Matthew Goetz, MD, Mayo Clinic, Rochester, MN, highlights the ELAINE 1 trial exploring lasofoxifene vs fulvestrant for patients with locally advanced/metastatic breast cancer and an estrogen receptor 1 (ESR1) mutation who progressed on aromatase and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

Results from the trial, which were presented at the European Society for Medical Oncology (ESMO) Congress, favored lasofoxifene over fulvestrant for all clinical outcomes. ELAINE 1 is the first clinical trial demonstrating activity of a novel selective estrogen receptor modulator (SERM) in this setting.

Transcript:

My name is Dr. Matthew Goetz. I'm a medical oncologist at the Mayo Clinic in Rochester, Minnesota. I'm talking today about the ELAINE-1 study that we presented here at the 2022 ESMO Congress. The ELAINE-1 clinical trial was focusing on an old target, the estrogen receptor, but it was focusing on a new aspect of this old target, namely these activating mutations in the ligand binding domain that confer an endocrine resistance.

And we know from pre-clinical research as well as clinical data that patients who develop these mutations tend to have a worse prognosis. They exhibit resistance to standard-of-care endocrine therapy, and they have a worse overall survival. So there's been a lot of interest in developing new drugs that would target these ESR1 mutations. One of the most common drugs that we think about that may have efficacy in this group is the SERDs, selective estrogen receptor degraders.

And we've seen a lot of data emerge with the SERDs. But in this study, we actually looked at a novel drug, a drug that is called lasofoxifene, which is a selective estrogen receptor modulator. It's novel in the sense that it's different than the other trials testing SERDs, but it's not novel in the sense that lasofoxifine has actually been around for quite some time. It was developed years ago and demonstrated substantial benefit in terms of preventing breast cancer. But this is really the first set of studies that we've looked at, ELAINE-1 and ELAINE-2, where we've tested the drug in patients who have these ESR1 mutations. The ELAINE-1 trial simply looked at women who had metastatic ER-positive/HER2-negative breast cancer, who had progressed on an aromatase inhibitor and a CDK4/6 inhibitor, and who had circulating tumor DNA evidence for an ESR1 mutation.

Patients were randomized to either fulvestrant or lasofoxifene, and the primary endpoint was progression-free survival. What we found was that the progression-free survival for lasofoxifene was prolonged compared to fulvestrant, about 6 months versus 4 months. However, this was not statistically significant, although there was a trend certainly toward that direction. We additionally looked at some secondary endpoints of response rates and clinical benefit rate and in both cases, again, lasofoxifene was numerically better than fulvestrant, for example, a response rate of over 13% for lasofoxifene versus fulvestrant, less than 3%. I would point out that the safety has always been a question mark. Of course, with SERMs, we know that tamoxifen has a slightly higher risk of developing [deep vein thrombosis] DVT and pulmonary embolism] PE, and so we were very encouraged to see that there was no thrombotic events in patients treated with lasofoxifene, and it was really well tolerated.

The final thing I'll mention was an exploratory analysis, but was really one of the most interesting parts of the study to me, and that is looking at the circulating tumor DNA. When we are giving a drug, one of the things in this case, we know what the target is, and that's the mutated estrogen receptor, and we're able to follow that. So the mutated estrogen receptor is a pharmacodynamic target. And what we can look for is evidence of, are we actually hitting the target? Is it actually going away? And in fact, that's indeed what we saw. There was much better target engagement with lasofoxifene compared to fulvestrant with a substantial decrease in the mutant allele fraction with lasofoxifene compared to fulvestrant. And where this was most notable is in an ESR1 mutant called the Y537S. And the Y537S was a stratification factor, why? Because it tends to be a mutant that's a little bit more aggressive and even perhaps associated with worse endocrine resistance. And what we found was that patients with the Y537S had substantial decrease in their mutant allele fraction with lasofoxifene, but actually with fulvestrant there was an increase in the mutant allele fraction. This would suggest to us that lasofoxifene is having on-target effects.

In terms of future directions, where we're going to go with this, is lasofoxifene will be studied in combination with other drugs. Already we have results from the ELAINE-2 trial, which tested lasofoxifene along with abemaciclib. This was reported at the ASCO 2022 annual meeting demonstrating that the combination, again, in ESR1 mutated, highly refractory group of patients who had progressed on a CDK4/6 inhibitor, the response rate was 50% with a progression-free survival of almost 14 months. So it looks like the combination of abemaciclib along with lasofoxifene is really an outstanding combination based on these early data, and future studies are planned in this area.

Source:

Goetz MP, Plourde P, Stover DG, et al. Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors. Presented at: ESMO Congress; September 9-13, 2022. Paris, France and virtual. Abstract LBA20.