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

Aim: Proxalutamide is a novel second-generation non-steroidal androgen receptor (AR) antagonist. This study aimed to evaluate the preliminary efficacy and safety of proxalu-tamide in patients with AR-positive metastatic breast cancer (AR(+) mBC). Methods: 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). Results: 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 gamma-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. Conclusion: Proxalutamide showed promising anti-tumour activity with good tolerability in patients with heavily pretreated AR(+) mBC, supporting further investigation.(C) 2022 The Author(s). Published by Elsevier Ltd.