We recently shared some highlights from the 2021 San Antonio Breast Cancer Symposium (SABCS). Check out our first report here, if you missed it.
This week we highlight a couple of other findings from SABCS, regarding metastatic estrogen receptor-positive breast cancer, with a focus on patients who develop treatment resistance through an estrogen receptor (ESR1) mutation. These findings are based on the outcome of progression-free survival (PFS), which to date has not proven to be a good surrogate for clinical benefit such as overall survival and/or quality of life.
Treating ER+/HER2- Metastatic Breast Cancer
Nearly 70 percent of all breast cancers are hormone-sensitive breast cancers, which are treated with endocrine therapy of which there are several types:
These therapies can be combined with ovarian suppression in premenopausal women which reduces the production of estrogen.
Endocrine therapy plus a CDK4/6 inhibitor is the current standard of care for patients diagnosed with metastatic ER+/HER2- breast cancer. When a treatment fails a patient and their breast cancer progresses, it is referred to as “treatment resistance.” There are multiple ways in which resistance can occur, but one common way in ER+/HER2- breast cancer is the development of mutations in a gene that codes for the estrogen receptor (ESR1). Much research is exploring more effective endocrine treatments and treatment protocols. Below we highlight two studies addressing this topic at the 2021 SABCS.
Results of the EMERALD Trial – Oral Selective Estrogen Degraders in Advanced Breast Cancer
The EMERALD trial is examining the use of a new investigational oral selective estrogen receptor degrader (SERD), elacestrant, for the treatment of women with estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast tumors that have progressed on prior endocrine and targeted therapies.
The EMERALD trial is a global, phase III trial that randomized 477 metastatic ER+/HER2- patients who had progressed on a CDK4/6 inhibitor and also patients who had received no more than one line of chemotherapy. Patients were randomized to either 400 mg of elacestrant daily (treatment arm) or physician choice of a hormone-based treatment (control arm). The primary endpoint was PFS in all patients and also in a subgroup of patients with an ESR1 mutation. Overall survival was a key secondary endpoint.
In the intention-to-treat population (all patients in the study), median PFS was 2.8 months vs. 1.9 months for the treatment vs. control arm respectively, demonstrating about a 1-month difference. Among the subgroup of patients with an ESR1 mutation, median PFS was about 3.8 months vs. 1.9 months, demonstrating about a 2-month difference. Data for overall survival, though trending in the positive direction, were immature at the time of the presentation, and are expected in late 2022. This drug is also not without toxicities including a higher frequency of nausea and vomiting, and about twice as many grade 3 and 4 treatment-related adverse events (7.2% vs 3.1%).
This is clearly not a “home run” for metastatic HR+/HER2- breast cancer patients who have progressed on standard treatment. It does open the door to oral SERDs. At present, the only SERD approved for use in breast cancer is Fulvestrant, which requires intramuscular injections every 2 to 4 weeks. An oral SERD might be more appealing to some patients. However, the question is this: is it worth the added toxicities to choose an oral drug over intramuscular injections when the clinical outcome is the same. We do not yet know what it will cost, but it is bound to be priced as high as the market will bear if and when it is approved by the FDA.
Results of the PADA-1 Trial – Assessing the Clinical Utility of ctDNA testing for ESR1 Mutations
The key question in this multicenter “switch” trial of women newly diagnosed with metastatic ER+/HER2- breast cancer, is whether ESR1 mutations can be detected through a blood test before they become clinically relevant and breast cancer progresses. The theory is that if there is early evidence that a mutation is developing, doctors can switch a patient’s therapy from an AI to a SERD. In the trial, patients who were switched saw a doubling of PFS. Those in the control arm who were not switched and crossed over to a SERD at the time of progression (based on CT scan) saw a shorter PFS time, suggesting that earlier switching may have more benefit. Whether or not this is clinically relevant remains to be seen until survival data are available, which will be important to answer because this type of strategy could have cost implications.
More About the Trial. A total of 1,017 women newly diagnosed with metastatic ER+/HER2- breast cancer were enrolled, and all began treatment with an AI plus the CDK4/6 inhibitor palbociclib as first-line therapy. Patients provided blood samples for ESR1 mutation screening at baseline, 1 month, and every 2 months thereafter. There were 279 patients where the blood tests indicated a developing ESR1 mutation and there was no progressive disease. These patients were then randomized to either continue the AI plus palbociclib treatment (control arm) or to switch to Fulvestrant (a SERD) plus Palbociclib (treatment arm). The primary outcome measure was PFS following randomization. Overall survival (OS) was a key secondary outcome. Patients in the control arm were allowed to crossover when their breast cancer progressed.
According to results presented at SABCS, median PFS was 11.9 months vs. 5.7 months among patients in the treatment vs. control arm, respectively, a difference of 6.2 months. For those patients in the control arm who progressed and crossed over to the Fulvestrant arm, median PFS was 3.5 months. The results of this study suggest that blood-based monitoring for early ESR1 mutation development may allow for longer PFS benefit in the first-line treatment setting for ER+/HER- metastatic breast cancer. However, no OS data have yet been presented, so we don’t yet know if this earlier switch prolongs survival which is necessary to make this additional regular (every 2 months) testing worthwhile, especially considering the likely costs that this would incur to patients and the healthcare system. More data will be needed to answer that question.
