FDA Grants Fast Track Designation to Enobosarm for AR+/ER+ Metastatic Breast Cancer

The FDA has granted a fast track designation to enobosarm as a potential therapeutic option for patients with androgen receptor–positive, estrogen receptor–positive, HER2-negative, metastatic breast cancer who progressed on a nonsteroidal aromatase inhibitor, fulvestrant, and a CDK4/6 inhibitor, and who have AR staining of 40% or more in cancer tissue.

The FDA has granted a fast track designation to enobosarm as a potential therapeutic option for patients with androgen receptor (AR)–positive, estrogen receptor (ER)–positive, HER2-negative, metastatic breast cancer who progressed on a nonsteroidal aromatase inhibitor (AI), fulvestrant (Faslodex), and a CDK4/6 inhibitor, and who have AR staining of 40% or more in cancer tissue.1

An oral, first-in-class, non-steroidal, selective AR agonist, enobosarm was designed to have selectivity to activate the AR without cross-reactivity to other steroidal hormone receptors.2 Selective tissue activities are thought to translate to a strong safety profile that has shown to be non-masculinizing, to be without liver toxicity, and without changes in hematocrit.

Because the agent is not a substrate for aromatase, it cannot be aromatized to estrogen. Notably, enobosarm has been shown to both build and heal bone, thus possessing the potential to treat antiestrogen-induced osteoporosis and prevent skeletal-related events. Moreover, the agent has also been hypothesized to be able to improve muscle mass and physical function.

“We are very pleased that enobosarm has received fast track designation from the FDA, a distinction that underscores the urgent need for new, novel targeted therapies for this important patient population suffering from this aggressive disease,” Mitchell Steiner, MD, chairman, president, and chief executive officer of Veru Inc., stated in a press release. “We look forward to ongoing, productive regulatory interactions with the FDA, which are further enabled with this designation.”

Findings from a phase 2 trial (NCT02463032) showed that among 50 evaluable patients with AR-positive breast cancer who received the agent at 9 mg, the clinical benefit rate (CBR) at 24 weeks was 32% (95% CI, 19.5%-46.7%). In a cohort of patients who received the agent at a dose of 18 mg (n = 52), the 24-week CBR was 29% (95% CI, 17.1%-43.1%).

Further data from a post-hoc AR expression subset analysis showed that among patients with AR staining of 40% or higher (n = 47), the 24-week CBR was 52% with enobosarm, with a best overall response rate (ORR) of 34% and a median progression-free survival (PFS) of 5.47 months. Among a subset of patients with AR staining of less than 40% (n = 37), the 24-week CBR was 14%, a best ORR of 2.7%, and a median PFS of 2.70 months.

Regarding safety, enobosarm was found to be well tolerated with most events being just grade 1 or 2 in severity. The agent resulted in serious adverse effects (AEs) in 10.7% of those who received the agent at 9 mg (n = 75) and 16.4% of those who received it at 18 mg (n = 61). In these cohorts, grade 3 treatment-related AEs (TRAEs) were reported in 5 and 9 patients, respectively; grade 4 TRAEs were reported in 1 patient in each cohort.

The most common grade 3 or 4 TRAEs reported with enobosarm in the 9- and 18-mg cohorts, respectively, included increased alanine aminotransferase (1.3% and 3.3%), increased aspartate aminotransferase (2.7% and 0%), hypercalcemia (2.6% and 3.3%), headache (1.3% and 1.6%), anemia (1.3% and 0%), dry mouth (0% and 1.6%), decreased white blood cell count (0% and 1.6%), decreased appetite (0% and 1.6%), fatigue (1.3% and 3.3%), tumor flare (0% and 3.3%), agitation (0% and 1.6%), lymphadenopathy (0% and 1.6%), and acute kidney injury (0 % and 1.6%).

The phase 3 ARTEST trial (NCT04869943) is examining enobosarm as third-line treatment in patients with metastatic ER-positive, AR-positive, HER2-negative, advanced breast cancer. To be eligible for enrollment, patients must have progressed on a nonsteroidal AI, fulvestrant, and a CDK4/6 inhibitor.

Specifically, patients must have received a nonsteroidal AI as a single agent or part of a combination regimen for adjuvant or metastatic disease and fulvestrant for metastatic disease. At least 1 of the nonsteroidal AIs or fulvestrant must have been given in combination with a CDK4/6 inhibitor.

Moreover, patients must have previously responded to hormone therapy for metastatic disease at 6 months or longer before study treatment initiation, had centrally confirmed AR nuclei staining of 40% or higher on breast cancer tissue, and measurable disease per RECIST v1.1 criteria. Patients could not have previously received chemotherapy for metastatic disease.

Study participants (n = 210) will be randomized 1:1 to receive either enobosarm at 9 mg or an active control regimen of exemestane with or without everolimus (Afinitor) or a selective estrogen receptor modulator.

The primary end point of the trial is median radiographic PFS, and key secondary end points include ORR, duration of response, overall survival, change in short physical performance battery, and change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.

“Clearly, we have an unmet need in the population of patients who are resistant to CDK4/6 inhbitors. We have PI3K inhibitors and everolimus, but we need other targeted agents with low toxicity…” Adam M. Brufsky, MD, PhD, FACP, told OncLive® in a recent interview. “The nice thing about enobosarm is that if it does work, it will improve quality of life since it is an anabolic agent. There could be a lot of interest in moving [enobosarm] up to patients who are doubly positive for ER and AR. It could be used both as first-line therapy and potentially as adjuvant therapy. That is getting ahead of ourselves though because the first thing we need to do is see the results of the pivotal ARTEST trial.”

Enobosarm is also under evaluation in combination with abemaciclib (Verzenio) in the second-line treatment of patients with AR-positive/ER-positive breast cancer who have progressed following treatment with palbociclib and a nonsteroidal AI or fulvestrant combination with an AR nuclei staining of 40% or higher, as part of the phase 3 ENABLAR-2 trial (NCT05065411).

In another phase 2 trial, investigators will explore the use of enobosarm in combination with sabizabulin (VERU-111) for the treatment of patients with metastatic triple-negative breast cancer following 2 systemic chemotherapies.


  1. Veru announces FDA grant of fast track designation for enobosarm for the treatment of AR+ ER+ HER2- metastatic breast cancer. News release. Veru Inc.; January 10, 2022. Accessed January 10, 2022. https://bit.ly/3F7lxyt
  2. Brufsky A, Linden H, Rugo H, et al. Randomized, multicenter, international phase 3 ARTEST study to evaluate the efficacy and safety of enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who progressed on a nonsteroidal aromatase inhibitor, fulvestrant and CDK4/6 inhibitor. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. Poster OT2-17-01. https://bit.ly/3srjumc