Endocrine Therapy in Breast Cancer: Improving Clinical Benefits

Most breast cancers express the estrogen and/or progesterone hormone receptors, which fuel tumor growth upon engagement with their respective hormone ligands. Fortunately, patients with hormone receptor-positive breast cancers have the highest rates of survival compared with other subtypes, in part because of the many treatments available to them. 

As discussed in part I of this two-part series on endocrine therapies, patients with estrogen receptor (ER)-positive breast cancer may be treated with drugs that suppress estrogen-dependent tumor growth by inhibiting estrogen production, preventing the binding of estrogen to the estrogen receptor, or by degrading the estrogen receptor. 

Drugs that degrade the estrogen receptor are categorized as selective estrogen receptor degraders (SERDs). Currently, fulvestrant (Faslodex) is the only SERD approved by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer. While fulvestrant has shown clinical benefit for postmenopausal women with advanced ER-positive breast cancer, there are several limitations to this therapy. 

One drawback is that resistance to fulvestrant commonly develops due to mutations in ESR1, the gene that encodes the ER. Since fulvestrant is the only FDA-approved SERD to date, patients whose tumors become resistant to it are left with limited treatment options. This highlights a need for alternative, and potentially more effective, SERDs for patients whose tumors develop resistance to fulvestrant. Furthermore, there is great interest in developing an orally administered SERD, which may have greater absorption and enhanced inhibition of ER compared with the intramuscularly delivered fulvestrant. 

Another challenge comes from the reduced benefit of fulvestrant when administered in the second-line setting. Postmenopausal patients whose tumors develop resistance to first-line hormone therapy may receive second-line treatment with fulvestrant; however, the advanced stage of the cancer limits the efficacy of fulvestrant in this setting. Researchers are, therefore, interested in identifying patients who may benefit from earlier fulvestrant treatment. 

Strategies to overcome these challenges are currently under clinical investigation and were discussed at the 2021 San Antonio Breast Cancer Symposium, which was co-sponsored by the AACR and held December 7-10, 2021. 

Clinical efficacy of an investigational oral SERD: Results from the phase III EMERALD trial 

A clinical trial presented by Aditya Bardia, MD, MPH, evaluated the clinical efficacy of the investigational SERD elacestrant. Unlike fulvestrant, elacestrant is administered orally and has demonstrated greater absorption, improved pharmacokinetics, and enhanced inhibition of ER in preclinical studies.  

To understand how elacestrant compares to the current standard of care, Bardia and colleagues conducted the phase III EMERALD trial, making elacestrant the first oral SERD to be studied in a randomized phase III clinical trial. The results were shared at SABCS last December and published in May 2022.  

The trial enrolled 477 postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer who had received one or two prior lines of endocrine therapy without chemotherapy in the metastatic setting, and who had progressed on prior treatment with a CDK4/6 inhibitor. Patients were randomly assigned to receive either elacestrant or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor). Among the enrolled patients, 228 had tumors with mutated ESR1 (115 in the elacestrant arm and 113 in the standard-of-care arm). 

Bardia reported that patients in the elacestrant arm had a 30 percent lower risk of death or disease progression compared with those in the standard-of-care arm. Among patients whose tumors had ESR1 mutations, those in the elacestrant arm had a 45 percent reduced risk of death or disease progression. Elacestrant improved outcomes regardless of the presence of visceral metastases, the number of prior lines of therapy, pretreatment with fulvestrant, or geographic region, he noted.   

At 12 months, patients in the elacestrant arm had a significantly higher rate of progression-free survival than those who received the standard of care (22.32 percent vs. 9.42 percent). Among patients with ESR1-mutated tumors, 26.76 percent of those treated with elacestrant had progression-free survival at 12 months compared with 8.19 percent of patients treated with standard of care.  

“Elacestrant is the first oral SERD that has demonstrated a statistically significant and clinically meaningful improvement in clinical outcome as compared with standard-of-care endocrine therapy in a phase III clinical trial for patients with ER-positive/HER2-negative metastatic breast cancer,” Bardia concluded.  

“The study provides proof-of-principle of the superiority of a novel oral SERD as compared to standard endocrine therapy,” he added. “Elacestrant has the potential to become a new treatment option in the studied patient population.” 

Optimizing the timing of SERD treatment: Results from the phase III PADA-1 trial 

Although estrogen production by the ovaries ceases after menopause, other tissues in the body continue to produce residual estrogen, which can activate ER-dependent breast tumor growth. Therefore, postmenopausal patients with ER-positive breast cancer are often treated with aromatase inhibitors, which block this residual estrogen production.  

However, breast cancers can become resistant to aromatase inhibition if ESR1 develops mutations that allow it to function without estrogen engagement. Patients whose tumors develop resistance to aromatase inhibitors may be treated with fulvestrant in the second-line setting; however, fulvestrant has limited benefit when used in this context, according to François-Clément Bidard, MD, PhD. 

Bidard and colleagues reasoned that identifying patients whose tumors are likely to become resistant to aromatase inhibitors would allow for fulvestrant to be administered earlier, before the cancer progresses and when it may be more effective. To test this hypothesis, they utilized patient blood samples to detect ESR1 tumor mutations that arose during aromatase inhibitor treatment. 

“Our goal was to track the emergence of ESR1 mutations in patients’ blood during first-line therapy and act on them as soon as they appeared, before they led to an actual clinical progression of the disease,” said Bidard.  

The impact of this strategy was evaluated in the phase III PADA-1 clinical trial, the results of which were reported by Bidard at SABCS. 
 
The trial recruited 1,017 patients with ER-positive/HER2-negative breast cancer receiving first-line treatment with an aromatase inhibitor plus palbociclib. Emergent mutations in ESR1 were detected by analyzing circulating tumor DNA from patient blood samples that were provided every two months during treatment. 

ESR1 mutations were detected in the circulating tumor DNA of 279 patients prior to or concurrent with disease progression. Patients whose tumors had ESR1 mutations prior to disease progression were randomly assigned to continue treatment with an aromatase inhibitor plus the cyclin-dependent kinase inhibitor palbociclib (Ibrance) (84 patients) or to switch to fulvestrant plus palbociclib (88 patients). 

After a median follow-up of 26 months, the median progression-free survival of patients who switched to fulvestrant was over twice as long as those who remained on an aromatase inhibitor (11.9 months vs. 5.7 months). 

Some patients who progressed after continuing aromatase inhibitor treatment crossed over to the fulvestrant arm of the study. The median progression-free survival for patients in the crossover cohort was 3.5 months, supporting previous studies showing a relatively short benefit of fulvestrant when used as a second-line therapy and emphasizing the importance of early detection of ESR1 mutations, Bidard noted. 

“PADA-1 is the first trial to demonstrate that, in most patients, resistance-associated mutations in the estrogen receptor gene can be detected and targeted before tumor progression,” said Bidard in an AACR press release on the study. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”