New SERM Shows Activity in Metastatic Cancer

SAN FRANCISCO—In a multicenter phase II trial reported at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 178), the new selective estrogen-receptor modulator (SERM) arzoxifene showed antitumor efficacy without endometrial hyperplasia in 112 patients with advanced or metastatic breast cancer.

The lead author was Aman Buzdar, MD, professor of breast medical oncology, M.D. Anderson Cancer Center.

Arzoxifene has been shown to be antagonistic in preclinical breast and endometrial models while agonistic on bone and lipids. This phase II trial evaluated the safety, toxicity, and efficacy of two dose levels (20 mg and 50 mg daily) of arzoxifene.

Patients had either tamoxifen (Nolvadex)-sensitive disease (no prior systemic therapy or disease-free interval of at least 12 months after discontinuation of adjuvant tamoxifen) or tamoxifen-refractory disease (relapse on adjuvant tamoxifen or relapse on tamoxifen for first-line treatment of metastatic cancer).

The arms were balanced for tamoxifen sensitivity, degree of estrogen-receptor positivity, and number of metastatic sites. Patients were randomized in a double-blind design to 20 mg or 50 mg daily. Patients who progressed were given 50 mg daily or went off study.

"There are unmet needs with tam-oxifen, which is the SERM standard," said Allen S. MeLemed, MD, clinical research physician for Lilly Research Laboratories, which is developing the drug. "Particularly, there are concerns about endometrial cancer and hyperplasia. We want to see if this compound is a better SERM. Arzoxifene seems to have better preclinical efficacy than raloxifene [Evista], which is why we took this phase II study forward."

Both doses showed efficacy. The combined objective response rate for protocol-qualified patients in the tamoxifen-sensitive cohort was 19%, with a clinical benefit seen in 40% (complete response plus partial response plus stable disease). In the tamoxifen-refractory patients, the objective response rate was 9%, and clinical benefit rate was 12%.

Tamoxifen-sensitive patients treated with the 20-mg dose had the best objective response rate (30%) and clinical benefit rate (47%) of all the patients tested, Dr. Buzdar and his colleagues reported.

Time to progression in the tamoxifen-sensitive patients was 8.3 months with the 20-mg dose and 3.2 with the 50-mg dose. Disease progression occurred in about 2.7 months for tamoxifen-refractory patients receiving either dose.

Overall, 46% of patients reported hot flashes, and nausea occurred in 22%. There were no significant differences in toxicity rates between the treatment arms.

Importantly, the researchers said, endometrial disorders did not occur. The majority of women had no change in endometrial thickness on serial transvaginal ultrasound, and there were no pathologically confirmed new cases of endometrial hyperplasia or carcinomas.

This study laid the foundation for a multinational phase III study, which will evaluate the efficacy and safety of arzoxifene 20 mg daily, compared with tamox-ifen, in tamoxifen-sensitive patients.