Dr. Sheheryar Kabraji, Roswell Park Breast Service Chief, On Oral SERDs – ‘Not a Home Run’ – & The Future of Treatment Sequencing

In conversation with SurvivorNet, Dr. Sheheryar Kabraji discussed his views on the evolving role of oral selective estrogen receptor degraders (SERDs) in clinical practice. Drawing on data from pivotal trials, Dr. Kabraji offered a measured assessment of where these agents fit today—and where they may be headed.

Framing the discussion and noting that there are currently two FDA approved oral SERDs for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer–elacestrant and imlunestrant–Dr. Kabraji emphasized that clinicians are still working to understand both relative efficacy and tolerability across agents.

What The Data Shows

Data from pivotal studies, he explained, show consistent—but limited—benefit across agents. “In the EMERALD trial, the use of elacestrant was associated with a longer progression-free survival and compared to a comparator endocrine therapy in patients who have previously been treated with a CDK-4-6 inhibitor and endocrine therapy.” Imlunestrant, he added, “and its approval is currently as a monotherapy. Although actually in the EMBER Trial, it was also combined with a CDK-4-6 inhibitor.”

Across studies, Dr. Kabraji said, the magnitude of benefit is similar.  Despite interest in comparing agents, Dr. Kabraji cautioned against over-interpreting differences. From a tolerability standpoint, he said, toxicity profiles are largely overlapping. “They have very similar side effects. So for example, that can include fatigue, nausea, arthralgia, these are the most common ones that we’ve identified in the trials.” Differences that do emerge, he noted, are often driven by combination partners. “When imlunestrant was combined with abemaciclib, there was more diarrhea in that group and that was largely due to the abemaciclib drug.”

The Future For Oral SERDs

Looking ahead, Dr. Kabraji stressed that expectations for oral SERDs should remain grounded. “As monotherapies, the results of orals SERDs are an improvement, but they are by no means a home run. They are delaying the progression of disease by around three months or so–which is good, but it’s not great.” Where the field appears to be moving, he said, is toward combination strategies. “What we’re mostly seeing is that these oral SERDs when combined with other drugs are probably getting better disease control.”

That shift, Dr. Kabraji suggested, could ultimately change sequencing in ER-positive metastatic disease. “You’ll see third-based combinations becoming the sort of treatment of choice,” he said, describing a future in which endocrine backbones evolve earlier. “Instead of a standard endocrine therapy like Tamoxifen or an AI, they actually had that first-line therapy with SERD plus a CDK-4-6 inhibitor. And, then, subsequently we’ll have a targeted therapy with a second generation or advanced SERD.”

The goal, he concluded, is not incremental substitution but strategic repositioning. “That’s how we change the overall benefit of this class of drugs is not sort of keeping things static as they are, but continually sort of finding ways to bring our most effective treatments potentially earlier so that they can potentially control disease more effectively and for longer.”