Adding SERDs to the Adjuvant Armamentarium

In the United States, breast cancer is second only to skin cancer as the malignancy most commonly diagnosed among women. Nearly 300,000 women will be diagnosed with invasive breast cancer this year, according to the American Cancer Society, accounting for just over 30% of the cancer diagnosed in women.

How breast cancer is treated in women depends on certain biomarkers expressed by breast cancer cells, including estrogen receptors (ERs), progesterone receptors (PRs) and human epidermal growth factor receptor 2 (HER2). Breast cancer tumors that have at least 1% of cells with ERs or PRs are classified as ER or PR positive, respectively. The ER-positive cells become activated when estrogen binds to their receptors; progesterone fires up the PR-positive cells. The HER2 protein is essential for epithelial cell growth and differentiation. Breast cancer cells that overexpress HER2 are classified as HER2 positive, and those with normal expression of the protein are HER2 negative. Most breast cancers are either ER or PR positive, particularly ER positive; collectively, they are refeered to as HR positive.

Breast cancer is now diagnosed often at an early stage of the disease. Many women are treated with lumpectomy, which surgically removes the cancer but leaves the rest of the breast intact. Five years of follow-up (or adjuvant) therapy has been the standard for reducing breast cancer relapse and mortality. Agents used in adjuvant therapy include aromatase inhibitors that decrease estrogen production and selective estrogen receptor modulators (SERMs), such as tamoxifen, that block estrogen from binding to receptors. Although these agents are effective in improving survival and reducing relapse rates, mechanisms of resistance have been identified.

Selective estrogen receptor degraders

To combat drug resistance in ER-positive breast cancers, new molecules with novel mechanisms of action are under development. The experimental treatments include a new class of drugs called selective estrogen receptor degraders (SERDs). Similar to SERMs, SERDs bind to ERs, thereby blocking estrogen from binding to the site. Unlike SERMs, however, SERDs are pure ER antagonists and are designed to target the receptor for degradation after binding.

AstraZeneca’s Faslodex (fulvestrant) injection was the first SERD approved by the FDA when the agency gave it a green light in 2002. In January 2023, Menarini Group, an Italian pharmaceutical company, gained FDA approval for Orserdu (elacestrant), the first oral SERD indicated for the treatment of ER-positive, HER2-negative breast cancer. The company’s New York–based subsidiary, Stemline Therapeutics, markets the drug in the U.S. Currently, three other companies have SERDs in phase 3 trials.

Giredestrant

San Francisco–based Genentech, a member of the Roche group, is developing giredestrant as a potential adjuvant treatment in patients with ER-positive, HER2-negative early breast cancer, as well as first-line treatment for ER-positive metastatic breast cancer and ER-positive, HER2-negative metastatic breast cancer. The phase 3 lidERA Breast Cancer trial is evaluating the safety and efficacy of adjuvant giredestrant versus physician’s choice of therapy in adults with ER-positive, HER2-negative early breast cancer.

The study plans to enroll 4,100 volunteers from around the world who will be randomly assigned to receive giredestrant 30 mg orally once daily on days 1 through 28 of each 28-day cycle or the physician’s choice of tamoxifen or one of the following aromatase inhibitors: Arimidex (anastrozole), Aromasin (exemestane) or Femara (letrozole). Male, premenopausal and perimenopausal participants will also receive a luteinizing hormone-releasing hormone agonist. Treatment will continue for five years or until disease recurrence or unacceptable toxicity.

The investigators are optimistic about giredestrant’s performance. “Being a potent oral agent with an excellent safety profile, giredestrant may enable better disease control (and) lower toxicity, thus maximizing the therapeutic benefit and (adherence) for patients with breast cancer,” Aditya Bardia, M.B.B.S., M.P.H., the study’s co-chair and director of the Breast Cancer Research Program at Massachusetts General Hospital in Boston, said in a press release.

The primary end point is invasive disease-free survival, and secondary end points include overall survival and disease-free survival, among others. The study has an estimated primary completion date of May 2025.

After missing a primary end point in a previous trial, the company is now testing giredestrant combined with Phesgo (pertuzumab, trastuzumab, and hyaluronidase) versus Phesgo treatment alone in the phase 3 heredERA Breast Cancer trial of patients with locally advanced or metastatic breast cancer. Phesgo is also a Genentech product. Primary completion for this trial is estimated in August 2026.

Camizestrant

AstraZeneca’s camizestrant is being evaluated in the phase 3 CAMBRIA-1 trial as an extended adjuvant treatment in HR-positive, HER2-negative breast cancer. The company is also running two separate phase 3 trials that are investigating the use of camizestrant as first-line treatment for certain HR-positive, HER2-negative breast cancers.

The CAMBRIA-1 study is enrolling 4,300 participants who have completed at least two years and up to five years of standard adjuvant therapy. Patients will be randomly assigned to receive oral camizestrant or continue standard adjuvant therapy of the investigator’s choice for five years. Participants will be followed for 10 years from randomization of the last patient.

The primary end point is invasive breast cancer–free survival. Secondary end points include overall survival and invasive disease-free survival. The study’s estimated primary completion date is April 2027.

Imlunestrant

Eli Lilly and Company’s oral imlunestrant is also in the pipeline for the potential treatment of advanced or metastatic breast cancer, as well as extended adjuvant treatment. The phase 3 EMBER-3 trial is evaluating the safety and efficacy of imlunestrant monotherapy compared with imlunestrant plus Ely Lilly’s kinase inhibitor Verzenio (abemaciclib), Aromasin and Faslodex in patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

The study plans to enroll 860 participants who will be randomly assigned to receive imlunestrant alone or with Verzenio or the investigator’s choice of exemestane or fulvestrant therapy for up to 5 years. The primary end points are progression-free survival in the intent-to-treat population and the estrogen receptor 1 (ESR1)-mutation detected population. Secondary outcomes include overall survival in both populations. The primary completion date for this study is estimated in April 2024.

The EMBER-4 study is evaluating imlunestrant as adjuvant treatment compared with standard adjuvant therapy in participants with ER-positive, HER2-negative early breast cancer who have received two to five years of adjuvant therapy.

Patients will be randomly assigned to receive imlunestrant or the investigator’s choice of tamoxifen or one of the aromatase inhibitors. Participants will be followed for up to 10 years. The primary outcome is invasive disease-free survival, and a key secondary outcome is overall survival. The study has an estimated completion date of October 2027.

If approved, all these investigational drugs will have to compete with Orserdu and Faslodex, which are now available in generic forms, in treating locally advanced or metastatic breast cancer. However, any of these agents could become the first oral SERD approved as adjuvant treatment in patients with HR-positive, HER2-negative breast cancer.

Rosanna Sutherby, Pharm.D., is an independent medical writer and community pharmacist in High Point, North Carolina, and a regular contributor to Managed Healthcare Executive.