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Emerging Therapies in HR+/HER2- Metastatic Breast Cancer – The Oral SERDs

Presentation by Dr Reshma Mahtani, Miami Cancer Institute

At the 2023 Community Oncology Educational Dinner Series (COEDS) Conference held in Fort Lauderdale Florida, Reshma Mahtani, DO from Miami Cancer Institute presented an overview of current and future endocrine therapy strategies in breast cancer, including a discussion of supporting data for an emerging class of therapies, the orally administered selective estrogen receptor degraders (SERDs).

What are SERDs?

A primary treatment strategy for breast cancers that are designated as hormone receptor-positive (HR+) is endocrine therapy (ET), which functions to inhibit the growth-stimulatory activity of the sex hormone estrogen and/or the estrogen receptor (ER) in breast cancer. Among the currently approved ET agents are aromatase inhibitor drugs (AIs) which inhibit the conversion of other androgen precursors to estrogen, tamoxifen, a selective estrogen receptor modulator (SERM), and fulvestrant, a SERD that is administered by intramuscular injection. In the early-stage setting, AIs and tamoxifen are limited by their toxicity profiles and have historically been poorly tolerated as a long-term ET, with high rates of treatment discontinuation. In the metastatic setting, mutations in the gene encoding the estrogen receptor, ESR1, may occur with continued, long-term ET, leading to treatment resistance. SERDs such as fulvestrant act by binding to the ER and in so doing cause it to be degraded. The major disadvantages to the use of fulvestrant are its intramuscular route of administration (which is inconvenient for patients), and its poor pharmacokinetic (PK) properties. In addition, its activity may be limited for patients who have specific ESR1 mutations, such as ESR1 Y537S.

As noted earlier, ESR1 mutations are a driver of ET resistance, and whereas these mutations are relatively uncommon (<1%) in primary breast tumors, they are frequently observed (~40% of the time) in patients with metastatic disease, and Dr Mahtani noted that this is most likely due to the selective pressure of prior ET. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), in combination with an AI or fulvestrant, are indicated for patients with locally advanced or metastatic HR+/HER2- breast cancer as initial therapy, or upon progression with hormonal therapy. Dr Mahtani noted that a high unmet need in breast cancer is therapy for patients whose cancers have progressed after combined ET + a CDK4/6i.

Pivotal Data for Oral SERDs

In 2023, the United States Food and Drug Administration (US FDA) approved the first orally administered SERD, elacestrant for the treatment of ESR1-mutated advanced or metastatic HR+/HER2- breast cancer. Of note, the oral route of administration for elacestrant provides a significant benefit over the intramuscularly-administered SERD fulvestrant. Dr Mahtani noted that the approval was based on results from the EMERALD trial, a phase III clinical study that examined the efficacy of elacestrant versus the standard of care (SOC) therapy, (fulvestrant, letrozole, anastrozole, or exemestane). Importantly, patients in the trial had to have ER+/HER2- disease, and had to have progressed on prior endocrine therapy (1 or 2 lines of treatment), at least one of which included treatment with a CDK4/6i. As such, the trial addressed efficacy in the critical population of patients with progression after a CDK4/6i. In addition, approximately 70% of patients in the trial had visceral metastases, 40% had received 2 lines of prior ET, and 24% had received 1 line of chemotherapy. The co-primary endpoints were progression-free survival (PFS), as assessed in all patients, and those with ESR1-mutated tumors.

Although the primary results of the EMERALD trial showed a marginal benefit of elacestrant, Dr Mahtani outlined a post hoc analysis of PFS, based on the duration of prior CDK4/6i therapy, which provided more clinically meaningful information. Specifically, the duration on prior CDK4/6i therapy (a surrogate for overall endocrine sensitivity) was positively associated with a longer PFS with elacestrant as compared to SOC ET in all patients. In the ESR1-mutated population with at least 18 months of prior exposure to CDK4/6i, the median PFS was 8.6 months with elacestrant versus 2.1 months with SOC, and results were similar for those with at least 12 months of prior treatment with CDK4/6i, and Dr Mahtani noted these are clinically relevant improvements.

Dr Mahtani also noted results from the SERENA-2 trial, a phase II trial investigating the efficacy of different doses for another oral SERD, camizestrant, as compared with single agent fulvestrant. In this trial, about one-third of patients had ESR1 mutations, 60% had visceral metastases, and, in contrast to the EMERALD trial, only about half of the patients had received a prior CDK 4/6i. The results for the primary endpoint of investigator-assessed PFS showed a median PFS of 7.2 and 7.7 months for patients on 75 and 150 mg of camizestrant, respectively, versus 3.7 months for those on fulvestrant (HR=0.58; P=0.0124 and HR=0.67; P=0.0161, respectively), and as such, the trial did meet its primary endpoint. Of note, Dr Mahtani cautioned against cross-trial comparisons with the EMERALD data, given that only 50% of the patients in SERENA-2 had received a prior CDK4/6i and most (77%) had received only one line of prior ET. In terms of safety profile, an unusual ocular side effect was reported, photopsia (flashing lights), which was observed in between 12 and 25% of patients at the low and high doses of camizestrant, respectively. Dr Mahtani noted that a phase III trial with camizestrant is ongoing, with a target dose of 75 mg which should shed further light on its efficacy and adverse event profile. Lastly, she briefly noted some data for imlunestrant, another oral SERD in the EMBER trial and cited several ongoing trials for these drugs in metastatic breast cancer.


In view of the recent approval of elacestrant and the positive results seen for clinically relevant subgroups of patients in the EMERALD trial, Dr Mahtani expects that both elacestrant and other oral SERDs will become an important component of treatment for patients with advanced/metastatic breast cancer who have progressed after ET and CDK4/6i and/or those with ESR1 mutations. Ongoing studies are expected to provide additional data with these and other oral SERD agents in metastatic breast cancer and to determine their optimal use in this setting.

Quick Summary

· Orally administered selective estrogen receptor degraders (SERDs) are an important new class of drugs for endocrine therapy (ET) in breast cancer.

o Orally administered SERDs are more convenient to administer and have proven more efficacious as compared to the currently available, intramuscularly administered SERD, fulvestrant.

· The US FDA recently approved the first oral SERD, elacestrant, for patients with ESR1-mutated HR+/HER2- advanced/metastatic breast cancer.

o Elacestrant demonstrated efficacy in the highly clinically relevant subgroup of patients that have progressed after prior ET in combination with a CDK4/6 inhibitor.

· Other oral SERDs (e.g., camizestrant) are under investigation in phase III clinical trials, and further oral SERD approvals are expected.


Speaker Disclosure Information: Dr Mahtani lists her disclosures as follows: Consultant/Advisor: Agendia, Amgen, Astra Zeneca, Daiichi, Eisai, Genentech, Gilead, Hologic, Lilly, Merck, Novartis, Pfizer, Puma, Sanofi, Seagen, Stemline.

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