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SAN FRANCISCO -- A tamoxifen-like drug slowed progression of advanced postmenopausal breast cancer previously treated with a nonsteroidal aromatase inhibitor, according to results of a small Japanese trial.

In a phase II trial, patients with hormone receptor-positive breast cancer treated with toremifene (Fareston) had a clinical benefit rate almost double that of women treated with the steroidal aromatase inhibitor exemestane (Aromasin), reported Hirotaka Iwase, MD, of Kumamoto University, and colleagues at the Breast Cancer Symposium.

The progression hazard was reduced by 38% in the toremifene arm, although objective response rate and overall survival did not differ between treatment groups.

"This study suggests that toremifene at a dose of 120 mg should be regarded as an appropriate secondary and tertiary endocrine therapy for recurrent breast cancer, which fails to respond to nonsteroidal aromatase inhibitors (AIs), since treatment was effective against AI-resistant breast cancer and demonstrated known favorable actions of a selective estrogen receptor modulator (SERM)," the group concluded in a poster presentation.

"Additionally, steroidal aromatase inhibitors may not be appropriate for patients after prior nonsteroidal AI failure," they added.

Investigators have begun another trial to examine the role of toremifene in AI-resistant breast cancer, comparing the agent against fulvestrant (Faslodex), a selective estrogen receptor down-modulator.

Nonsteroidal aromatase inhibitors have established a role in adjuvant therapy and in the treatment of recurrent, hormone receptor-positive breast cancer in postmenopausal women. Treatment failure can lead to clinical uncertainty with respect to the next step in endocrine therapy, Iwase's group noted.

SERMs, steroidal aromatase inhibitors, and fulvestrant are among the treatment options for patients whose disease has progressed in response to a nonsteroidal aromatase inhibitor.

In an effort to provide therapeutic guidance, Iwase and colleagues performed an open-label, multicenter, randomized trial involving 91 patients with postmenopausal, hormone receptor-positive breast cancer that had progressed after treatment with a nonsteroidal aromatase inhibitor. The trial was conducted from 2008 to 2011.

Patients were randomized to toremifene or exemestane and treated until disease progression, development of unacceptable toxicity, or death. The primary endpoint was clinical benefit rate (objective response plus stable disease).

The patients had a median age of about 60, prior disease-free interval of 8 to 10 months, and about three-fourths of the patients had received two or more prior endocrine regimens. About 70% of the patients had responded to prior treatment with a nonsteroidal AI.

The primary efficacy analysis included 40 patients from the toremifene arm and 45 from the exemestane group. Clinical activity in the toremifene group consisted of four partial responses, one complete response, and 14 patients with stable disease of 24 weeks or longer, resulting in a clinical benefit rate of 47.5%.

In the exemestane arm, one patient had a complete response and 11 had prolonged stable disease, resulting in a clinical benefit rate of 26.7%.

Objective response rate (a secondary endpoint) favored toremifene (12.5% versus 2.2%).

Median progression-free survival was 5.7 months with toremifene and 3.5 months with exemestane, which translated into a 38% reduction in the hazard for progression in the toremifene arm (HR 0.62, P=0.047). Overall survival favored the toremifene group but did not achieve statistical significance (18.6 versus 15.4 months).

Adverse events occurred more often in the toremifene arm but were infrequent in both groups. Adverse events most commonly associated with toremifene were nausea (four patients), and fatigue, hot flushes, and night sweats (three each). No grade 3-4 adverse events occurred in either group.

Invited discussant Matthew Ellis, MB BChir, PhD, of Duke University, characterized exemestane as a weak endocrine agent for use in the setting of resistance to nonsteroidal AI. A more interesting, and potentially more effective strategy would be to combine everolimus (Afinitor) with fulvestrant (Faslodex), toremifene, or tamoxifen, which might be compared with a control arm of everolimus plus exemestane, he said.

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