Enobosarm Shows Clinical Benefit in AR+, ER+ Metastatic Breast Cancer

Enobosarm demonstrated clinical benefit at varying dose levels in patients with androgen receptor (AR)–positive, estrogen receptor (ER)–positive metastatic breast cancer, according to phase 2 findings of the G200802 study that were presented during the virtual 2020 San Antonio Breast Cancer Symposium.^1,2 

At the 9-mg and 18-mg doses of enobosarm, the 6-month clinical benefit rate (CBR) was 32% and 29% in evaluable patients, respectively, and the best overall response was 35.3% and 25.6%, respectively. The median progression-free survival (PFS) was 5.6 months at the 9-mg dose and 4.2 months at the higher dose.

Enobosam was also found to be well tolerated and safe, and quality-of-life (QoL) measurements showed an overall improvement in mobility, anxiety/depression, and pain. 

In ER-positive breast cancer, AR agonists are known to inhibit tumor growth, and AR is a highly expressed sex hormone receptor in breast cancers. Therefore, novel strategies that target AR in heavily treated patients with ER-positive breast cancer are needed. 

Enobosarm is a first-in-class, novel, oral, nonsteroidal, selective AR agonist designed to treat patients with AR-positive, ER-positive advanced breast cancer. It is given daily in 3-mg capsules. In cell- and patient-derived xenograft models, enobosarm was found to inhibit AR-positive, ER-positive breast cancers and also has vast clinical experience in other studies.

In the open-label, multicenter, international, parallel-design phase 2 G200802 trial, investigators randomized 136 postmenopausal patients with AR-positive, ER-positive breast cancer to receive enobosarm at 9 mg (n = 72) or 18 mg (n = 64). Patients must have had metastatic or locally recurrent disease not amenable to surgery, and previously responded to adjuvant endocrine treatment for at least 3 years or more endocrine treatment for metastatic disease for 6 months or longer.

The primary end point was CBR at 6 months via RECIST 1.1 criteria, and investigators also assessed biomarkers including serum prostate-specific antigen and circulating tumor cells.

Baseline characteristics were similar between the 2 cohorts. In the 9- and 18-mg arms, the median age was 60.5 years and 62.5 years, more than half of patients had an ECOG performance status of 0 (60.0% and 53.8%), and most had received prior chemotherapy (90.0% and 92.3%), respectively.

Fifty patients on the 9-mg cohort were evaluable compared with 52 on the 18-mg group. The 35.3% ORR in the 9-mg cohort comprised 1 complete response and 11 partial responses (PRs). In the 18-mg cohort, the 25.6% ORR comprised 3 patients who demonstrated PRs, and 7 patients who had PRs.

In the intent-to-treat population, the CBR at 6 months was 25.4% on the 9-mg dose (n = 71) and 26.6% on the 18-mg cohort (n = 64). The median PFS was 5.3 months and 2.9 months, respectively. 

Regarding safety, the majority of adverse events (AEs) were of grade 1/2; serious AEs occurred in 8 (10.7%) and 10 patients (16.4%) on the 9-mg and 18-mg doses, respectively. Six patients and 10 patients, respectively, had grade 3/4 treatment-related AEs (TRAEs), including increased alanine aminotransferase (1.3% vs 3.3%), increased aspartate aminotransferase (2.7% vs 0%), hypercalcemia (2.6% vs 3.3%), headache (1.3% vs 1.6%), anemia (1.3% vs 0%), and fatigue (1.3% vs 3.3%). Additional events only occurred at the higher dose: tumor flare (3.3%), dry mouth, decreased white blood cell count, decreased appetite, agitation, lymphadenopathy, and acute kidney injury (1.6% each).

EuroQol-visual analogue scale scores were obtained at baseline and during the trial at week 24 and end of treatment. Results showed that, overall, there was an 8.6 (14.69; P = .002) and 7.3 (16.67; P = .011) improvements in score from baseline to the end of treatment visit. At 24 weeks, improvements in mobility were reported in 40 patients on the 9-mg cohort and 50 on the 18-mg cohort, as well as anxiety/depression (50 and 29, respectively), and pain discomfort (50 and 31).

In December 2020, Veru Inc. announced that it had exclusively licensed worldwide rights to enobosarm. Additionally, the FDA has agreed to the phase 3 registration clinical trial design to evaluate the efficacy and safety of enobosarm compared with exemestane or tamoxifen for the treatment of patients with metastatic ER-positive/HER2-negative breast cancer whose cancer has progressed following a nonsteroidal aromatase inhibitor and fulvestrant (Faslodex).

“Having led and participated in the prior two phase 2 clinical studies involving approximately 150 heavily pretreated women in which enobosarm had demonstrated efficacy and was extremely well tolerated, we are excited both about the prospects of enobosarm in the phase 3 trial and the potential for enobosarm to be an important therapeutic agent for women with metastatic breast cancer,” said senior study author Beth Overmoyer, MD, founder and director of the Inflammatory Breast Cancer Program at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School.

References

1. Palmieri C, Linden H, Birrel S, et al. Efficacy and safety of enobosarm, a selective androgen receptor agonist, to target AR in women with advanced AR+/ER+ breast cancer– final results from an international Phase 2 randomized study (G200802). Presented at: 2020 San Antonio Breast Cancer Symposium; December 4-8, 2020; virtual. Abstract PD8-10.
2. Veru expands oncology drug pipeline; exclusively licenses phase 3 clinical stage targeted therapy for endocrine resistant metastatic breast cancer. Veru Inc. News release. December 9, 2020. Accessed December 20, 2020. https://bit.ly/3reKQc5.