ER Modulation May Overcome AI Resistance in ESR1-Mutant Breast Cancer

Hope Rugo, MD

Resistance to aromatase inhibitors (AIs) is a growing concern in patients with advanced hormone receptor (HR)—positive, HER2-negative breast cancer, said Hope S. Rugo, MD, FASCO, who added that although fulvestrant (Faslodex) has shown some activity in patients who develop ESR1 mutations, more effective treatment options are needed.

One such drug that has emerged in this space is lasofoxifene, which is a new-generation selective estrogen receptor (ER) modulator (SERM). This agent is currently being compared with fulvestrant in the phase II ELAINE trial (NCT03781063) in postmenopausal women with locally advanced or metastatic, ESR1-mutant, ER-positive, HER2- negative disease.

“AIs are our standard adjuvant therapy, and if ESR1 is a mechanism of escape, [lasofoxifene] could be an important treatment for these patients who are at risk for early recurrence and resistance to an AI,” said Rugo, a professor of medicine at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center. “Resistance is complicated, but lasofoxifene seems to have efficacy, even in the presence of an ESR1 mutation.”

Preclinical data showed proof of concept of lasofoxifene’s activity in ESR1-mutant cancers,¹ and positive data from the phase II ELAINE trial would provide the first demonstration of clinical efficacy. Due to its potential, the FDA granted a fast track designation to lasofoxifene in May 2019 for use in women with metastatic ER-positive, HER2-negative breast cancer who harbor ESR1 mutations.²

In an interview with OncLive, Rugo, who is also the director of Breast Oncology and Clinical Trials Education at UCSF, discussed the current prognosis for patients with advanced HR-positive, HER2-negative breast cancer who harbor an ESR1 mutation and the research being done to develop more effective therapies for these patients.

OncLive: What is the current prognosis of patients with ESR1-mutant breast cancer?

Rugo: It’s not really clear that the prognosis of patients with ESR1-mutant breast cancer is worse than [that of] patients without the mutation. ESR1 mutations are largely acquired with hormonal treatment; it’s very uncommon to see them in patients who are hormone therapy—naïve. [These mutations develop] under pressure of treatment with AIs, fulvestrant, and other selective ER degraders (SERDs). The main thing we know is that patients with ESR1 mutations are less sensitive to AI therapy. Patients retain their sensitivity to fulvestrant, even though [ESR1] mutations can occur in those who are receiving treatment with that agent.

What are the current unmet needs of this patient population?

It’s very similar to any patient with metastatic HR-positive breast cancer. [The challenge is] understanding who is more likely to develop [ESR1-mutant breast cancer] and being able to treat them more effectively. We know that these patients have disease that’s more resistant to nonsteroidal AIs in particular, including exemestane, based on correlative research. Right now, these patients don’t have any other hormonal therapy [options] available to them other than fulvestrant.

Our first-line treatment for patients who have metastatic HR-positive breast cancer includes a CDK4/6 inhibitor. Now we have overall survival data [on CDK4/6 inhibitors] in combination with AIs in the first- and second-line settings in premenopausal women and in combination with fulvestrant in postmenopausal women, albeit in a subset of the larger MONALEESA-3 trial.

Overall, the lack of toxicity with [CDK4/6 inhibitors] and improvement in survival has moved them to the frontline setting, regardless of the endocrine partner. Now we have to consider what we’re going to do for patients who develop resistance to AIs. As we know, 1 mechanism of resistance to AIs is ESR1 mutations. In that case, blocking the production of estrogen is not sufficient to control the cancer.

The question is, “What is the optimal therapy for these patients?” CDK4/6 inhibitors appear to work regardless of the mutation, but the hormonal partner is in question. That’s led some [of us] to use fulvestrant more, but we don’t really know if that’s the right approach. It would be great to have an endocrine therapy that could work regardless of the presence of an ESR1 mutation.

There is an interesting drug called lasofoxifene. It falls into a similar class as tamoxifen, [a SERM, as] opposed to fulvestrant, which is considered to be a SERD. Lasofoxifene was approved [at a different dose in Europe] as a treatment for patients with osteoporosis, as a sort of raloxifene-type drug, [but it was never launched].

Now we’re accruing patients to the randomized phase II ELAINE trial. Of course, the rational drug to compare lasofoxifene with is fulvestrant. Patients can acquire ESR1 mutations while on fulvestrant, but it doesn’t appear to be the mechanism of resistance to fulvestrant. In the ELAINE trial, patients with an ESR1 mutation who have progressed on a CDK4/6 inhibitor and an AI will be randomized to receive either lasofoxifene or fulvestrant. Approximately one-third of patients who are on AIs [develop an ESR1 mutation]. Patients could have progressed on the AI in the metastatic setting and potentially in the adjuvant setting. It’s going to be fascinating to see how this drug works in patients with a common mutation that correlates with resistance to AIs.

What have been the regulatory developments with lasofoxifene thus far?

The FDA granted a fast track designation to lasofoxifene in the middle of 2019. It’s important to recognize that we do need sequential endocrine therapy in this setting. Historically, we haven’t checked for ESR1 mutations because we would just give fulvestrant. It’s important that we understand which treatments work best for patients with ESR1 mutations. Lasofoxifene could play an important role here. If we look at cell-free DNA in the blood and see evidence of an ESR1 mutation, we could switch patients who have been on an AI to lasofoxifene. We don’t know yet whether switching therapy based on [minimal residual disease] will impact outcomes, but it’s an intriguing question.

Is there any other ongoing research that’s being conducted in this group of patients?

There has been a lot of interest in oral SERDs, such as fulvestrant. Exploratory phase Ib trials are ongoing, as well as phase II and III trials. The original slate of agents that came through had toxicity and minimal efficacy. Now, we’re on a much better path. The EMERALD trial is probably the furthest along in development and has shown intriguing efficacy data with elacestrant (RAD-1901); the agent seems to work regardless of mutation status. Hopefully, we’ll have a whole host of new effective endocrine therapies we can use [in the future].

References

1. Laine M, Fanning SW, Greene M, et al. Lasofoxifene as a potential treatment for ER+ metastatic breast cancer. J Clin Oncol. 2019;37(suppl 15; abstr 1056). doi: 10.1200/JCO.2019.37.15_suppl.1056.
2. Sermonix receives FDA fast track designation for investigational drug lasofoxifene [news release]. Columbus, OH: Sermonix Pharmaceuticals LLC; May 28, 2019. bit.ly/2HH9Ofm?rel=0. Accessed November 5, 2019.