Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer

Abstract

Purpose To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. Methods The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. Results GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. Conclusion GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2− advanced breast cancer

“…These data may suggest that primary tumors with higher-than-average AR but lower-than-average ESR1 are poised to become resistant to AI therapy and may benefit from anti-androgen therapy. This is in line with the high AR to ER percent cells positive data summarized in the introduction 36 . Interestingly, enobosarm, a selective androgen receptor modulator (SARM) with both agonist and antagonist activity depending on tissue type, showed activity in preclinical 5 , 37 and clinical studies 38 .…”

Potential Therapeutic Targets for Luminal Androgen Receptor Breast Cancer: What We Know so Far

“… 49 More recently, proxalutamide (GT0918), a newer second-generation anti-androgen, showed anti-proliferative effects in AR positive TNBC mouse xenograft models. 51 All these compounds have been tested in clinical trials with inconsistent results.…”

Inducing ferroptosis has the potential to overcome therapy resistance in breast cancer

“…As the most refractory type of breast cancer ( 33 , 34 ), TNBC can be divided into four subtypes base on the heterogeneity of molecular characteristics, metabolomics and tumor microenvironment ( 35 – 38 ), which including mesenchymal-like (MES), luminal androgen receptor (LAR), basal-like and immune-activated (BLIA), basal-like and immune-suppressed (BLIS) subtypes ( 39 , 40 ). Most of the current clinical trials focus on LAR in TNBC, applying an AR antagonist alone ( 41 , 42 ) or in combination with a phosphatidylinositol 3-kinase (PI3K) inhibitor ( 43 , 44 ), or combining immunotherapy to achieve AR inhibition with immune checkpoint blockade ( 45 ). The use of CDK4/6 inhibitors and hormone therapy in luminal B patients provides a strategy for the treatment of breast cancer without chemotherapy ( 46 ).…”