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Selective Estrogen Receptor Degraders, Modulators Show Promise in ESR1-Mutant Breast Cancer

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This story has been updated to reflect a more recent analysis of data from the ELAINE 2 trial.

NEW YORK – While several newly presented studies of next-generation selective estrogen receptor degraders (SERDs) and a selective estrogen receptor modulator (SERM) have yielded mixed results for patients with advanced ER-positive HER2-negative breast cancer, evidence points toward efficacy in patients with ESR1 resistance mutations.

The studies were presented this weekend at the European Society for Medical Oncology Congress in Paris. Two Phase II studies of oral SERDs compared to endocrine therapy failed to meet their primary endpoints. In the case of the AMEERA-3 study of amcenestrant, interim data from the Phase III AMEERA-5 study had already prompted Sanofi to discontinue development of the drug.

In AMEERA-3, 290 patients with ER-positive HER2-negative advanced breast cancer who had progressed on up to two lines of prior therapy were enrolled to receive 400 mg amcenestrant orally once daily or physician's choice endocrine monotherapy, which could be the injectable SERD fulvestrant, an aromatase inhibitor, or tamoxifen. The trial missed its primary endpoint of being able to show amcenestrant's progression-free survival superiority over physician's choice therapy. The group receiving amcenestrant had a median progression-free survival of 3.6 months compared to 3.7 months on physician's choice.

However, patients with an ESR1 mutation did show a trend favoring amcenestrant, with a median progression-free survival of 3.7 months compared to 2 months for physician's choice therapy. This was in a population of patients where 80 percent were being treated in the second-line metastatic setting, 80 percent had a prior CDK4/6 inhibitor, and 90 percent of patients in the control arm received fulvestrant. Although the trial didn't achieve its primary objective, there was a "numerically longer progression-free survival observed with amcenestrant in those patients with an ESR1 mutation at baseline," said presenter Sara Tolaney, an oncologist at Dana-Farber Cancer Center.

Similar results came from another study discussed at the meeting, the Phase II acelERA trial of Roche's SERD giredestrant versus physician's choice of endocrine monotherapy in around 300 previously treated patients with ER-positive HER2-negative advanced or metastatic breast cancer. That trial also failed to meet its primary endpoint of improved progression-free survival with giredestrant in the overall population, while showing a benefit for patients with ESR1 mutations.

Median progression-free survival for patients receiving giredestrant was 5.6 months, compared to 5.4 months for physician's choice therapy. However, in the subgroup of patients with ESR1 mutations, patients on giredestrant had a median progression-free survival of 5.3 months, compared to 3.5 months in the control arm.

Miguel Martin Jimenez, head of the medical oncology service at the Hospital General Universitario Gregorio Marañón in Madrid, noted in presenting this data that while giredestrant did not impart a statistically significant improvement in progression-free survival, the numerical improvement seen on this endpoint compared to physician's choice therapy "support the continued investigation of giredestrant in further studies."

In discussing this data at the meeting, Shaheenah Dawood, an oncologist at the Mediclinic City Hospital Dubai in the United Arab Emirates, highlighted why the field is excited by the emergence of newer oral SERDs. "The promise of oral SERDs is that it's better to give an oral tablet rather than intramuscular administration of fulvestrant, it has a bit better bioavailability, it may have better efficacy compared to fulvestrant, and it may have the ability to overcome endocrine resistance conferred by the presence of an ESR1 mutation," Dawood said.

She compared the AMEERA-3 and acelERA results to the findings of the Phase III EMERALD trial, reported last year at the San Antonio Breast Cancer Symposium. In that study involving ER-positive HER2-negative metastatic breast cancer patients, the oral SERD elacestrant, being developed by the Menarini Group, showed a 30 percent lower risk of death or disease progression compared to investigator's choice of fulvestrant or an aromatase inhibitor.

Moreover, with this SERD, patients with an ESR1 mutation had an even greater benefit — a 45 percent lower chance of death or disease progression. The 12-month progression-free survival rate was 22.3 percent in the elacestrant group, compared to 9.4 percent in the control arm. For patients with the ESR1 mutations, the progression-free survival rate was 26.8 percent with elacestrant, compared to 8.2 percent on fulvestrant or an aromatase inhibitor.

When considering whether a single-agent oral SERD is effective in an endocrine-resistant cohort, Dawood said, "In the EMERALD trial, the simple answer was yes, it was effective, although the median progression-free survival benefit was modest." Although cross-trial comparisons are not ideal, she noted that the progression-survival times for endocrine-resistant patients between the investigational and control arms in the AMEERA-3 and the acelERA trials appear similar.

Dawood also pointed out that EMERALD showed a modest benefit in terms of progression-free survival for patients who had progressed on a CDK4/6 inhibitor, but AMEERA-3 and acelERA again failed to replicate that benefit with their respective oral SERDs.

Meanwhile, ESR1-mutated breast cancer patients are a subset in need of treatment options. Previous studies of fulvestrant's efficacy in breast cancer patients with the ESR1 mutation have yielded conflicting answers on the efficacy of a SERD in that patient cohort. The two new studies, while not achieving statistical significance, do show a "strong trend towards an improvement associated with the use of oral SERDs in that ESR1 mutation cohort," Dawood said.

In a third study presented at the meeting, called ELAINE 1, researchers showed that Sermonix Pharmaceuticals' SERM lasofoxifene also numerically improved progression-free survival compared to fulvestrant in women with locally advanced or metastatic ER-positive HER2-negative breast cancer who had progressed on prior CDK4/6 inhibitors and harbored ESR1 mutations. Median progression-free survival for lasofoxifene was 6.04 months compared with 4.04 months for fulvestrant. The progression-free survival rate at 12 months was 30.7 percent for lasofoxifene, compared with 14.1 percent for fulvestrant.

Matthew Goetze, a professor of oncology at Mayo Clinic, said that lasofoxifene could be a new treatment option following endocrine and CDK4/6 inhibitors if efficacy can be confirmed in a larger study.

Earlier this year, Sermonix reported results from the ELAINE 2 trial of lasofoxifene with Eli Lilly's CDK4/6 inhibitor Verzenio (abemaciclib) in ER-positive HER2-negative breast cancers with ESR1 mutations. That open-label trial showed a median progression-free survival of 13.9 months for the drug combo, an overall response rate of 50 percent, and a clinical benefit rate of 69 percent. Dawood said that the ELAINE 2 study had demonstrated the efficacy of lasofoxifene after progression on fulvestrant and "added to the growing body of evidence of efficacy of CDK4/6 beyond progression of disease."

"Today we see the results of the ELAINE 1 trial looking at lasofoxifene versus fulvestrant in those patients with an ESR1 mutation post-progression on [aromatase inhibitors] and CDK4/6 [inhibitors], a truly second-line study where there was an improvement in progression-free survival, although not statistically significant," said Dawood, highlighting that the authors also demonstrated in an exploratory analysis that lasofoxifene reduced the fraction of ESR1 mutation allele frequency, even in those hard-to-treat patients who have an ESR1 Y537S mutation.

Overall, Dawood said AMEERA-3, acelERA, and ELAINE 1 results presented this weekend, along with past trials like EMERALD and ELAINE 2, suggest that the presence of an ESR1 mutation enriches for a cohort more likely to respond to oral SERDs or SERMs, "possibly due to tumor dependence on ER-mediated signaling." However, as seen with fulvestrant, ESR1 mutation status has not shown to be "clinically reliable" as a predictive biomarker and not all ESR1-mutated tumors respond the same way with treatment.

For example, patients with the ESR1 Y537C mutation tend to have a longer progression-free survival on fulvestrant compared to those with a Y537S mutation. As well, the ESR1 F404L mutation leads to fulvestrant resistance, even though in preclinical models, it has shown sensitivity to novel SERDs and tamoxifen.

"Characterizing metastatic tumors by ER positivity or ESR1 mutation is simply not enough, and we need better methods of selecting patients post-progression on CDK4/6 inhibitors who remain endocrine sensitive," said Dawood, suggesting that the emergence of an ESR1 mutation may signal a need to intervene early and switch therapy.

"Are oral SERDs more effective than fulvestrant in an ESR1 cohort? My belief is yes," concluded Dawood, adding that larger studies are needed to confirm lasofoxifene's superiority to fulvestrant particularly in the endocrine-resistant cohort. "Combination strategies are the way forward."