Investigators are exploring whether lasofoxifene can stop disease progression in women with advanced or metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer with an ESR1 mutation in the multicenter phase II ELAINE trial (NCT03781063).
Matthew Goetz, MD
Investigators are exploring whether lasofoxifene can stop disease progression in women with advanced or metastatic estrogen receptor (ER)—positive, HER2-negative breast cancer with an ESR1 mutation in the multicenter phase II ELAINE trial (NCT03781063).
Hormone receptor positive breast cancer is the most common type of breast cancer: About 2 of 3 breast cancers diagnosed express the estrogen receptor.1 Standard of care (SOC) for this disease type includes endocrine-based therapies that target the ER pathway, including aromatase inhibitors (AIs) or tamoxifen in the adjuvant setting.2 However, endocrine resistance develops in nearly all patients who are treated with endocrine based therapies in the metastatic setting.
“Over the past 5 to 10 years researchers have focused on the genomic alterations that drive resistance to hormonebased therapy,” said Matthew Goetz, MD, principal investigator of the ELAINE trial in Rochester, Minnesota, in an interview with OncologyLive®. “When we think of resistance to hormonal therapy, one of the most critical factors to understand is the mechanism that underlies the resistance. In this way, our subsequent therapies can be better targeted to address the resistance.”
The phase II trial comes in response to the need for more treatment options and the reality that the optimal systemic therapy after disease progression on a CDK4/6 inhibitor is currently unknown. In the study, 100 postmenopausal women with advanced or metastatic ER-positive/HER2- negative breast cancer whose disease progressed on an AI in combination with a CDK4/6 inhibitor will be randomized 1:1 to receive lasofoxifene or first-line SOC fulvestrant (Faslodex; Figure). Investigators hypothesize that lasofoxifene will double the median progression-free survival compared with fulvestrant in this patient population, for a hazard ratio of 0.5 and a power of 89% to reach a 1-sided P <.05.2
Two types of resistance, which Goetz terms “de novo” and “acquired,” dominate this disease setting. The former type refers to instances when patients with ER-positive breast cancer have either a very short response to treatment or no response.
“The most prevalent type of resistance that we see is acquired resistance. In this scenario, we administer hormone based therapies and observe evidence for clinical benefit, but then eventually the tumor cells develop changes that allow them to adapt and grow,” Goetz said. “We now know that
ESR1 mutations occur quite commonly in women with acquired resistance. The exact proportion is unclear, but some studies suggest that anywhere between 30% to 50% of patients with acquired endocrine resistance will [also have] these mutations.” ESR1 mutations occur in the ligand-binding domain of the ER. “The mutations activate the estrogen receptor independent of ligand binding,” Goetz said. “Typically, in order to activate the estrogen receptor, you need both the receptor and the ligand present. But in this situation, the presence of the mutation confers activation of the estrogen receptor which can lead to resistance to standard endocrine based therapies.”
Goetz said AIs would not be an appropriate choice for those with ESR1 mutations because AIs only remove the ligand. In contrast, other agents, such as fulvestrant, have demonstrated activity in ESR1-mutated tumors. A selective ER degrader, fulvestrant binds to the ER resulting in ER degradation.3 Although fulvestrant’s mechanism of action is ideal for tumors bearing ESR1 mutations, fulvestrant cannot wholly halt disease progression. In this setting, CDK4/6 inhibitors have demonstrated substantial antitumor activity in patients with ESR1 mutations who have progressed on prior endocrine therapy.
Figure. Lasofoxifene Versus Fulvestrant Phase II ELAINE Trial (Click to Enlarge)
Lasofoxifene is a selective ER modulator (SERM) that binds to the ER with high affinity to inhibit estrogen-dependent cancer cell proliferation in ER-expressing cancers.4 Like lasofoxifene, tamoxifen is a SERM that binds to the ER to promote antiestrogenic activity. The nonsteroidal compound is a recommended treatment option for both pre- and postmenopausal women with breast cancer and is most commonly used in the adjuvant setting in patients with early-stage disease to reduce the risk of recurrence. The National Comprehensive Cancer Network guidelines recommend 5 to 10 years of treatment with tamoxifen.5
“The difference is lasofoxifene appears to be a bit more potent than tamoxifen and has a favorable conformational change in the estrogen receptor when [the receptor is] mutated,” Goetz said. Preclinical data showed lasofoxifene’s efficacy in in vivo and in vitro nonclinical breast cancer models with and without ESR1 mutations.2 The agent notably reduced metastases in the ESR1-mutated models. “That lasofoxifene showed promise in these models suggests that it could be a good approach to treating women with ESR1 mutations,” Goetz added.
In May 2019, lasofoxifene notably received a fast track designation for use in women with ER-positive/HER2-negative metastatic breast cancer who harbor ESR1 mutations.6 The agent was also the focus of the phase III, placebo-controlled PEARL trial (NCT00141323), initiated in 2001. The study evaluated the experimental agent’s ability to reduce new spinal fractures in 8556 postmenopausal women aged 59 to 80 years with osteoporosis.7 An additional primary measure was the number of new cases of breast cancer. The women were randomized to receive lasofoxifene 0.25 mg/day, lasofoxifene 0.5 mg/day, or placebo for 5 years.
At 5 years, 11 women in the lower-dose lasofoxifene group (0.9 cases per 1000 person-years) and 4 women in the higher- dose lasofoxifene group (0.3 cases per 1000 person-years) had ER-positive breast cancer compared with 21 women in the placebo group (1.7 cases per 1000 personyears). This represented 48% (P = .07) and 81% (P <.001) decreases in risk, respectively, in the lower-dose and higher-dose lasofoxifene groups. Lasofoxifene did not increase the risk for endometrial cancer or hyperplasia in postmenopausal women.
“The [PEARL] trial, as a proof of principle, demonstrated that lasofoxifene was efficacious and also extremely well tolerated,” Goetz said. “Unlike tamoxifen, which has a very slight risk of endometrial cancer, there was no evidence of risk with lasofoxifene.”
The ELAINE study will assess 12 ESR1 mutations: D538G, E380Q, L536H, L536P, L536Q, L536R, P535H, S463P, V534E, and Y537C, Y537N, Y537S. The study, which includes secondary endpoints of clinical benefit rate, objective response rate, and adverse events, is now active.
“However, like any other agent, disease will eventually progress on CDK4/6 inhibitors,” Goetz said. “[Resistance] is a major clinical problem. We need new approaches to treat these women.”