Assessing Elacestrant Across Patient Subgroups in ESR1+ Advanced Breast Cancer

CASE SUMMARY

A 52-year-old, postmenopausal woman presents with a palpable right breast mass with no clinically abnormal axillary lymph nodes​.

Diagnostic and Surgical Procedures​

• Diagnostic mammogram: Spiculated mass at 11 o’clock​
• Ultrasound: 1.8 cm solid mass on ultrasound ​
• Core biopsy: grade II invasive ductal carcinoma (IDC), estrogen receptor positive (ER+) and progesterone receptor positive (PR+), HER2 immunohistochemistry (IHC) 0, Ki-67 20%​
• Lumpectomy and sentinel lymph node (SLN) biopsy: 2.8 cm grade 2 IDC, 2 SLN negative for malignant cells​
• Real-time polymerase chain reaction 21-gene recurrence score: 27​

Adjuvant Therapy​

• Docetaxel and cyclophosphamide given intravenously every 3 weeks for 4 cycles ​
• Radiation therapy​
• Anastrozole for 5 years

3 Years After Completing Anastrozole​

• Patient presented with persistent low back pain radiating to the bilateral hips, which restricted activity​.

Follow-Up Diagnostics​

• Fludeoxyglucose (FDG) 18F PET/CT: FDG uptake seen in multiple vertebrae and bilateral iliac crests​.
• MRI spine: multiple sclerotic vertebral and pelvic bone lesions without cord compromise​
• Bone marrow aspiration: malignant cytokeratin-positive cells​
• ER+/PR+, HER2 IHC 0​
• ECOG performance status: 1​
• Laboratory studies revealed mild anemia but were otherwise normal​.
• Diagnosis: stage IV​ breast cancer

First-Line Therapy​

• She started letrozole and ribociclib (Kisqali) with marked improvement in her pain​.
• Required 1 dose reduction to 400 mg ribociclib due to neutropenia
• Twenty months after starting therapy, routine staging scans showed new FDG avid sclerotic and lytic bone lesions​.
• She noted mild increase in lower back pain​.
• Laboratory studies were normal.
• Routine staging scan revealed new, FDG-avid sclerotic and lytic bone lesions.
• Circulating tumor DNA (ctDNA) analysis confirmed an ESR1 mutation​.

Second-Line Treatment​

• Elacestrant (Orserdu) 345 mg once a day was initiated.
• Mild nausea well controlled when taking elacestrant with food and an occasional ondansetron tablet​.
• Also given low dose olanzapine (2.5 mg) to take at bedtime as needed.
• Her pain improved on therapy with resolution of FDG avidity in bone on PET/CT scan.

Targeted Oncology: Of the efficacy results from the phase 3 EMERALD trial (NCT03778931), what stood out to you?

WILLIAM J. GRADISHAR, MD: [The longer patients were on a CDK4/6 inhibitor] the duration of their progression-free survival [PFS] increased.¹ Those patients who were on [a CDK4/6 inhibitor] for at least 18 months had a median PFS on elacestrant of 8.6 months [95% CI, 5.45-16.9] vs 2.1 months [95% CI, 1.87-3.75] in those patients getting some other form of endocrine therapy with fulvestrant or an AI [HR, 0.47; 95% CI, 0.27-0.79]. [So, patients] more endocrine responsive based on their duration of time on a CDK4/6 inhibitor is somewhat predictive of benefit with elacestrant.

William J. Gradishar, MD

Chief of Hematology and Oncology in the Department of Medicine

Betsy Bramsen Professor of Breast Oncology

Professor of Medicine

Northwestern Medicine Feinberg School of Medicine

Robert H. Lurie Comprehensive Cancer Center at Northwestern

What other subgroup efficacy results are notable to consider when deciding on using elacestrant?

Whether you look at patients with bone disease or patients with more visceral disease, there’s a similar finding for patients with ESR1 mutations [in their tumor] that did better with elacestrant, as well....² There are few subgroups [from the EMERALD trial that benefitted] from elacestrant, compared with the current options considered standard of care [SOC]. Patients [with disease positive for] PIK3CA mutations—of which there were approximately 90 patients who also had an ESR1 mutation who received elacestrant—did better [than those on SOC with a median PFS of 5.45 months (95% CI, 2.14-10.84) vs 1.94 months (95% CI, 1.84-3.94), respectively (HR, 0.42; 95% CI, 0.17-0.94)].²

If [the patient] was positive for a TP53 mutation, and they had been on a CDK4/6 inhibitor for at least a year, [those patients who] received elacestrant did better than those on SOC [with a median PFS of 8.61 months (95% CI, 3.65-24.25) vs 1.87 months (95% CI, 1.84-3.52), respectively (HR, 0.30; 95% CI, 0.13-0.64)].² Across different subgroups, both clinically as well as having other mutations, elacestrant seemed to be better with respect to PFS.

What was the toxicity profile of this therapy on the trial?

The most common AE that patients on elacestrant experience is an uptick in gastrointestinal [GI] symptoms, often mild nausea [35.0%], but some patients can experience vomiting [19.0%] with it, but high-grade GI symptoms are generally uncommon.³

This is the one distinguishing [factor] with elacestrant that’s different than the other endocrine agents. Now, if patients do experience AEs you can go down on the dosing. Dose reductions for AEs [with elacestrant consist of] basically taking a pill away for the first dose reduction [to 258 mg daily] to a second reduction [of 172 mg given daily].⁴

If the patient still needs something beyond that point, then you should probably discontinue treatment. If their toxicity is very mild, you don’t have to change anything, but if it becomes greater than that, you have to consider [treatment] interruption until the AE is reduced to grade 1 or less. Then you could continue [treatment] at the same dose, but anything greater than that is going to lead to a dose reduction.⁴

Would there be any situation that would give you pause when deciding to continue treatment?

If there are any clinical symptoms arising that make you think that the disease is getting worse, then that would be troubling. Particularly, for example, if a patient with bony disease is having more pain, even in the absence of more lesions, I would be concerned. If everything were stable, then maybe I’d continue [therapy] if the patient didn’t have any threatening disease. It’s somewhat of a clinical call, but anything that’s worsening on scans I’d stop. And although I don’t [use] a lot of tumor marker [tests], obviously if those were going in the wrong direction, I’d be a bit concerned as well.

REFERENCES:

1. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

2. Bardia A, O’Shaughnessy J, Bidard F-C, et al. Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract PS17-02.

3. Bardia A, Bidard FC, Neven P, et al. Abstract GS3-01: GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting. Cancer Res. 2023;83(Suppl 5):GS3-01. doi:10.1158/1538-7445.SABCS22-GS3-01

4. Orserdu. Prescribing Information. Stemline Therapeutics, Inc, 2023. Accessed April 1, 2024. https://tinyurl.com/yc7bncbx