Abstract P1-07-02: Primary results of ONAWA (SOLTI-1802) trial: A window of opportunity trial of onapristone in postmenopausal women with progesterone receptor-positive/HER2-negative early breast cancer (EBC)
Authors: Bellet Meritxell , Morales Serafin , Gasol Ariadna , Amillano Kepa , Chic Nuria , González-Farré Xavier , Villagrasa Patricia , Paré Laia , Falato Claudette , Nuciforo Paolo , Martínez Débora , Ferrero-Cafiero Juan M , Pascual Tomás , Prat Aleix , Lange Carol , Saura Cristina 
Published: March 2022

Abstract
Background PgR expression is a biomarker of ER functionality, cellular progression to malignancy, and response to endocrine therapy (ET) in HR+ BC. Onapristone (ONA), a type 1 antiprogestin, was shown to have a single agent anti-tumor activity in patients with metastatic breast cancer (Robertson et al., 1999; Jonat et al., 2002). However, this once daily immediate-release formulation was associated with liver function test abnormalities in one-third of patients. A new, extended-release formulation (ONA XR) was developed and was evaluated in a BID schedule that reduced peak serum concentrations while sustaining the minimum plasma concentrations previously associated with the higher dose. Safety results of two phase I-II studies confirmed this hypothesis (Cottu et al., 2018; Jayaram et al., 2017; Lewis et al, 2020). Considering BC heterogeneity and that PgR analysis by standard immunohistochemistry (IHC) does not perfectly correlate with PgR target gene expression, the identification of biomarkers allowing the selection of patients with PgR-driven tumors that may benefit from antiprogestins treatment is currently an unmet need. Patients and Methods ONAWA (NCT04142892) is an open-label, single-arm, multicenter window of opportunity clinical trial of ONA XR (50 mg BID for 21 days) for postmenopausal women with EBC amenable to receive a short course of ET before surgery. Ten patients with ER+/PgR+/HER2- and Ki-67 ≥ 15% BC were enrolled. The primary objective is to evaluate the biological activity of ONA by the rate of Complete Cell Cycle Arrest (CCCR) determined by Ki-67 (≤2.7%). Secondary endpoints include safety and correlating biological activity with IHC of tumor expression (ER, PgR, Ser294-PgR, CD24, CD44, ALDH1, Ki-67), estradiol, and progesterone blood levels, and gene expression profile (NanoString nCounter® Breast 360TM panel). Relative Ki-67 suppression was defined as (1 - Ln(Ki-67 Baseline)/Ln(Ki-67 surgery)) Results Assessment of the treatment effects was possible for the 10 patients who successfully completed the protocol and the 10 paired samples (100%) were analyzed. Main patient characteristics were mean age 68 (range 53-81 years), mean tumor size 20.2 mm (range 15-26 mm), stage I (40%) and grade 2 (100%). No patients achieved a CCCR. Tumor Ki-67 expression decreased in six patients was stable in one patient and increased three patients. The mean percentage suppression of Ki-67 was 19.58%. Overall, no statistically significant change was observed in Ki-67 between paired samples (p=0.234). Baseline IHC PgR (%) expression correlated with Ki-67 decrease (r = -0.635). Mean percentage suppression of Ki-67 for tumors with IHC PgR expression ≥90% (N=4) and &lt;90% (N=6) was -25.23.0% and +2.54%, respectively. Six (60%) patients reported AEs at any grade. Most common grade 1 or 2 AEs were post-procedural pain, dry mouth and GGT increased. Grade 3 reversible GGT and AST increase occurred in 1 patient. Conclusion: ONA XR significantly increases suppression of tumor cell proliferation in PgR-high primary breast cancer. The safety profile was consistent with that previously reported. Additional correlative analysis including gene expression will be presented. Acknowledgments: Funding and drug provided by Context Therapeutics Inc., USA.
Citation Format: Meritxell Bellet, Serafin Morales, Ariadna Gasol, Kepa Amillano, Nuria Chic, Xavier González-Farré, Patricia Villagrasa, Laia Paré, Claudette Falato, Paolo Nuciforo, Débora Martínez, Juan M Ferrero-Cafiero, Tomás Pascual, Aleix Prat, Carol Lange, Cristina Saura. Primary results of ONAWA (SOLTI-1802) trial: A window of opportunity trial of onapristone in postmenopausal women with progesterone receptor-positive/HER2-negative early breast cancer (EBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-02.