Leading Oral SERD Shows Prolonged Activity

The leading oral drug candidate designed to degrade the estrogen receptor (ER) can maintain prolonged antitumor activity, with data presented at the ESMO Congress 2022, held September 9–13 in Paris, France, showing that some recipients of elacestrant (Menarini) have lived without disease progression for 18 months and counting.

But not all oral selective estrogen receptor degraders (SERD) have demonstrated such impressive efficacy. In August, Sanofi announced that it was ending development of its oral SERD, amcenestrant, after an interim analysis of the pivotal AMEERA-5 trial found that the study would likely end in failure. Data presented at the ESMO meeting from an earlier phase II trial also showed that amcenestrant did not improve progression-free survival (PFS) compared with standard therapy.

Oral SERDs are vying to supplant the injectable SERD fulvestrant, a mainstay of treatment for ER-positive breast cancer, especially among patients who develop resistance to aromatase inhibitors (AI) or tamoxifen.

Fulvestrant both antagonizes ER-dependent transcriptional activity and harnesses the cell's natural protein disposal system to mediate receptor destruction. But owing to poor oral bioavailability, it must be given intramuscularly, a route of administration that can be painful and inconvenient for patients. Fulvestrant is also inferior to many newer oral SERDs—elacestrant included—in terms of absorption rates, pharmacokinetics, and inhibitory effects on the ER.

Analysts and clinicians now expect elacestrant to earn the FDA's blessing and become the first SERD in pill form approved for patients with previously treated ER-positive/HER2-negative advanced breast cancer. A regulatory decision is expected early next year.

Initial data from the phase III EMERALD trial showed that elacestrant was tolerable and reduced the risk of progression or death by 30% compared with standard-of-care options (J Clin Oncol 2022;40:3246–56). That benefit was especially pronounced among patients with ESR1 mutations, who had a reduction in the relative risk of disease progression or death of 45%. (ESR1 encodes the ER protein and, when mutated, can make breast tumors resistant to standard hormonal therapies.)

Updated trial results presented at the ESMO meeting then further demonstrated elacestrant's superior efficacy. Landmark PFS analyses at 15 and 18 months showed that a greater percentage of the oral SERD recipients were living without disease progression.

Elacestrant's effects on overall survival are not yet fully known. However, an analysis of the initial EMERALD data indicated that, as with PFS, the drug's life-extending benefits were greatest among patients with ESR1 mutations—a result that leads trial investigator Virginia Kaklamani, MD, of The University of Texas Health Science Center in San Antonio, to conclude that elacestrant is “an improved version of fulvestrant, at least in the ESR1 mutants.”

Kaklamani continued: “Then the question is: Is it an improved version of fulvestrant regardless [of mutational status]? And we don't know that.” But “it's at least equivalent—and it's an oral drug.” As such, it could become the treatment of choice for many patients—especially as adjuvant therapy, for which at-home administration is the norm.

Several other companies, including the makers of camizestrant (AstraZeneca), imlunestrant (Eli Lilly), and giredestrant (Roche), are running phase III trials of their oral SERDs. However, as Aditya Bardia, MD, MPH, of Massachusetts General Hospital in Boston, points out: “It's tough to know without head-to-head comparisons” if one is better than any other and why some earlier studies have yielded disappointing results. As Bardia and his colleagues reported at the ESMO meeting, giredestrant showed signs of efficacy in phase II development but did not prove statistically superior to physician's choice of endocrine therapy as a second- or third-line treatment.

Drugmakers are also investigating earlier use of oral SERDs. According to Bardia, who has been involved in testing several of these products, that's where the drugs could truly shine.

“In the earlier setting, the tumors are generally more endocrine-responsive and -sensitive,” he says. “So, if any of these agents are truly better than AIs or fulvestrant, it's in the early breast cancer setting that we should be able to see a signal.” –Elie Dolgin

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