Burris, Howard A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2022
• Subjects: Androgen receptor; Androgens - therapeutic use; Breast Neoplasms - pathology; Estrogens - therapeutic use; Female; HR+/HER2; Humans; Imidazoles; Male; Metastatic breast cancer; Naphthalenes; Orteronel; Receptors, Androgen - metabolism; Triple-negative breast cancer (TNBC); Metastatic breast cancer; Triple-negative breast cancer (TNBC); HR+/HER2; Androgen receptor; Orteronel
• ISSN: 1526-8209; 1938-0666
• DOI: 10.1016/j.clbc.2021.10.011

AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC).
Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint.
Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%).
Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.
Treatment with orteronel had no significant activity in patients with refractory AR+ MBC selected using an IHC AR staining threshold of ≥10%. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.