Elacestrant and Trastuzumab Deruxtecan Approvals Prompt Sequencing Considerations in HR+ Breast Cancer

Manali Bhave, MD

Emerging data on antibody-drug conjugates (ADCs) and other novel treatments for patients with hormone receptor (HR)–positive breast cancer have added another challenge in this space: the need to better understand how to sequence various agents based on new data and prior knowledge, according to Manali Bhave, MD.

“This is an exciting time for both providers who are treating patients for HR-positive, HER2-negative or -low breast cancer, and for patients who are undergoing [treatment],” Bhave said following an OncLive^® State of the Science Summit™ on breast cancer, which she chaired. “We are now finding targeted treatments and investigating more novel agents that are geared at increasing efficacy, reducing toxicity, and hopefully improving quality of life and tolerability for patients who are living with the disease.”

In an interview with OncLive, Bhave discussed the effect of emerging therapies on the treatment landscape for patients with HR-positive, HER2-negative or -low breast cancer, highlighted her stance on sequencing decisions for these patients, and expanded on the additional work being done to optimize treatment sequencing from a growing list of options. Bhave is a medical oncologist at the Winship Cancer Institute and an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia.

OncLive: Could you provide an overview of the cases you discussed at the OncLive State of the Science Summit?

Bhave: I utilized the case studies to demonstrate how we [consider both] newer data and existing data, then integrate them into the treatment of patients with advanced or metastatic HR-positive, HER2-negative or -low breast cancer. The key takeaways from my cases were how we now sequence endocrine therapies, and, as we get into patients who are refractory to endocrine therapy, [how we sequence] the ADCs that are now approved or making their way into everyday care for patients with HR-positive advanced breast cancer.

Based off some of the data that [Kevin Kalinsky, MD, MS, of Winship Cancer Institute], presented about CDK4/6 inhibitors, we have established that frontline [treatment with a] CDK4/6 inhibitor and endocrine therapy is what most patients benefit from, including those with visceral metastases.

After progression on [a CDK4/6 inhibitor and endocrine therapy], we now get into some of the newer data with the approval of elacestrant [Orserdu] in patients with ESR1 mutations who have progressed on at least 1 line of endocrine therapy. However, [these patients also] have a standard-of-care options available, including fulvestrant [Faslodex] with everolimus [Afinitor], or fulvestrant with exemestane [Aromasin] or another aromatase inhibitor.

We asked our expert speakers about how to integrate and sequence some of these newer therapies, and how we use biomarkers to help target which patients may benefit from some of these newer treatments.

Expanding on Dr Kalinsky’s presentation on CDK4/6 inhibitors, how have additional analyses with ribociclib (Kisqali), abemaciclib (Verzenio), and palbociclib (Ibrance) affected practice patterns?

All 3 CDK4/6 inhibitors are approved in combination with endocrine therapy for patients with advanced or metastatic HR-positive, HER2-negative breast cancer. That is based off the significant progression-free survival benefit that we have seen across all 3 CDK4/6 inhibitors in combination with endocrine therapy vs endocrine therapy alone.

We now have seen differing data on results in terms of overall survival [OS] between the CDK4/6 inhibitors that have led to questions about whether all 3 agents are the same or if there are any differences. What we were seeing in terms of OS is that there was a statistically significant improvement in OS in patients that had received ribociclib in combination with endocrine therapy in both the first- and second-line settings per the [phase 3] MONALEESA-2 [NCT01958021] and MONALEESA-3 [NCT02422615] studies.

Additionally, [we saw] an OS advantage with abemaciclib with endocrine therapy in the second-line setting of the [phase 3] MONARCH 2 trial [NCT02107703], and a trend toward a [potential] OS advantage with abemaciclib in the first-line [adjuvant] setting in the [phase 3] monarchE trial [NCT03155997], although that data is still immature and pending.

Unfortunately, data from the [phase 3] PALOMA-2 trial [NCT01740427] data with palbociclib and endocrine therapy in the first-line setting did not meet statistical significance in terms of OS. There are [probably] a couple reasons that may have contributed at least in part to that. One was that the eligibility criteria between all 3 trials were different, including potentially a higher-risk population of patients who had enrolled into PALOMA-2. There was also some long-term follow-up data that was missing for PALOMA-2, so some of those things may be contributing [factors].

Unfortunately, not only did palbociclib not reach statistical significance for OS in PALOMA-2, but now there are now adjuvant data with palbociclib that did not reach statistical significance. It begs the question whether all 3 CDK4/6 inhibitors are truly the same, or whether there are some differences. That’s why we’re seeing some clinical outcome differences, as well.

The bottom line is that it comes down to not just the data, but also tolerability of these agents, patient comorbidities, and physician preference and experience. Based off these data, a lot of us are now recommending ribociclib with endocrine therapy in the first-line setting. In some patients, we may consider abemaciclib and endocrine therapy in the first-line setting. However, I have had a number of patients who have tolerated palbociclib and endocrine therapy very well and have been doing very well. There are also some patients who, because of comorbidities or the inability to conduct electrocardiogram assessments, are receiving palbociclib.

Stephanie Graff, MD, FACP, of Lifespan Cancer Institute, discussed the promise of oral selective estrogen receptor degrader (SERDs) for HR-positive breast cancer. What is the importance of these agents when there are other options, such as PI3K inhibitors and ADCs?

For patients with advanced HR-positive, HER2-negative or -low breast cancer, our primary goal is not just to extend life, but to improve quality of life. For a lot of these patients, that means finding targeted options that are going to be better tolerated and allow them to live their lives for whatever time they do have remaining. Many of these women live extended periods of time, in the order of years.

We are now focusing on not just efficacy, but tolerability. As part of that, both from an efficacy standpoint and tolerability standpoint, there has been an unmet need to create and utilize more oral targeted therapies in this patient population, and that is where the oral SERDs are fitting in.

Julia E. McGuinness, MD, of Columbia University Herbert Irving Comprehensive Cancer Center, discussed novel therapeutics for patients with metastatic HR-positive, HER2-negative breast cancer, including CDK7 inhibitors, PROTAC estrogen receptor degraders, and AKT inhibitors. How do you envision sequencing playing out if further research with these agents proves positive?

The million-dollar question is how to sequence all these agents. What it will come down to is further biomarker selection, in terms of which patients may benefit from certain types of oral SERDs or PROTACs, depending on what type of ESR1 mutation they have. Also, [we need to] look at the use of some of these agents to reinvigorate estrogen sensitivity or endocrine therapy sensitivity, which will then help sequence the use of both monotherapy endocrine agents and these combination strategies.

There are still a lot of questions regarding sequencing, and this increasingly will become a problem as we start to get more approvals. It will all come down to better biomarker selection for patients, and then we will have to look at potentially holding clinical trials where we evaluate patients who have progressed on CDK4/6 inhibitors, fulvestrant, an oral SERD, or a combination of an endocrine agent plus a targeted agent. Enrollment on these [types of] studies can help us sequence [treatments as new agents are approved].

In terms of the ADCs, there are some ongoing clinical trials looking at the sequencing of a HER2-targeted ADC followed by a Trop-2 ADC, or the reverse, in both HR-positive, triple-negative, and HER2-low populations. We’re all anxiously awaiting those trials that are currently enrolling.

Suchita Pakkala, MD, of Winship Cancer Institute at Emory University, discussed the evolving landscape for ADCs for patients with HR-positive, HER2-low breast cancer. What is important to note about changes to the treatment paradigm that have been created with the addition of ADCs?

With a lot of these treatments—not just the ADCs, but also with the elacestrant approval for patients with ESR1 mutations—we are doing more liquid biopsies to detect mutations, such as ESR1 or PIK3CA. In terms of ADC selection, I’ve had a lot of questions come up regarding when to re-biopsy patients who perhaps were HER2-zero at the time of initial diagnosis. That may be a sampling error, or things may change in patients who have metastatic breast cancer.

With the recent approval of fam-trastuzumab deruxtecan-nxki [Enhertu] per the phase 3 DESTINY-Breast04 trial [NCT03734029], this question is coming up on redoing a tissue biopsy, and repeating [testing] for HER2, then using trastuzumab deruxtecan if patients are HER2 low. In patients that have HR-positive, HER2-low breast cancer, because of the robust data from DESTINY-Breast04, I am using trastuzumab deruxtecan first, prior to considering sacituzumab govitecan-hziiy [Trodelvy].

In terms of sequencing those 2 [agents], that question is still up in the air on whether we will see activity [with sacituzumab govitecan] in patients who have progressed on trastuzumab deruxtecan. In the interim, I have used both in a few patients, and I have generally used another chemotherapy in between those ADCs, given the similarity in the payload between them.

How have all these changes and updates helped shape changes in practice for the treatment of patients with HR-positive breast cancer?

In terms of advances, I would like to highlight a couple of the recent FDA approvals that were discussed during our presentations. One was the recent approval of elacestrant for patients with HR-positive, HER2-negative advanced breast cancer who harbor an ESR1 mutation. These patients are able to then move on to elacestrant monotherapy as long as they’ve progressed on at least 1 line of endocrine therapy. This is a key practice-changing point and something that we can integrate today into our practice.

The second was to highlight 2 new ADCs. Trastuzumab deruxtecan from the DESTINY-Breast04 study is now FDA approved for patients with advanced HR-positive, HER2-low, endocrine- refractory disease who have progressed on at least 1 line of chemotherapy. Additionally, sacituzumab govitecan, which is a Trop-2–targeted ADC, is now approved for patients with HR-positive advanced breast cancer who have progressed on endocrine therapy and at least 2 other systemic therapies.

These are recent FDA approvals that we can integrate into our practice right now. There are several more that are likely to come out in the next couple of years. One of them that is going to be on my radar will be capivasertib, which is being evaluated in the [phase 3] CAPItello-291 study [NCT04305496]. In this trial, we saw an advantage with the combination of capivasertib and fulvestrant [vs placebo plus fulvestrant] in patients with HR-positive, HER2-negative breast cancer.

Is there any ongoing or planned research at Winship Cancer Institute that you would like to highlight?

There are a couple of clinical trials that we have ongoing at Emory’s Winship Cancer Institute. One of them that we’re excited about is a clinical trial investigating datopotamab deruxtecan [Dato-DXd], which is a Trop-2–directed ADC, in the first-line setting for patients with metastatic triple-negative breast cancer [TNBC] who are ineligible for immunotherapy. There have been some exciting data from the phase 1 [TROPION-PanTumor01 trial (NCT03401385)] regarding datopotamab deruxtecan, and now we have the phase 3 [TROPION-Breast02 trial (NCT05374512] in the first-line setting for patients with metastatic TNBC.

Another clinical trial that is open is a phase 1 trial [NCT04247126] regarding an oral CDK7 inhibitor [SY-5609] for patients that have both TNBC and HR-positive metastatic breast cancer who are endocrine refractory. That CDK7 inhibitor will be evaluated both as monotherapy and in combination with fulvestrant in an expansion cohort.

We also have a [phase 1/2] study [NCT04505826] evaluating OP-1250, which is a different form of an endocrine agent that is geared toward women with HR-positive breast cancer and central nervous system disease. That is also an important subgroup of patients, where we don’t have enough clinical trials that allow for patients who have active or even stable brain metastases.