Evaluation of biomarker association with efficacy for abiraterone acetate (AA) plus prednisone (P) with or without exemestane (E) in postmenopausal patients (pts) with estrogen receptor-positive (ER+) metastatic breast cancer (mBCa) progressing after a nonsteroidal aromatase inhibitor (NSAI).

Liu, Weimin; O’Shaughnessy, Joyce; Ricci, Deborah; Griffin, Thomas W.; Kheoh, Thian; Yu, Margaret K.; Gormley, Michael; Martin, Jeffrey W.; Schäffer, Michael; Zelinsky, Kathy; Hayes, Daniel F.; Campone, Mario; Bondarenko, Igor; Zbarskaya, Irina; Brain, Étienne; Стенина, М. Б.; Иванова, О. А.; Graas, Marie-Pascale; Neven, Patrick; Johnston, Stephen

doi:10.1200/jco.2014.32.15_suppl.520

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“…Although a reasonable hypothesis could be that HR+ metastatic breast cancer expressing AR would benefit the most from agents suppressing androgens and estrogens, biomarker analysis from the abiraterone study failed to show any predictive value from AR expression in tissue and circulating tumor cells predicting benefit. [26] Preclinical studies have shown a high AR/ER ratio (≥ 2) is predictive of resistance to endocrine therapies alone and this may be a population, which could benefit from combined androgen and estrogen suppression with lyase inhibitors. [20] Another key therapeutic question is whether lyase inhibitors need to be combined with aromatase inhibitors in the treatment of HR+ breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer

et al. 2016

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Intro Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3+3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47–73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1–2 nausea (n=4) and bone pain (n=3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n=2). The only grade 3 AE was hypertension (n=2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer.

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Section: Discussionmentioning

confidence: 99%