Phase II trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies.

Abstract

TPS1107 Background: Endocrine therapy (ET) targeting ER signaling is the mainstay of care for ER+ metastatic BC. There remains an unmet need in patients (pts) whose tumors become resistant to currently available ET. Selective ER degraders (SERDs) were developed to overcome resistance to existing ER-directed therapies by both competitively antagonizing and degrading ERs, while exploiting continued dependence of the tumor on ER signaling. SAR439859 is a potent SERD with robust preclinical ER degrading activity. In a Phase I dose escalation trial, SAR439859 demonstrated a favorable safety profile with no dose-limiting toxicities across all doses (20–600 mg QD). ER occupancy generally exceeded > 87% with plasma concentrations > 100 ng/mL. Overall response rate was 6.3% and clinical benefit rate was 50% (Campone. SABCS 2019. P5-11-02). The recommended Phase II monotherapy dose was 400 mg QD. Methods: This international, prospective, open-label, randomized Phase II study (NCT04059484; ACT16105) assesses safety and efficacy of SAR439859 in pts with ER+ (> 1%)/HER2- metastatic or locally advanced BC progressing on ≥ 6 months of continuous ET (0–2 lines in the metastatic setting). Prior CDK inhibitors are allowed. Exclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, life expectancy < 3 months, > 1 chemotherapy or targeted therapy in the metastatic setting, concomitant illness and factors potentially affecting SAR439859 absorption. Pts are randomized 1:1 to SAR439859 400 mg QD orally or physician’s choice of endocrine monotherapy (fulvestrant, tamoxifen, aromatase inhibitor). Pts receive 28-day cycles until unacceptable toxicity, progression, death, investigator decision or pt request. Stratification factors include visceral metastases, prior CDK4/6 inhibitors, and ECOG PS. Primary endpoint is progression-free survival (RECIST v1.1). Secondary endpoints include overall survival, response rate, duration of response, clinical benefit, pharmacokinetics, quality of life and safety. Target enrollment: n = 282; current enrollment: n = 9. Funding: Sanofi Clinical trial information: NCT04059484 .