Abstract OT2-01-02: The SMILE Study: A phase II trial of onapristone in combination with fulvestrant for patients with ER-positive and HER2-negative metastatic breast cancer after progression on endocrine therapy and CDK 4/6 inhibitors
Authors: Kamaraju Sailaja , Fowler Amy , Chaudhary Lubna N. , Burkard Mark , Giever Thomas , Hegeman Robert N , Pipp-Dahm Michele , Cheng Yee Chung , Lange Carol , Jorns Julie M. , Stella Amy , Siddiqui Nauman , Zurbriggen Luke , Rajguru Saurabh , Tarima Sergey , Sriram Deepika , Retseck Janet , Rui Hallgeir , Sahmoud Tarek , Wisinski Kari B. 
Published: March 2023

Abstract
Background Antiprogestins, including selective progesterone receptor (PgR) modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance including in patients who develop activating estrogen receptor alpha (ESR1) mutations after prior endocrine therapy (ET). 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 (MBC). Methods Patients with locally advanced or MBC who progress on ≥2 lines of prior therapy with ET as a single agent or in combination with CDK4/6 inhibitors, mTOR inhibitors and one line of chemotherapy in the metastatic setting are eligible. Other criteria include ECOG performance status ≤ 2, measurable disease per RECIST 1.1 criteria, adequate organ function, availability of an archived tumor biopsy block confirming the diagnosis of MBC, optional biopsy at disease progression on trial, and optional 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging. Ovarian suppression is allowed. Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. Patients with prior exposure to fulvestrant, antiprogestins, or CDK inhibitors in the adjuvant setting are ineligible. Following consent, all subjects will receive fulvestrant at the recommended dosing schedule plus onapristone 50 mg orally, twice daily, until disease progression, unacceptable toxicity, or discontinuation for any other reason. Using the Simon Two-Stage design, a total of 39 patients will be enrolled over two years from 6-8 sites within Wisconsin Oncology Network (WON); study enrollment began in November 2021. In the first stage of the trial, thus far, nine patients were accrued who are tolerating the trial regimen well with no reported toxicities or serious events. The safety monitoring is planned when the cohort size reaches eleven patients, and interim analysis at 21 patients; if ≥2 responses are observed, then 18 additional subjects will be enrolled in the second stage. This design yields a one-sided type I error rate of 5% if the ORR is 7% and power of 80% when the combination’s true response rate is 20%. The primary objective is to evaluate the objective response rate; secondary objectives include safety and tolerability, progression-free survival, disease control rate, and duration of response. Other correlates include optional functional imaging of PgR binding with 18F-FFNP PET/CT and biomarker analysis (ER, total PgR, HER2, Ki67, CD24, CD44, LDH1, KLF4, CK 5/6, PhosphoSer294-PgR on tissue samples, ESR1 mutations, and circulating tumor DNA analysis).
Citation Format: Sailaja Kamaraju, Amy Fowler, Lubna N. Chaudhary, Mark Burkard, Thomas Giever, Robert N Hegeman, Michele Pipp-Dahm, Yee Chung Cheng, Carol Lange, Julie M. Jorns, Amy Stella, Nauman Siddiqui, Luke Zurbriggen, Saurabh Rajguru, Sergey Tarima, Deepika Sriram, Janet Retseck, Hallgeir Rui, Tarek Sahmoud, Kari B. Wisinski. The SMILE Study: A phase II trial of onapristone in combination with fulvestrant for patients with ER-positive and HER2-negative metastatic breast cancer after progression on endocrine therapy and CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-02.