A Phase II Trial of Onapristone and Fulvestrant for Patients With ER+ and HER2- Metastatic Breast Cancer

The SMILE study is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone, in combination with fulvestrant as second-line therapy for patients with ER+, PgR+/-, HER2- metastatic breast cancer. This study was terminated early and herein, we report patient characteristics, and outcomes.

Eligibility criteria included disease progression on ≥2 lines of prior therapy, ECOG performance status ≤ 2, measurable disease per RECIST 1.1 criteria, and optional ¹⁸F-fluorofuranylnorprogesterone (¹⁸F-FFNP) PET/CT imaging.

Consented subjects received standard-dose fulvestrant plus onapristone 50 mg orally, twice daily, until disease progression, or unacceptable toxicity. The study enrolled 11 women from 2 sites within the Wisconsin Oncology Network from November 2021 through March 2023. Mean age of the subjects was 58.5 years. Other than grade 1 toxicities, the treatment was well tolerated. None of the 11 subjects met RECIST 1.1 definition of response. The median time to progression was 63 days. A total of 4 of 11 patients had stable disease as best response and 2 of them were on treatment for 5.5 and 7.7 months. Two of the 11 subjects underwent functional imaging with ¹⁸F-FFNP PET/CT before and 10 or 14 days after starting treatment. For both subjects, tumor uptake of ¹⁸F-FFNP was stable or increased in all target lesions while ¹⁸F-FFNP uptake in the uterus, a normal PgR-rich internal control organ, was decreased.

The study regimen was well-tolerated with no significant toxicities. Future studies may evaluate antiprogestins with various combinations such as targeted therapies.