Second Oral SERD Shines in ER⁺ Breast Cancer

Oncologists eager for new selective estrogen receptor degraders (SERD) have been buoyed by initial findings from the phase II SERENA-2 trial: In postmenopausal women with advanced estrogen receptor (ER)–positive, HER2-negative breast cancer, camizestrant (AstraZeneca), an investigational oral SERD, outperformed fulvestrant, significantly prolonging progression-free survival (PFS).

Fulvestrant, the sole approved SERD so far, “has been around for a couple of decades,” said Jason Mouabbi, MD, of The University of Texas MD Anderson Cancer Center in Houston. Oral formulations of these drugs have long been sought to increase clinical utility—fulvestrant is delivered by slow intramuscular injection into the buttocks once a month—but “developing them has been a huge challenge,” he noted. “It's taken many years of research to find a recipe that works well.”

During the 2022 San Antonio Breast Cancer Symposium in December, SERENA-2's lead investigator, Mafalda Oliveira, MD, PhD, of Vall d'Hebron University in Barcelona, Spain, presented trial results from 240 women randomly assigned to receive camizestrant at 75 mg or 150 mg, or fulvestrant. The oral SERD improved the median PFS considerably, she said—7.2 months (75 mg) and 7.7 months (150 mg) versus 3.7 months with fulvestrant. Side effects, including flashes of light, sinus bradycardia, fatigue, and anemia, were largely low-grade and manageable.

Camizestrant also held its own in several subgroup analyses. Compared with fulvestrant, the two doses reduced disease progression risk by 51% and 32%, respectively, in 75 patients previously treated with a CDK4/6 inhibitor and by 57% and 45%, respectively, in 86 patients with liver and lung metastases. These are cohorts that lack other therapeutic options and generally fare poorly, Mouabbi observed.

Notably, among 83 patients with ESR1 mutations, disease progression risk was cut by 67% and 45%, respectively, with camizestrant, Oliveira reported. By cycle 2 of treatment, these mutations were “undetectable, or nearly so” in circulating tumor DNA analyses. “Some reduction was seen with fulvestrant too, but not to the same extent,” she said.

“This is where camizestrant truly shines over fulvestrant,” Mouabbi remarked. “Historically, the goal has been to strike a balance between antagonizing the ER and degrading it outright. But if the ER is constantly ‘on’ due to ESR1 mutations, older endocrine therapies like fulvestrant, which is more of a pure antagonist, won't work as well. You need a next-gen optimized degrader, which is what we have here.”

With camizestrant and another candidate oral SERD, elacestrant (Stemline Therapeutics), “we have consistent data showing that patients with ESR1 mutations derive clinically meaningful benefit,” agreed discussant Fabrice André, MD, PhD, of Institut Gustave Roussy in Villejuif, France. Further trials are underway, he added, to determine “if these drugs prevent the occurrence of such mutations when given frontline.”

Elacestrant is already under priority review and could soon garner FDA approval, Mouabbi said. Meanwhile, camizestrant will continue to be evaluated in the phase III SERENA-4 and SERENA-6 trials, Oliveira said, “and we've decided to go with the 75 mg dose level.”

“I'll give the investigators credit for choosing what provides the most benefit with the least toxicity, not simply pursuing the maximum tolerated dose [MTD] by default, as many still do,” Mouabbi said. In line with the FDA's Project Optimus—which, broadly, seeks to revamp current clinical trial dosing strategies in collaboration with companies, academia, and other stakeholders—“I hope we'll see more randomized, multidose phase II studies” like SERENA-2, “where you don't assume that the MTD is what's optimal.” –Alissa Poh

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