Enobosarm Generates Overdue Excitement in AR+/ER+ Metastatic Breast Cancer

Lee S. Schwartzberg, MD

After decades of research, investigators are hopeful that the nonsteroidal selective androgen receptor (AR) agonist enobosarm could become an important treatment strategy following CDK4/6 inhibition in patients with AR-positive, estrogen receptor (ER)–positive, metastatic breast cancer based on robust understanding of the drug’s mechanism of action, preclinical findings, and phase 2 efficacy and safety data, explained Lee S. Schwartzberg, MD, FACP.

“We always need to look back into history and try to elevate some of the seminal clinical observations that were made in the past and repurpose them now in a modern era. Enobosarm is an evolution of what we knew 40 years ago in breast cancer––that the androgen axis is important and can be manipulated to improve the outcomes of some patients with breast cancer. Hopefully, we’re going to have a better way of doing that, a more effective way of doing that, and a more rational place in the sequence to do it. I’m very excited about [the research that’s to come],” said Schwartzberg.

In an interview with OncLive^®, Schwartzberg, chief medical officer and board member of OneOncology, discussed the culmination of research with androgen-targeted agents in metastatic AR-positive, ER-positive breast cancer and ongoing research that could lead to a paradigm shift in the second-line setting.

OncLive^®: What work has been done to define treatment approaches targeted toward the AR in ER-positive breast cancer?

Schwartzberg: We’ve known for decades that in ER-positive, advanced breast cancer there was a role for endocrine therapy in the form of androgens. We know from the early days before we had drugs like aromatase inhibitors [AIs] and when our armamentarium was limited to tamoxifen and other [similar] drugs that standard kinds of androgens, like natural androgens and semi-synthetic androgens like fluoxymesterone [Halotestin], played a role. We saw responses to the use of androgens in advanced breast cancer decades ago, so why don’t we think about those today? Well, we have a lot of better agents now, and the [older agents] caused a lot of toxicity and adverse effects [AEs] that women did not like, particularly [because of] the fact that they’re androgens and most of them were virilizing. So, the women grew hair and had other problems from those agents, and they weren’t the easiest agents to give either. There’s no question that the use of androgens in advanced hormone receptor [HR]–positive breast cancer has been firmly established for a long time.

Now, what is the biology behind that? About 70% to 80% of ER-positive breast cancer also contains positive AR. The way that AR works in an ER-positive cell has been a mystery and is not completely clear. We now believe that in HR-positive patients, the AR functions more as a tumor suppressor gene. It’s not like if you suppress ER as we do with most of our endocrine therapies that the androgen turns on like it does in prostate cancer. It seems to have a different role in this group of patients. In the past, we’ve tested blockers of AR based on what was probably an erroneous principle, that it could be a resistance mechanism by signaling through AR as opposed to HR. We used drugs like enzalutamide [Xtandi] and other drugs that inhibited androgens either directly or [through] the production of androgens like fulvestrant [Faslodex], which were also used in the past. It turned out [those drugs] didn’t have a great benefit in that setting.

As the biology and the understanding has matured, we have found that with selective estrogen receptor modulators [SERMs], which can be thought of as analogous to drugs like tamoxifen, which is also SERM, that we can create drugs that do not have the virilizing effect of a direct androgen or testosterone. In other words, [agents that are not] testosterone derivatives but that target and stimulate or block the AR depending on the agent and how it interacts with the receptor. One of those drugs is enobosarm, which is a selective AR modulator that has been looked at extensively in preclinical models. In AR-positive, HR-positive preclinical models, enobosarm has a profound effect at inhibiting the growth of cancers, and that’s true in cell lines that are estrogen sensitive and estrogen resistant. In mouse models, it also is extremely inhibitory and combines well with CDK4/6 inhibitors. There are at least additive effects of using enobosarm and CDK4/6 inhibitors in HR-positive murine models of cancer. That led to the decision to look at enobosarm from a clinical perspective to see its activity in humans with metastatic breast cancer.

What has the phase 2 experience been like with enobosarm?

Enobosarm was tested first in a phase 1 setting and was found to be well tolerated. Then it was tested in a small phase 2 setting and that led to a larger phase 2 trial of 2 different doses of oral, continuous enobosarm at 9 mg daily or 18 mg daily.

The now updated results of the larger phase 2 trial that included over 100 patients in the 2 arms were presented at the ESMO Breast Virtual Congress 2021. In this group of heavily pretreated patients with HR-positive disease––the median number of prior lines of endocrine therapy was 3, and over 90% had been exposed to chemotherapy––the 6-month clinical benefit rate [CBR], which was the primary end point of the phase 2 trial was 32% in the 9-mg arm and 29% in the 18-mg arm. The progression-free survival [PFS] for enobosarm was [more than] 5.6 months vs 4.2 months in the 9-mg vs 18-mg arms, respectively. The overall response rate [ORR] was reasonable [at] 30% in patients who had prior CDK4/6 inhibition and 30% in the patients who had measurable disease, which included complete responses.

The 9-mg dose turned out to be the better dose; it was a little less toxic and had at least as good activity with numerically better efficacy than the 18-mg dose. Enobosarm is clearly an active agent that has relatively little toxicity. Most of the AEs that were seen in that phase 2 trial were mostly grade 1 and 2; there were a few increased liver function tests from enobosarm, and hypercalcemia was seen in some patients. That was the dose-limiting toxicity early on, but that was only seen in a couple of patients and was easily managed.

What was also interesting about that trial was that in 50% of the patients who had had prior exposure to CDK4/6 inhibition, which represents today’s patients, almost all of whom get a CDK4/6 inhibitor in the first- or second-line setting with endocrine therapy, the CBR was 50%. In other words, stable disease or better at 24 weeks was seen in 50% of a small number of patients. The phase 2 data recapitulated nicely the preclinical work. Enobosarm is an active agent and after multiple lines of endocrine therapy with our usual agents, including CDK4/6 inhibitors, [we know] it’s worthy of further discussion and trials.

During the 2021 San Antonio Breast Cancer Symposium, the ARTEST trial (NCT04869943) design was presented. Could you shed light on the trial design?

The ARTEST trial is an interesting phase 3 trial, which is looking at patients that are HR positive, HER2 negative, and AR positive.

One of the things that the investigators found in the phase 2 trial is when they looked retrospectively at the level of AR that supported a response or clinical benefit, it turned out that there was a good breakpoint at an AR level of 40%. Up to 90% of ER-positive breast cancer will contain AR, but just like ER, there’s a wide range of expression of the biomarker.

ARTEST will be looking at enrolling patients who have at least 40% expression of AR as determined by immunohistochemistry. AR testing is widely commercially available. It’s used in other diseases like prostate cancer. AR testing can be done in any pathology lab. Patients who are ER positive, at least 40% AR positive, and HER2 negative are eligible for ARTEST. Patients must have had 2 lines of prior therapy, including a CDK4/6 inhibitor and an AI or fulvestrant. [Patients are eligible] after 2 lines of prior endocrine therapy, including a CDK4/6 inhibitor.

Patients will be randomized to 9 mg of enobosarm vs physician’s choice of endocrine therapy: exemestane, exemestane and everolimus [Afinitor], or a SERM like tamoxifen or another drug of that kind. The primary end point of ARTEST is PFS, and the secondary end point is ORR. Patients can be postmenopausal or premenopausal as long as they are on ovarian function suppression with an LHRH [luteinizing hormone-releasing hormone] agonist, and they have to have measurable disease; they can’t have bone only disease, as we see in this population.

This trial is just launching. If enobosarm shows activity that is better than the endocrine therapy of physician’s choice as an active control, this will become an important treatment modality in our armamentarium. Despite the excellent advances with CDK4/6 inhibitors, and now the oral SERDs [selective estrogen receptor degraders] that are coming out, none of these drugs are going to be curative. We also know now that patients do very well with endocrine therapy for a prolonged period. If we can get another agent that works in a completely different mechanism for these patients that are HR positive, we can potentially prolong their time to live and prolong their time until they need chemotherapy. Everyone agrees that endocrine therapy is kinder and gentler, and often more effective than chemotherapy in this large subgroup of patients that are HR positive, HER2 negative with advanced breast cancer.

Where else is enobosarm being evaluated?

A fascinating trial is looking at enobosarm and abemaciclib [Verzenio] for patients who have had prior treatment with palbociclib [Ibrance] and endocrine therapy. This gets to a central debate that we’re having now in the breast cancer community: What is the best approach after failure with standard CDK4/6 inhibition and endocrine therapy? Is it changing to a different CDK4/6 inhibitor? Is it changing to a different endocrine therapy? Is it both? This study, which looks from the endocrine component at a wholly different agent, which targets AR [is going to be interesting to see if] we get a good signal in patients with endocrine resistance. I’m excited about that trial because it’ll be excellent proof of principle.