1. The clinical benefit rate was 32% in the 9 mg group and 29% in the 18 mg group.

2. Grade 3 or higher treatment-related adverse events occurred in 8% of the 9 mg group and 16% in the 18 mg group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Androgen receptors (AR) have been shown to act as a tumour suppressor in estrogen receptor (ER)-positive, HER2-negative breast cancer, however, their use was limited due to virilizing side effects. Recent developments in selective AR modulators (SARMs), such as enobosarm, have prompted a reevaluation of AR agonism in ER-positive breast cancer. This phase 2 trial studied the activity and safety of enobosarm in women with AR-positive, ER-positive, and HER2-negative advanced breast cancer. The primary endpoint was clinical benefit rate (CBR, which includes complete, partial, and stable response), and secondary endpoints included progression-free survival (PFS), and safety. The study found that CBR was 32% in the 9 mg group and 29% in the 18 mg group. The best overall response included some complete (6% in the 9mg group) and partial responses (6% in the 9mg group and 5% in the 18mg group). The median PFS was 5.6 months in the 9 mg group and 4.2 months in the 18 mg group. With regards to safety, grade 3 or higher treatment-related adverse events occurred in 8% in the 9 mg group and 16% in the 18 mg group, with the most common events including increased hepatic transaminases (4% in the 9 mg group and 3% in the 18 mg group), hypercalcemia (3% in both), and fatigue (1% and 3% respectively). The patient-reported health questionnaire found no significant changes over time in either dose group (9 mg group p=0.93; 18mg group p=0.54). The limitations of this study included the lack of a control group, small sample size, and conflicting results. Overall, it was found that enobosarm had some improvement in endpoints in both doses (8mg and 18mg) in women with AR-positive, ER-positive, and HER2-negative advanced breast cancer.

Click to read the study in the Lancet

Click to read an accompanying editorial in the Lancet

Relevant Reading: The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer

In-Depth [randomized controlled trial]: This multinational, open-label phase 2 trial enrolled postmenopausal women with ER-positive, AR-positive, HER2-negative advanced breast cancer who have shown some sensitivity to hormone therapy and randomized them (1:1) to receive either 9mg (n=50) or 18mg (n=52) of oral daily enobosarm for up to 24 months. Baseline demographics were similar across both groups apart from de novo metastatic disease, 12% in the 9mg group and 27% in the 18mg group. The median follow-up was 7.5 months. The CBR was 32% (95%CI, 20-47) in the 9 mg group and 29% (95%CI, 17-43) in the 18 mg group. The objective response rate was 0% (95%CI, 0-10) in the 9 mg group and 2% (95%CI, 0–14) in the 18 mg group (one partial response), although it was also noted that the best overall response included some complete (6% in the 9mg group) and partial responses (6% in the 9mg group and 5% in the 18mg group). The median PFS was 5.6 months (IQR 2.8-NR) in the 9 mg group and 4.2 months (IQR, 2.7-11.8) in the 18 mg group. With regards to safety, grade 3 or higher treatment-related adverse events occurred in 8% in the 9 mg group and 16% in the 18 mg group, with the most common events including increased hepatic transaminases (4% in the 9 mg group and 3% in the 18 mg group), hypercalcemia (3% in both), and fatigue (1% and 3% respectively). The patient-reported health questionnaire found no significant changes over time in either dose group (9 mg group p=0.93; 18mg group p=0.54). Overall, it was found that enobosarm had some improvement in endpoints in both doses (8mg and 18mg) in women with AR-positive, ER-positive, and HER2-negative advanced breast cancer.

Image: PD

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