Clinical trials and FDA approval for a drug can take 10-15 years,

How long a new drug takes to go through clinical trials. Cancer Research UK. February 1, 2022.

but elacestrant, a novel treatment for breast cancer, has had a 30-year journey to approval. This new medication is intended for the treatment of late-stage breast cancer patients who have ESR1 mutations and have not responded to endocrine treatments. Elacestrant (marketed as Orserdu™) was approved on January 27, 2023.

 

Interestingly, elacestrant did not start off as a cancer drug. Instead, it has worn multiple hats as companies attempted to bring it to market as a treatment option for varied health conditions. 

 

From dementia, to hot flashes, to breast cancer

 

In the late 1990s, the drug started out as a dementia medication, but its use for that purpose was very short-lived. Then, in 2009, Radius Pharmaceuticals initiated Phase 2 clinical trials for the drug as a treatment for vasomotor symptoms (hot flashes) in postmenopausal women.

Radius Pharmaceuticals, Inc. A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Phase 2, Multi-Center, Dose-Finding Study to Evaluate the Effects of Rad1901 in the Treatment of Vasomotor Symptoms in Postmenopausal Women. clinicaltrials.gov; 2018. NCT00875420.

 

 

However, the clinical trial results were not favorable and exhibited a dose-dependent phenomenon. At low doses, RAD1901, the name of the drug at the time, was able to demonstrate improvements in the frequency and severity of hot flashes. Yet, ironically, at higher doses, it appeared to exacerbate hot flashes. Needless to say, researchers terminated the project without seeking FDA clearance. 

But, in this case one researcher’s trash was another’s treasure. In 2012, researchers at the Duke Cancer Institute—namely, Suzanne Wardell, MD, and Erik Nelson, PhD—were intrigued by the paradoxical dose-dependency of RAD1901 and began to explore the mechanism behind this phenomenon.

Harbin JP. Luck favors the prepared mind. Duke Cancer Institute. January 27, 2023.

 

 

 

How it works

 

In healthy normal cells, the Duke researchers knew, estrogen binds to estrogen receptors and triggers normal changes in breast tissue. But some breast cancers also expresses hormone receptors, and in these cells, binding of estrogen to the receptor stimulates growth, survival, and progression of the cancer.

To combat this deviant response, oncologists generally prescribe medications to alter the effect of estrogen on breast cancer cells. But despite these efforts, metastatic breast cancer can develop. 

This is where researchers at Duke had their “Aha” moment and discovered that RAD1901 destroyed the estrogen receptors themselves in the tumors, thereby affecting tumor growth.

Rosenbluth T. After 30 years of research, pill for breast cancer approved for use. Medical XPress. February 8, 2023.

It was at this time that RAD1901 transitioned to become a potential breast cancer drug. 

 

It took several more years to convince Radius Health Inc., the owners of the drug, to pursue the drug as a treatment for breast cancer, as they were not a company focused on cancer therapeutics. In 2017, they agreed to pursue the drug’s clinical development, and in December of 2018, the clinical trials were initiated.

 

The clinical evidence: EMERALD

 

The EMERALD trial (NCT03778931) was the pivotal clinical trial on which the approval of elacestrant was based.

US Food and Drug Administration. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. January 27, 2023.

 

EMERALD was a randomized, open-label, active-controlled, multicenter trial enrolling 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer. Of these participants, 228 patients had ESR1 mutations. 

All patients in the study were required to have experienced therapy failure on one or two prior types of endocrine therapy. One line of prior chemotherapy was permitted.

Progression-free survival was the primary study outcome.

Results of the trial showed that in patients with ESR1 mutations, progression-free survival was 3.8 months with elacestrant, as opposed to 1.9 months in the patients given standard of care (fulvestrant or aromatase inhibitor). 

 

Expedited FDA review

 

Recognizing the significance of these results in addressing an unmet need for ESR1-positive patients, the FDA granted elacestrant expedited review. With its 2023 approval, elacestrant finally made it to market as the first-ever therapy for ER-positive, HER2-negative advanced or metastatic breast cancer patients with ESR1 mutations.