Murthy Highlights Second-Line Treatment Considerations in ER+/HER2– Metastatic Breast Cancer


Pooja Murthy, MD, discusses second-line treatments in ER+/HER2– metastatic breast cancer for patients following progression on endocrine therapy plus a CDK4/6 inhibitor.

Pooja Murthy, MD

Pooja Murthy, MD

Although endocrine therapy in combination with a CDK4/6 inhibitor remains the primary frontline treatment option for patients with estrogen receptor (ER)–positive/HER2-negative metastatic breast cancer, tumors will often become resistant to endocrine therapy and clinicians must then consider alternate approaches in the second line and beyond, according to Pooja Murthy, MD.

“Sequencing in the second-line setting is becoming an increasingly complicated question. We have new agents that have been FDA approved, such as capivasertib [Truqap] and elacestrant [Orserdu], and more [research] is being done in the translational space regarding mechanisms of endocrine therapy resistance,” Murthy said in an interview with OncLive®. “After progression on a CDK4/6 inhibitor, fulvestrant [Faslodex] alone has limited activity. The median progression-free survival [PFS] across trials was modest at [approximately] 2 to 3 months. Therefore, in the second line setting combination approaches or next-generation medications are key. [Additionally], molecular testing is increasingly important to inform next line therapy [selection]. Developing this idea of estrogen dependence vs independence [to identify] patients who may benefit more from a strategy that continues to target the estrogen pathway such as oral SERDs vs another approach is going to be key.”

The phase 3 EMERALD study (NCT03778931) examined elacestrant in postmenopausal patients with ER-positive/HER2-negative advanced or metastatic breast cancer. Patients with ESR1-mutated disease who received elacestrant (HR, 0.55; 95% CI, 0.39-0.77; P = .0005) and those in the intention-to-treat population (HR, 0.70; 95% CI, 0.55-0.88; P = .0018) experienced a statistically significant PFS benefit compared with those who received investigator’s choice of endocrine therapy. Findings from EMERALD supported the January 2023 FDA approval of elacestrant in postmenopausal women or adult men with ER-positive, HER2-negative, advanced or metastatic breast cancer harboring an ESR1 mutation who experienced disease progression on at least 1 line of endocrine therapy.1 

The phase 3 CAPItello-291 study (NCT04305496) evaluated capivasertib in combination with fulvestrant in patients with hormone receptor-positive/HER2-negative breast cancer following disease progression during or after treatment with an aromatase inhibitor, with or without prior CDK4/6 inhibitor therapy. Patients in the capivasertib arm (n = 355) experienced a median PFS of 7.2 months (95% CI, 5.5-7.4) compared with 3.6 months (95% CI, 2.8-3.7) in the placebo plus fulvestrant arm (n = 353; HR, 0.60; 95% CI, 0.51-0.71; P < .001). Notably, patients with PIK3CA/AKT1/PTEN-altered disease achieved a median PFS of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7), respectively (HR, 0.50; 95% CI, 0.38-0.65; P < .001).2

In the interview, Murthy, an assistant professor of Clinical Medicine at Weill Cornell Medicine and an attending physician at NewYork-Presbyterian Queens in New York, discussed second-line treatment considerations for patients with ER-positive/HER2-negative metastatic breast cancer shared during her presentation at a recent OncLive State of the Science Summit™ on breast cancer.

OncLive: What treatment sequencing considerations should clinicians be aware of following progression on first-line endocrine therapy plus a CDK4/6 inhibitor?

Murthy: In the second-line setting, I always [conduct] molecular testing. When a patient has progressive disease, and typically they’re progressing [following] a CDK4/6 inhibitor and endocrine therapy, we look at the molecular testing results to help guide the next line of treatment. The other considerations are a patient’s clinical features [such as] how long they were on first-line endocrine therapy, sites of metastatic disease, and pace of progression. This [information] helps inform the concept of the patient developing endocrine resistance vs continued endocrine dependency. That is a key decision point in the space and helps inform next treatment.

What were the key data from the EMERALD trial with elacestrant vs standard endocrine monotherapy?

EMERALD was an important trial; it was the first prospective phase 3 trial with published results supporting the use of an oral SERD in this setting. In EMERALD, elacestrant was compared with standard of care endocrine therapy at progression. All patients had received a prior CDK4/6 inhibitor. Elacestrant demonstrated an improved PFS compared with standard of care endocrine therapy.

[Additionally], the secondary analysis of this trial showed that there were certain patient populations who benefited more [from treatment with elacestrant vs standard endocrine therapy]. Data showed that for patients with an ESR1 mutation [there was] a deeper separation of the curves. Also, for patients who had a longer duration of treatment on a first-line CDK4/6 inhibitor and endocrine therapy—particularly more than 12 months and more than 18 months—[data] demonstrated an even wider separation of the curves.

There is a specific patient population benefitting from treatment with elacestrant, particularly patients with ESR1-mutated disease who have a long duration of treatment on prior CDK4/6 inhibitor [therapy]. In EMERALD, there was a clinically meaningful difference; the median PFS for this patient population was approximately 9 months compared with approximately 2 or 3 months in the standard-of-care arm.

What was the significance of data from CAPItello-291 with capivasertib or placebo plus fulvestrant?

CAPItello-291 was a phase 3 double-blind placebo-controlled trial evaluating capivasertib, which is an AKT inhibitor, in combination with fulvestrant vs placebo plus fulvestrant. Data demonstrated improved PFS in the capivasertib arm, particularly in patients who had a mutation in the PIK3CA/AKT1/PTEN pathway, [which led to the combination’s] FDA approval for these patients.

How do any safety concerns observed in EMERALD or CAPItello-291 contribute to sequencing decisions?

In EMERALD, elacestrant was very well tolerated; there were primarily only grade 1 and 2 toxicities. Dosing is once daily and it’s an oral agent, which many patients prefer. Elacestrant is a very tolerable option.

[With] capivasertib, we think about the phase 3 SOLAR-1 [NCT02437318] data when we think about CAPItello-291. Alpelisib [Piqray] was approved in this space and in SOLAR-1, approximately 25% of patients discontinued treatment [with alpelisib] due to toxicities. There were higher rates of grade 3 and 4 hyperglycemia, diarrhea, and rash.

Cross trial comparisons are somewhat problematic, but capivasertib seemed to be better tolerated. There was less hyperglycemia, most of the toxicities were grade 1 and grade 2, and there was less treatment discontinuation. It’s an attractive option, especially in the metastatic setting [where] patients are looking for more tolerable treatments. Capivasertib plus fulvestrant does require patients to come in more frequently for laboratory checks, and fulvestrant is a monthly injection. That has to be taken into consideration, but it is a fairly well tolerated treatment option.

What are some unmet needs or unanswered questions that persist regarding treatment selection in the second line?

I’m very interested to see the development of biomarkers in this space. One of the key thoughts is differentiating which patients have continued estrogen dependency vs activation of different pathways. Having biomarkers to add nuance to this thought process is very important. Also, more work [is needed] on the mutations themselves. The way we’re thinking about it previously, and up until now, is if patients have an ESR1 mutation or a PIK3CA mutation, but there are different mutations [including] different ESR1 mutations. Which patients with those mutations may benefit from one oral SERD vs other oral SERDs in development will be important to know.


  1. Shah M, Lingam H, Gao X, et al. US Food and Drug Administration approval summary: elacestrant for estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced or metastatic breast cancer. J Clin Oncol. 2024;42(10):1193-1201. doi:10.1200/JCO.23.02112
  2. Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Study Group. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
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