Aditya Bardia, MD, MPH

Based on the results of the EMERALD trial, Elacestrant potentially could be used in the second-line setting for patients with ER-positive HER2-negative metastatic breast cancer. EMERALD trial was as a single agent. There's also interest in combination therapy combining endocrine agents with other targeted agents such as PI3 kinase inhibitors as well as everolimus so that would be of interest as well.

Aromatase inhibitors are currently used in the adjuvant setting for patients with postmenopausal early breast cancer and they're also used in the metastatic setting as first-line therapy in combination with a CDK4/6 inhibitor. In terms of second, third-line setting, we sometimes do use aromatase inhibitors in combination with everolimus so if Elacestrant is FDA approved in the second, third-line setting, some physicians would consider using it as a single agent but there are others who would be interested in combination therapy in combination with a PI3 kinase mTOR or other targeted agents.

In terms of unmet need for patients with ER-positive, HER2-negative breast cancer, I can highlight three. The first is we need better endocrine agents. For example, fulvestrant is a selective estrogen receptor degrader but is given as an intramuscular shot, which can be inconvenient for patients so we need oral options for patients with ER-positive HER2-negative metastatic breast cancer. The second unmet need is once patients have endocrine-resistant disease, the mainstay of management right now is chemotherapy. Their interest in antibody-drug conjugates, trastuzumab deruxtecan, sacituzumab govitecan, but we need better agents that can help prolong survival for patients with ER-positive metastatic breast cancer and also improve quality of life in this setting. Then finally, the unmet need is to prevent metastatic ER-positive breast cancer. If we have good therapies in early breast cancer, if we can diagnose early breast cancer early, potentially we can prevent the emergence of metastatic disease, which would be wonderful for our patients.

Videos

Dr Bardia provides his opinion on the current state of the ER+/HER2- treatment landscape and where elacestrant belongs in the current treatment paradigm.

The Future of ER+/HER2- mBC Treatment

Dr. Aditya Bardia: EMERALD trial evaluated Elacestrant was a standard of care endocrine therapy aromatase inhibitor fulvestrant for patients with ER-positive HER2-negative metastatic breast cancer. The trial overall was positive, showed an improvement in progression-free survival in all comers. You could see a stronger signal in ESR1 mutant metastatic breast cancer. The trial did allow one prior line of chemotherapy so we saw subset analysis looking at patients who had not received prior chemotherapy. Essentially patients who had not received prior chemotherapy could see treatment with Elacestrant was associated with prolonged progression-free survival compared to standard-of-care endocrine therapy hazard ratio of 0.68. The median progression-free survival was 3.7 months with Elacestrant versus two months with standard-of-care endocrine therapy. If you look at landmark analysis, and that's important for EMERALD trial because if you look at the curves, you see an initial drop in the curves and then separation highlighting that median PFS might not be the best way to look at efficacy in the EMERALD trial. Landmark analyses like six months and 12 months PFS is a good metric. If you look at 12-month PFS, it was 27% with Elacestrant versus 12% with standard-of-care endocrine therapy. You could clearly see a separation in patients who have endocrine sensitive disease. This was particularly seen in patients with mutant ESR1 breast cancer. As I mentioned earlier, in tumors that have mutations in the estrogen receptor, the tumor is still ER-dependent so drugs that would directly bind to ER like Elacestrant would work in this setting. In patients with mutant ESR1 breast cancer, you could see improvement in progression-free [00:18:00] survival hazard ratio of 0.54 with Elacestrant median PFS 5.3 months versus 1.9 months with standard endocrine therapy. Finally, if you look at the landmark 12-month PFS analysis, it was 31% with Elacestrant so one in three patients being without disease progression at 12 months with Elacestrant versus 12% with standard endocrine therapy. Overall you could see that in patients who had not received prior chemotherapy, that was a prognostic factor and you could clearly see benefit with Elacestrant as compared to standard endocrine therapy.

The most common adverse events seen with Elacestrant was nausea in the EMERALD trial, which is not surprising because it's an oral pill. In general, patients do not need anti-nausea medications. The percentage of treatment discontinuation was quite low with Elacestrant. It's just something that's seen because it's an oral agent. Outside of nausea, the AEs are pretty much similar between Elacestrant and endocrine therapy in terms of arthralgia and hot flashes. A side effect that was not seen with Elacestrant was pain that's associated with intramuscular shot because it's an oral agent. That's something that we see with fulvestrant which is given as an intramuscular injection.

In subset analyses of the EMERALD trial, Elacestrant was compared to the individual endocrine therapy agents that were utilized, aromatase inhibitors as well as fulvestrant. This was presented at ESMO 2022 by Dr. Philippe Aftimos. Essentially benefit with Elacestrant was seen both against AI as well as against fulvestrant. Patients who received Elacestrant had prolonged PFS at six, 12, even 18 months as compared to fulvestrant both in the overall population as well as patients who had ESR1 mutations. For example, if we compare Elacestrant to fulvestrant, the six-month PFS rate in the ESR1 mutant subgroup was 40.8% as compared to 20.8% with the use of endocrine agents. Similarly, you could see an improvement at 12 months, 26.8% with Elacestrant versus 8.4% with the fulvestrant. You could clearly see benefits with Elacestrant as compared to fulvestrant in these landmark analyses.

Taking a closer look at the EMERALD trial, Dr Bardia shares key efficacy outcomes from the sub-group analyses 1) of patients with no prior chemotherapy and 2) comparing elacestrant to fulvestrant or AI.

Key Efficacy Data from Sub-Group Analyses of Patients from the EMERALD Trial

Dr. Aditya Bardia: Elacestrant is a novel selective estrogen receptor degrader. It's oral. The drug binds to the estrogen receptor, blocks it and degrades it. In a phase 1/2 clinical trial that we were involved with, we could see evidence of clinical activity in pretreated patients with ER-positive HER2-negative metastatic breast cancer. Subset analysis revealed that patients who have ESR1 mutant metastatic breast cancer, you could clearly see activity with Elacestrant. This led to the design of the phase 3 trial, the EMERALD trial that looked at Elacestrant versus standard-of-care endocrine therapy in the second third-line setting for patients with ER-positive HER2-negative metastatic breast cancer. There are three features I would like to highlight related to the study design. The first is that it was a randomized global phase 3 trial in multiple regions so it was important to consider the practice patterns in different countries. The second is that the trial required patients to have prior CDK4/6 inhibitor because that's what we use in the first-line setting. That was required in this trial. Then the third is that the trial had two primary endpoints and was powered for both the primary endpoints. The first one was progression-free survival of Elacestrant was a standard of care endocrine therapy which would either be fulvestrant or aromatase inhibitor in patients who have ESR1 mutant metastatic breast cancer. A second primary endpoint was in all comers regardless of ESR1 mutations, progression-free survival with Elacestrant versus standard-of-care endocrine therapy.

Elacestrant is a selective estrogen receptor degrader. Besides Elacestrant, there are other selective estrogen receptor degraders example being giredestrant, camizestrant. These are all agents that bind to the estrogen receptor and degrade it. There are also SERMs or selective estrogen receptor modulators. Example being tamoxifen, also interest in a new SERM called lasofoxifene. Those are agents that bind to the estrogen receptor but do not degrade it per se, but they can modulate the function of the estrogen receptor. In clinical trials, we've seen data from different selective estrogen receptor degraders including the second, third-line setting. The EMERALD trial evaluating Elacestrant was positive. It showed improvement in progression-free survival and a trend towards improvement in overall survival as well. Elacestrant was a standard of care endocrine therapy, but we've also seen two negative studies. The first one was AMEERA03 which looked at amcenestrant was a standard of care endocrine therapy in the second-line and third-line setting, although was predominantly second-line. The second trial with acelERA which looked at giredestrant was a standard of care endocrine therapy in the second third-line setting for patients with ER-positive HER2-negative metastatic breast cancer. It should be noted that there were differences in the study design between these three trials. EMERALD, acelERA, as well as AMEERA03 in terms of the second third-line setting, in terms of the proportion of patients who got fulvestrant, the use of prior CDK4/6 inhibitor and perhaps most important, the proportion of patients who had ESR1 mutations. Only EMERALD had two primary endpoints looking at overall population as well as population of patients who had ESR1 mutant metastatic breast cancer. This was not a primary endpoint, the ESR1 mutant group in either EMERALD or acelERA.

Dr Bardia discusses the mechanism of action of elacestrant, how elacestrant compares to other SERDS, and introduces the EMERALD trial.

The EMERALD Trial: Elacestrant Mechanism of Action, Study Design, and Outcomes

Dr. Aditya Bardia: In the first-line setting, the management of ER-positive, HER2-negative metastatic breast cancer involves use of endocrine plus CDK4/6 inhibitor but patients have disease progression. In the second-line setting, at this time we use fulvestrant without other targeted therapies in the second-line setting. The challenge is that fulvestrant is given as an intramuscular shot, so can it be inconvenient for patients. As a single agent, the activity of fulvestrant is limited. Fulvestrant can be used with other targeted agents such as PI3 kinase inhibitor alpelisib or PIK3CA mutant ER-positive breast cancer in the second-line setting. That can be associated with toxicity including rash and diarrhea as well as hyperglycemia. Clinically, there's unmet need for better endocrine agents in this setting. A lot of interest in novel endocrine-based therapies in the second-line setting.

In terms of deciding between different therapies in the second-line setting, there are two broad factors that can help with treatment decision-making. The first is the molecular profile of the cancer. For example, if a tumor has PIK3CA mutation, there would be interest in using a PI3 kinase inhibitor along with endocrine therapy such as fulvestrant. The other factor is the amount of disease and presence of bone-only mets versus bone-plus visceral mets. In patients who have a lot of disease including visceral metastasis, sometimes we tend to consider chemotherapy in the second-line setting to control the disease. The other factor that comes into this decision-making is the duration that the patient was on endocrine plus a CDK4/6. If that duration is shot, you worry about endocrine-resistant disease, and sometimes, particularly in the presence of visceral metastasis chemotherapy such as capecitabine is utilized in this setting.

Biomarker testing is routinely done for a patient with metastatic breast cancer. The first biomarker is to look at ER-PR and HER2. That's usually done at the time of diagnosis of metastatic disease. The second category of biomarker would include genotyping, which can either be tissue-based genotyping or plasma-based genotyping. The idea here is to look at mutations. An actionable mutation in metastatic ER-positive breast cancer is PIK3CA because there's a PI3 kinase inhibitor that could be utilized in this setting. There are other alterations as well. For example, BRCA. A subset of metastatic breast cancers have somatic BRCA which is different from germline BRCA. In that setting, one could consider the use of a PARP inhibitor, usually in a clinical trial. Another similar alteration is PALB2. If PALB2 alteration is present, be it somatic or germline, there would be interest in using a PARP inhibitor. There's value in doing genotyping in metastatic disease including ER-positive breast cancer.

In terms of testing methods for genotyping, it can broadly be divided into two categories. Tissue-based genotyping and plasma-based genotyping. For tissue-based genotyping, that could be done in the metastatic specimen. Usually, that's preferred over primary breast cancer. For truncal alterations like PIK3CA, you can usually detect it in primary as well as metastatic disease but for some alterations that are acquired like ESR1 mutations, which are acquired mutations usually under selective pressure from aromatase inhibitors. Then the reason these mutations come up is because these mutations confer estrogen independence. The tumor is still dependent on the ER receptor in the ER pathway but becomes estrogen-independent and thus resistant to aromatase inhibitors. Because these are acquired alterations, it's best to detect them utilizing plasma-based genotyping because over time the tumor can evolve and it's tough to do repeated biopsies, but it can collect blood and utilizing blood, do plasma-based genotyping that can help with detection of these acquired alterations like ESR1. ESR1 mutations are important in ER-positive HER2-negative metastatic breast cancer because they confer resistance to aromatase inhibitors, but still would confer sensitivity to drugs that directly bind ER such as selective estrogen receptor degraders, even selective estrogen receptor modulators because these drugs directly bind to the ER and thus would still work in the ESR1 mutant setting.

Dr Bardia talks about the role of biomarker testing and provides an overview of factors which may contribute to a clinician’s choice of treatment strategy for patients with ER+/HER- mBC.

Biomarker Testing in Patients With ER+/HER2- mBC

Dr. Aditya Bardia: Hello. I'm Aditya Bardia, a breast medical oncologist at Massachusetts General Hospital, Harvard Medical School, Boston.

Today, we'll review potential role of Elacestrant for the treatment of metastatic ER-positive HER2-negative breast cancer. We'll start with an overview of metastatic ER-positive breast cancer, the current landscape, and then review the EMERALD trial with I Elacestrant for metastatic ER-positive breast cancer.

Metastatic ER-positive HER2-negative breast cancer represents a subset of metastatic disease. Metastatic disease refers to patients who have evidence of breast cancer outside of the breast in the bones, liver, or other organs. ER-positive refers to tumors that express estrogen receptors and do not have HER2 amplification so therefore HER2-negative. In general, tissue biopsy is the mainstay for diagnosis of metastatic ER-positive HER2-negative breast cancer. It helps with confirmation of the diagnosis and also evaluation of the receptors.

Endocrine-based therapy is the mainstay of management of metastatic ER-positive HER2-negative breast cancer. It's also the mainstay of management for early ER-positive HER2-negative breast cancer. For metastatic ER-positive HER2-negative metastatic breast cancer, the first line of therapy includes endocrine therapy with a CDK4/6 inhibitor. Usually, it's aromatase inhibitor, but in specific situations fulvestrant is used as the first line endocrine therapy in combination with a CDK4/6 inhibitor. Options for CDK4/6 inhibitors include ribociclib, abemaciclib, and palbociclib. We've seen improvement in overall survival with the use of endocrine therapy plus abema, endocrine therapy plus ribociclib in the first-line setting.

Aditya Bardia, MD, MPH briefly explains metastatic ER+/HER2- breast cancer, and reviews existing treatment options for patients with ER+/HER2- mBC.

An Introduction to ER+/HER2- mBC and Current Treatment Options

Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, discusses the efficacy of sacituzumab govitecan (Trodelvy) in patients with triple-negative breast cancer (TNBC).

Of the many antibody drug conjugates in clinical development at the moment, Bardia says the furthest along for metastatic TNBC is sacituzumab govitecan. This antibody drug conjugate targets TROP-2, which is overexpressed in most TNBC cells. It is also links to SN-38, the active metabolite of irinotecan (Onivyde) and is a topoisomerase inhibitor.

In a phase I/II clinical trial investigating sacituzumab govitecan in a heavily pretreated patient population (NCT01631552), there was impressive clinical activity with a response rate of over 30%, according to Bardia. In this setting, there is usually a response rate of about 10% to 15% with standard chemotherapy. The responses for this therapy were durable as well.

The toxicity profile for an antibody drug conjugate is usually caused by the toxic payload, and depending on the type of toxic payload, patients will have different adverse events (AEs). Because sacituzumab govitecan has an SN-38 toxic payload, common AEs include myelosuppression, such as neutropenia and thrombocytopenia; gastrointestinal AEs, such as nausea and diarrhea; and alopecia.

<< View more resources and information regarding breast cancer

Aditya Bardia, MD, MPH, discusses the efficacy of sacituzumab govitecan in patients with triple-negative breast cancer.

Aditya Bardia, MD, MPH | Authors

Articles

The Future of ER+/HER2- mBC Treatment

Key Efficacy Data from Sub-Group Analyses of Patients from the EMERALD Trial

The EMERALD Trial: Elacestrant Mechanism of Action, Study Design, and Outcomes

Biomarker Testing in Patients With ER+/HER2- mBC

An Introduction to ER+/HER2- mBC and Current Treatment Options

Antibody Drug Conjugate Sacituzumab Govitecan Shows Efficacy in TNBC