Proxalutamide in patients with AR-positive metastatic breast cancer: Results from an open-label multicentre phase Ib study and biomarker analysis

• Published in: European journal of cancer (1990) Vol. 176; pp. 1 - 12
• Main Authors: Jiang, Hanfang, Ouyang, Quchang, Yin, Yongmei, Tong, Zhongshen, Shen, Kunwei, Yuan, Zhongyu, Geng, Cuizhi, Liu, Yaxin, Song, Guohong, Ran, Ran, Li, Wei, Qu, Qing, Wang, Meiyu, Meng, Luping, Tong, Youzhi, Li, Huiping
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2022; Elsevier Science Ltd
• Subjects: Androgen receptor; Androgen receptor antagonist; Androgen Receptor Antagonists - therapeutic use; Androgen receptors; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Aspartate aminotransferase; Biomarker; Biomarkers; Breast cancer; Breast Neoplasms - pathology; Deoxyribonucleic acid; Disease control; DNA; Efficacy; Female; Humans; Immunohistochemistry; Metastases; Metastasis; Metastatic breast cancer; Mutation; Phase Ib study; Proxalutamide; Safety; Subgroups; Treatment Outcome; Tumors; γ-Glutamyltransferase; Biomarker; Androgen receptor; Metastatic breast cancer; Efficacy; Androgen receptor antagonist; Safety; Phase Ib study; Proxalutamide
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2022.08.025

Proxalutamide is a novel second-generation non-steroidal androgen receptor (AR) antagonist. This study aimed to evaluate the preliminary efficacy and safety of proxalutamide in patients with AR-positive metastatic breast cancer (AR+ mBC). In this open-label, dose-expansion, multicentre phase Ib trial, patients with AR+ mBC (immunohistochemistry [IHC] ≥1%) received proxalutamide orally once daily. Two proxalutamide dose cohorts (cohort A: 200 mg; cohort B: 300 mg) were sequentially investigated. Primary endpoints were disease control rate (DCR) at 8 and 16 weeks and recommended phase II dose (RP2D). Forty-five patients with three median lines (range, 1–13) prior systemic therapy were enrolled (cohort A, n = 30; cohort B, n = 15). Among 39 evaluable patients, DCR at 8 and 16 weeks was 25.6% (95% confidence interval [CI], 11.9–39.4%), with 26.9% in cohort A and 23.1% in cohort B. No patient achieved partial response or complete response. Proxalutamide 200 mg/day was determined as RP2D. The 6-month progression-free survival (PFS) rate was 19.6% (95% CI, 10.2–37.5%). In the triple-negative subgroup, DCR at 8 weeks was 38.5%, with median PFS of 9.1 months (95% CI, 7.8–NA) in those who achieved response at 8 weeks (n = 5). Most common grade 3/4 adverse events were aspartate aminotransferase increase (8.9%) and γ-glutamyltransferase increase (8.9%). By biomarker analysis, patients with moderate AR expression of IHC (26%–75%), PIK3CA pathogenic mutations, or <60 ng/ml cell-free DNA yield showed longer PFS. Proxalutamide showed promising anti-tumour activity with good tolerability in patients with heavily pretreated AR+ mBC, supporting further investigation. This clinical study was prospectively registered at chinadrugtrials.org.cn (Identifier: CTR20170757) and clinical trials.gov (Identifier: NCT04103853). •Proxalutamide showed promising activity in heavily pretreated AR+ mBC patients.•Proxalutamide showed an acceptable safety profile in heavily pretreated AR+ mBC.•Recommended phase II dose of proxalutamide was defined as 200 mg once daily.•AR expression, cell-free DNA yield, CNV might be associated with response.•Patients with PIK3CA pathogenic mutation showed longer progression-free survival.