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

Abstract

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.

ARe we there yet? Understanding androgen receptor signaling in breast cancer

“…In breast cancer, there are currently phase I and II clinical trials assessing the use of orteronel in patients with metastatic breast cancers that express AR (NCT01808040, NCT01990209). NCT01808040 assesses the safety of orteronel use for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer in addition to measuring the estradiol levels in these patients following treatment 153 . NCT01990209 is a phase II trial for male or female patients with metastatic AR+ BC (TNBC or ER+ and/or PR+ BC) with primary outcome measures of response and disease control rates.…”

Breast Cancer Treatment: To tARget or Not? That Is the Question

“…An early phase 1b clinical trial showed that orteronel was well tolerated in postmenopausal women with HR+ metastatic breast cancer [9]. Of a cohort of eight heavily pretreated patients, a clinical benefit was seen in two patients who had a stable disease for more than 6 months.…”

“…Many studies have sought its effects specifically in castration-resistant prostate cancer to improve overall survival [6][7][8]. New trials are aiming to apply this mechanistic effect on breast cancer patients, specifically using drugs that inhibit androgens via the CYP17 lyase pathway [9,10].…”

Stereo flexible synthesis of the C8–C23 fragment of antarlides, androgen receptor antagonists

“…2 The androgen receptor (AR) plays a crucial role in both prostate and breast cancers, though with distinct implications. 3 In aggressive prostate cancer, the AR emerges as a pivotal therapeutic target, and the administration of androgen receptor antagonists has already shown positive outcomes. 4 In breast cancer, particularly in the androgen receptor-positive (AR + ) subtype, ongoing research and clinical trials are exploring the potential of AR antagonists, 5 indicating a potential avenue for targeted therapy.…”