Elacestrant vs Elacestrant + CDK4/6 Inhibitor for Breast Cancer

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must be taking: CDK4/6 inhibitors

Must not be taking: Steroids, CYP3A4 inducers

Disqualifiers: Brain metastases, Pneumonitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 64

Duration: Variable (until progression or other criteria)

174 Participants Needed

Trial Summary

What is the purpose of this trial?

Breast cancer is not only the leading cause of cancer in women, but also the leading cause of cancer deaths in women. Estrogen receptor-positive and HER2-negative breast cancer is the most prevalent breast cancer subtype. Endocrine therapy is the mainstay of treatment; however, due to the varied nature of the disease, development of resistance to this therapeutic approach is very common in the metastatic setting. The purpose of this study is to see whether the effectiveness of elacestrant can be enhanced by combining it with a targeted agent such as a CDK4/6 inhibitor to treat patients with ER+/HER2- or metastatic breast cancer with prior exposure to a CDK4/6 inhibitor.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop all current medications, but there is a 14-day washout period required if you were previously on a CDK4/6 inhibitor before starting a different one in the study. Additionally, you cannot take strong or moderate CYP3A4 inducers or inhibitors.

What data supports the effectiveness of the drug combination Elacestrant and CDK4/6 inhibitors for breast cancer?

Research shows that combining CDK4/6 inhibitors with endocrine therapy improves survival in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. This combination is now a standard treatment, as it increases response rates and prolongs disease control without reducing quality of life. ^{1 2 3 4 5}

Is the combination of Elacestrant and CDK4/6 inhibitors safe for humans?

CDK4/6 inhibitors like abemaciclib, palbociclib, and ribociclib have been shown to be generally safe in humans, but they can cause side effects such as neutropenia (low white blood cell count), diarrhea, QTc prolongation (heart rhythm changes), and liver issues. These side effects are manageable with proper monitoring and dose adjustments. ^{1 2 3 6 7}

What makes the drug elacestrant unique for breast cancer treatment?

Elacestrant is unique because it is an oral selective estrogen receptor degrader (SERD) that targets estrogen receptors in breast cancer cells, including those with ESR1 mutations, which are often resistant to other endocrine therapies. It is the first oral SERD approved by the FDA for metastatic breast cancer, offering a new option for patients who have developed resistance to standard treatments. ^{1 8 9 10 11}

Research Team

William Gradishar, M.D.

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for adults with ER+/HER2- advanced or metastatic breast cancer who have tried at least two endocrine therapies, including a CDK4/6 inhibitor. They should be in good physical condition (ECOG 0 or 1), have no severe heart issues, and not be at immediate risk due to visceral spread. Participants must not have had recent chemotherapy, major surgery, or certain other treatments.

Inclusion Criteria

My cancer has a confirmed ESR1 mutation.

I have at least one tumor that can be measured or a mainly lytic bone lesion.

I have had at least 2 hormone treatments for my cancer, including a CDK4/6 inhibitor.

Exclusion Criteria

I haven't had chemotherapy or radiotherapy in the last 28 days.

I do not have any uncontrolled illnesses.

My advanced cancer is causing symptoms and could lead to serious complications soon.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either elacestrant monotherapy or combination therapy with a CDK4/6 inhibitor for each 28-day cycle until progressive disease or other criteria are met

Variable (until progression or other criteria)

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for survival and disease progression every 36 weeks for 2 years, then every 72 weeks up to 5 years

Up to 5 years

Every 36 weeks for 2 years, then every 72 weeks

Treatment Details

Interventions

• Abemaciclib
• Elacestrant
• Palbociclib
• Ribociclib

Trial Overview The study tests if elacestrant's effectiveness improves when combined with a CDK4/6 inhibitor (palbociclib, abemaciclib, ribociclib) in patients previously treated with a CDK4/6 inhibitor. It aims to overcome resistance often seen in this common subtype of breast cancer after standard treatment.

Participant Groups

Group I: Elacestrant Monotherapy Experimental Treatment 1 Intervention

Elacestrant (345 mg) will be taken orally once daily for each 28-day cycle. Courses repeat until progressive disease.

Group II: Combination Therapy Experimental Treatment 1 Intervention

Patients will receive either: Elacestrant 345 mg orally once daily + Palbociclib 125 mg orally once daily for 21 days out of 28-day cycle OR Abemaciclib 150 mg orally twice daily OR Ribociclib 600 mg orally once daily for 21 days out of 28-day cycle

Elacestrant is already approved in United States, European Union for the following indications:

Approved in United States as Orserdu for:

• ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer

Approved in European Union as Orserdu for:

• ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Oral CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib significantly improve progression-free survival by 40-45% when combined with endocrine therapy in hormone-responsive HER2-negative advanced breast cancer, particularly in post-menopausal women.

These inhibitors have varying toxicity profiles and monitoring requirements, and ongoing clinical trials are exploring their use in other breast cancer subtypes and in combination with other therapies to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of CDK4/6 Inhibitors in Breast Cancer. Murphy, CG.[2020]

CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have shown positive results in clinical trials for treating estrogen receptor positive (ER+)/HER2-negative metastatic breast cancer, indicating a shift in treatment strategies.

These inhibitors work by targeting key kinases that promote cancer cell proliferation, leading to improved outcomes and potentially better quality of life for patients compared to traditional sequential endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of CDK4/6 inhibitor for breast cancer. Iwata, H.[2019]

CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have significantly improved treatment outcomes for hormone receptor-positive and HER2-negative breast cancer, establishing themselves as key options in both first- and second-line therapies.

While these inhibitors effectively prolong overall survival and progression-free survival in patients, they are also associated with notable adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials. Stanciu, IM., Parosanu, AI., Nitipir, C.[2023]

CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, significantly improve progression-free survival in patients with hormone-receptor-positive, HER2-negative advanced breast cancer when used in combination with endocrine therapy, as shown in multiple clinical trials.

Effective management of adverse events, such as neutropenia and diarrhea, is essential for patient safety and treatment success, highlighting the importance of monitoring and adjusting doses as needed during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Thill, M., Schmidt, M.[2020]

Elacestrant (RAD1901) effectively degrades estrogen receptors and inhibits the growth of estrogen receptor-positive (ER+) breast cancer cells in both laboratory and patient-derived models, showing significant antitumor activity.

The combination of elacestrant with other therapies like palbociclib or everolimus enhances its efficacy, suggesting it could be a valuable treatment option for patients with ER+ breast cancer, including those with resistant mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models. Bihani, T., Patel, HK., Arlt, H., et al.[2018]

Elacestrant is the first oral selective estrogen receptor degrader (SERD) approved by the FDA for treating ER/PR-positive, HER2-negative metastatic breast cancer with ESR1 mutations, showing improved median progression-free survival compared to standard endocrine therapy in the EMERALD trial.

The drug acts as a mixed ER agonist/antagonist and has specific metabolic considerations, being primarily processed by CYP3A4, which can lead to drug interactions; dose adjustments are recommended for patients with moderate hepatic dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and pharmacokinetics of elacestrant. Beumer, JH., Foldi, J.[2023]

References

1. Australia pubmed.ncbi.nlm.nih.gov

CDK4/6 inhibitor plus endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer: The new standard of care. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

The Role of CDK4/6 Inhibitors in Breast Cancer. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Cyclin‑dependent kinase 4/6 inhibitors in combination with fulvestrant for previously treated metastatic hormone receptor‑positive breast cancer patients: A systematic review and meta‑analysis of randomized clinical trials. [2020]

4. Australia pubmed.ncbi.nlm.nih.gov

Emerging data and future directions for CDK4/6 inhibitor treatment of patients with hormone receptor positive HER2-non-amplified metastatic breast cancer. [2018]

5. Japan pubmed.ncbi.nlm.nih.gov

Clinical development of CDK4/6 inhibitor for breast cancer. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. [2020]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Evaluating Elacestrant in the Management of ER-Positive, HER2-Negative Advanced Breast Cancer: Evidence to Date. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models. [2018]

11. Germany pubmed.ncbi.nlm.nih.gov

Pharmacology and pharmacokinetics of elacestrant. [2023]