Novel SERD shows promise for ER+/HER2– advanced/metastatic breast cancer

The novel oral SERD* elacestrant demonstrated potential as new treatment alternative for ER+/HER2– advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy, according to the phase III EMERALD trial.

“[S]tandard single-agent endocrine therapy (eg, fulvestrant) is associated with poor median progression-free survival (PFS) in second-/third-line post-CDK 4/6i setting, [and] it has been nearly 2 decades [since] fulvestrant was approved for metastatic ER+ mBC. [This highlights] a clinical unmet need for better endocrine therapy options for patients with ER+/HER2– mBC,” said Dr Aditya Bardia from the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, US, at SABCS 2021. “[Our] study was positive. It met its primary endpoint.”

Compared with standard-of-care (SoC) endocrine therapy, elacestrant was associated with reductions in the risk of progression or death, both in the overall cohort (median PFS, 2.79 vs 1.91 months; hazard ratio [HR], 0.697; p=0.0018) and in a subgroup of patients with tumours harbouring ESR1 mutations (mESR1; median PFS, 3.78 vs 1.87 months; HR, 0.546; p=0.0005). [SABCS 2021, abstract GS2-02]

 

PFS rate at 6, 12 months

Elacestrant also demonstrated a higher PFS rate than SoC, both at 6 months (34 percent vs 20 percent [overall] and 41 percent vs 19 percent [mESR1 subgroup]) and at 12 months (22 percent vs 9 percent and 27 percent vs 8 percent, respectively). Despite the initial drop in the Kaplan-Meier curves in both arms, the curves separated at about 2 months and was maintained over time, noted Bardia.

“[The 12-month findings] highlight that, in the endocrine-sensitive group, the benefit with elacestrant is much higher [than SoC],” said Bardia. “Among those with mESR1, the PFS rates at 12 months was about 25 percent with elacestrant and <10 percent with [SoC]. Therefore, one in four patients are likely not to have disease progression or death with elacestrant as compared to 1 in 10 patients with SoC. That is an important endpoint and potentially clinically meaningful for patients.”

 

Elacestrant vs fulvestrant

Greater PFS benefit was also seen with elacestrant vs fulvestrant, both in the overall cohort (HR, 0.68; p=0.0049) and the mESR1 subgroup (HR, 0.5; p=0.0005).

“To see activity of elacestrant in patients who received prior fulvestrant I think establishes two points. One is that, upon disease progression on first-line therapy, a subset of tumours are still endocrine-sensitive. So if you use a better endocrine agent, you could see clinical activity. That is why with … elacestrant, you could see activity in patients who had received prior fulvestrant,” Bardia explained.

“The second point is, elacestrant [performing] better than fulvestrant [highlights the] need for better endocrine therapies. Elacestrant is a great start. There are other oral SERDs in development as well, so this is good news for the field from that perspective,” he continued.

 

Safety

The incidence of grade 3/4 treatment-related adverse events (TRAEs) was low in both the elacestrant and SoC arms (7.2 percent and 3.1 percent), as were the rates of TRAEs leading to discontinuation (3.4 percent and 0.9 percent). No treatment-related deaths were reported in either arm. The most frequent side effect observed with elacestrant was nausea (35 percent).

“Elacestrant was safe and well-tolerated, with a predictable and manageable safety profile consistent with other endocrine therapies,” said Bardia.

 

Oral SERD bests SoC

The study included 477 men and postmenopausal women with ER+/HER2– mBC (median age 63 years, 99.4 percent female) who have progressed or relapsed on/after 1 or 2 lines of endocrine therapy for advanced disease. Participants were randomized 1:1 to receive daily elacestrant 400 mg or investigator’s choice of SoC (ie, fulvestrant [70 percent], anastrozole, letrozole, exemestane).

Roughly 70 percent of patients had visceral metastases, while up to 25 percent received one prior line of chemotherapy. “[This] represents a patient population with aggressive tumour biology,” said Bardia.

“Scientifically, our study provides proof of principle of the superiority of a novel oral SERD as compared to SoC,” he continued. “Further elacestrant combinations in earlier lines and with other targeted therapies, including CDK4/6 and mTOR inhibitors, are either ongoing or planned for patients with ER+/HER2– BC.”