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

• Published in: Clinical breast cancer Vol. 25; no. 3; pp. 251 - 260
• Main Authors: Kamaraju, Sailaja, Fowler, Amy M., Tarima, Sergey, Chaudhary, Lubna N., Burkard, Mark E., Giever, Thomas, Cheng, Yee C., Parkes, Amanda, Lange, Carol A., Pipp-Dahm, Michele, Hegeman, Robert, Siddiqui, Nauman, Stella, Amy, Rajguru, Saurabh, Twaroski, Kyleigh, Zurbriggen, Luke, Jorns, Julie M., Rui, Hallgeir, Keigley, Quinton J., Perlman, Scott B., Salem, Kelley, Bradshaw, Tyler J., Sahmoud, Tarek, Wisinski, Kari
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2025
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antiprogestins; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CDK4/6 inhibitors; Female; Fulvestrant - administration & dosage; Fulvestrant - adverse effects; Hormone receptor positive; Humans; Metastatic breast cancer; Middle Aged; Novel treatments; Positron Emission Tomography Computed Tomography; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Antiprogestins; Novel treatments; Metastatic breast cancer; Hormone receptor positive; CDK4/6 inhibitors
• ISSN: 1526-8209; 1938-0666; 1938-0666
• DOI: 10.1016/j.clbc.2024.11.019

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. The SMILE study, a phase II clinical trial of onapristone plus fulvestrant in ER+, PgR+/−, HER2− metastatic breast cancer, enrolled 11 women but was terminated early. Despite good tolerability and grade 1 toxicities, no RECIST 1.1 responses were observed, with a median time to progression of 63 days. Stable disease was achieved in 4 patients, with two remaining on treatment for >5 months. 18F-FFNP PET/CT imaging revealed stable or increased tumor uptake, suggesting potential for future studies combining antiprogestins with targeted therapies.