Positive Phase 2 Data Set the Stage for the Pivotal ARTEST Trial With Enobosarm in ER+/AR+ Metastatic Breast Cancer

Enobosarm, an investigational, nonsteroidal, selective androgen receptor (AR) agonist, could represent a new treatment approach in estrogen receptor (ER)–positive, AR-positive metastatic breast cancer, said Adam M. Brufsky, MD, PhD, FACP, who added that the agent could offer testosterone-like activity without testosterone-related toxicities and quality of life (QOL) improvement.

“The idea [of enobosarm] is that instead of giving antiandrogens, we can give androgen agonists that will activate [the AR] and potentially block ER-dependent signaling,” said Brufsky, a professor of medicine at the University of Pittsburgh School of Medicine, associate division chief for the Division of Hematology/Oncology in the Department of Medicine, medical director of the Magee-Women’s Cancer Program of UPMC Hillman Cancer Center, associate director for clinical investigations at UPMC Hillman Cancer Center, and codirector of the Comprehensive Breast Cancer Center.

Findings from a phase 2 trial (NCT02463032) demonstrated a clinical benefit rate (CBR) of 52% at 24 weeks in patients with ER-positive, HER2-negative advanced breast cancer and AR staining of at least 40%. The 24-week CBR was 14% in patients with AR staining of less than 40%. The best overall response rates (ORRs) were 34% vs 2.7%, respectively. The median progression-free survival (PFS) was 5.47 months compared with 2.7 months, respectively.

During the 2021 San Antonio Breast Cancer Symposium (SABCS), a trial-in-progress poster was presented overviewing the study schema of the phase 3 ARTEST trial (NCT04869943), which is evaluating enobosarm in the third-line setting for patients with metastatic ER-positive, AR-positive, HER2-negative advanced breast cancer. Patients must have progressed on a nonsteroidal aromatase inhibitor (AI), fulvestrant (Faslodex), and a CDK4/6 inhibitor; patients cannot have received prior chemotherapy.

Patients (n = 210) will be randomized 1:1 to receive 9 mg of enobosarm given once daily or an active control.

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

In an interview with OncLive^®, Brufsky discussed the rationale to evaluate enobosarm in ER-positive, AR-positive metastatic breast cancer, prior data observed with the agent, and the unmet needs positive results of the ARTEST trial could potentially fulfill.

OncLive^®: What is the mechanism of action of enobosarm that makes it a rational agent to evaluate in ER-positive, AR-positive advanced breast cancer?

Brufsky: It’s interesting what is going on in ER-positive metastatic breast cancer that is resistant to CDK4/6 inhibitors and hormone therapy. We are trying to figure out a mechanism of resistance, as well as trying to figure out interventions that can affect those mechanisms. There was an interesting translational paper [that was published] about a year ago in Nature Medicine. [The paper] showed that AR is a tumor suppressor. In other words, for patients with ER-positive, AR-positive metastatic breast cancer, stimulation of the AR displaces the ER or other molecules that bind to pieces of DNA called estrogen response elements. That is the basic science of it.

What data set the stage for the development of the pivotal ARTEST trial?

Enobosarm has been [evaluated] for a long time [as a way] to improve QOL. We figured that if [patients] get some anabolic [activity], [enobosarm could act like] lite testosterone without a lot of the testosterone adverse effects. [The agent has] been tried in multiple clinical trials. Unfortunately, one study in non–small cell lung cancer several years ago didn’t meet statistical significance. However, [enobosarm] does seem to enhance QOL.

A lot of trials have been done [in breast cancer]. Initially, [the agent] was tried in triple-negative breast cancer that was positive for AR. It was a nice phase 2 trial that will be published soon where enobosarm was given to patients who had progressive ER-positive metastatic disease. It turned out that patients had a reasonable response rate. If patients had greater than 40% staining of the AR in cells, the response rate was about 34% with a CBR of about 52%. The median PFS was over 5.5 months, which was better than the patients who had under 40% staining of the AR. The CBR for those patients was 14% with almost no response.

Putting this together, we have good preclinical rationale. In fact, that preclinical trial was published about 1 year ago. It was a cell-line, animal-model study where a human tumor was placed on a patient-derived xenograft model. That human tumor was from a patient who had progressed through CDK4/6 inhibitors. As a result, in this model, it looked like the cells that were resistant to CDK4/6 inhibitors benefitted from this [agent].

What is the design of the ARTEST trial?

The pivotal phase 3 ARTEST trial is a study of patients with ER-positive, AR-positive, HER2-negative metastatic breast cancer in the third-line setting. [Patients must have] greater than 40% [AR] staining [and] will have had to progress on a nonsteroidal AI, fulvestrant, and a CDK4/6 inhibitor. Patients cannot have had prior chemotherapy. Ultimately, 210 patients will be randomized 1:1 to 9 mg of enobosarm or a control, which is a typical third-line hormonal therapy of exemestane and everolimus [Afinitor] or a selective estrogen receptor modulator like tamoxifen. It’s an interesting study and it may help us figure out where to go next.

Although we are awaiting the data from the ARTEST trial, pending positive results, what could the future of enobosarm hold?

Clearly, we have an unmet need in the population of patients who are resistant to CDK4/6 inhibitors. We have PI3K inhibitors and everolimus, but we need other targeted agents with low toxicity. It is a very busy area and there is a lot of interest in figuring out what to do in this setting.

The nice thing about enobosarm is that if it does work, it will improve QOL 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.

Reference

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