Oral SERDs and ESR1 Mutation Monitoring Reshape Treatment of HR-Positive Metastatic Breast Cancer

Clinical Summary: 

• Sara Nunnery, MD, examines the evolving role of oral SERDs in HR-positive metastatic breast cancer, including ESR1 mutation testing, ctDNA monitoring, and treatment selection following endocrine resistance. 
• Recent oral SERD approvals have expanded treatment options for ESR1-mutated diease, while findings from SERENA-6 support switching to camizestrant before radiographic progression in patients with emerging ESR1 mutations receiving first-line aromatase inhibitors and CDK4/6 inhibitors. 
• These advances highlight the importance of molecular monitoring, endocrine therapy selection, and shared decision-making when determining the timing of treatment modification and sequencing of oral SERD monotherapy or combination regimens. 

Sara Nunnery, MD, Tennessee Oncology, Chattanooga, Tennessee, discusses the evolving treatment landscape of HR-positive, HER2-negative metastatic breast cancer, including recent oral SERD approvals, ESR1 mutation testing, and ctDNA-guided treatment strategies. 

Dr Nunnery reviews findings from the SERENA-6 trial supporting an early switch to camizestrant following detection of an ESR1 mutation before radiographic progression, as well as emerging treatment options involving elacestrant, imlunestrant, and vepdegestrant. She also discusses the integration of imluenstrant plus abemaciclib, the clinical considerations surrounding serial ctDNA monitoring, and how disease burden, prior CDK4/6 inhibitor exposure, and patient preferences can guide individualized endocrine treatment sequencing. 

Transcript: 

Hi, I'm Sara Nunnery. I am a breast medical oncologist and the director of breast cancer research at Tennessee Oncology. I gave a talk here at Great Debates on how oral SERDs are changing the treatment landscape for metastatic HR-positive breast cancer, especially with ESR1 mutations.

We talked abut the way that we are testing for ESR1 mutations is something that's actually changing this month. What we know right now that it is so critical to test for ESR1 mutations at disease progression. We know that ESR1 mutations are mutations that can develop over time as a result of exposure to standard endocrine therapies in the first-line setting. It is an emergent mutation, it is not a truncal mutation or a mutation that is present at baseline upon the development of metastatic disease, so it's critical to repeat testing with a liquid biopsy at disease progression to see if an ESR1 mutation has developed.

If you go back and do testing on archival tissue from when someone was diagnosed with metastatic disease or diagnosed with breast cancer, you won't find the ESR1 mutation on old disease, you really have to be sure to do liquid biopsy to detect it in the blood since it is an emergent mutation. 

We now have several oral SERD options that are FDA approved in the second-line setting for patients who do have an ESR1 mutation and who develop disease progression. We currently have FDA approval for elacestrant monotherapy, imlunestrant monotherapy, and we just in the last couple of weeks got FDA approval for imlunestrant combination therapy with abemaciclib. 

We also have FDA approval for vepdegasrant, which is not an oral SERD, but is a proteolysis targeting chimera (PROTAC), but we see very similar efficacy with vepdegasrant as what we've seen with our oral SERDs. Then also what's really changing the field right now is just in the last month, we saw FDA approval for camizestrant, our newest oral SERD, in combination with a CDK4/6 inhibitor. 

What is unique about this camizestrant approval is that that approval came as a result of data from the SERENA-6 clinical trial. In the SERENA-6 trial, patients who had been on their first-line therapy with an AI or CDK4/6 inhibitor for at least 6 months entered a screening period where they were tested with a liquid biopsy for an ESR1 mutation every 2 to 3 months. 

If an ESR1 mutation was detected, patients were then randomized to either stay on their current AI CDK4/6 inhibitor or switch to camizestrant and their CDK4/6 inhibitor. What we saw was a significant improvement in progression-free survival (PFS) by almost 9 months for those patients who made the switch to camizestrant. 

We also just saw some updated data at ASCO this year, which showed a significant improvement in PFS2 as well, which really just helps us determine that these patients are continuing to have sustained benefit beyond that first-line when they made the switch to camizestrant. 

We also saw some really interesting data that showed that over half of patients had a 100% clearance of circulating tumor DNA when they made the switch to camizestrant. Based on all that data from SERENA-6, the FDA approved camizestrant as an oral SERD that patients could switch to upon the detection of an ESR1 mutation before radiographic disease progression.

I think right now, the big question in the field is how do we implement all of this data. I think for sure we know it is critical to test for an ESR1 mutation upon radiographic disease progression for all of our patients, if they're still an appropriate candidate for endocrine therapy. 

The question really is, do we now need to start testing serially every 3 months or so for patients who are doing well on their first-line therapy? This is something that is going to be unique for each patient and it's going to be some shared decision-making and a discussion with the patient about how proactive do they want to be.

It's a really great strategy for patients who are not doing well on their first-line therapy, maybe they're having symptoms. 

We saw a lot of incredible patient-reported outcomes data from SERENA-6 that showed that patients who switched to camizestrant had significant improvements in quality-of-life in all types of different measures. It really might be a testament to that clearance of ctDNA and potentially treating some microscopic circulating disease that helps patients feel better. We all see those patients in the clinic who we see that they're not doing so well, but their scans are stable and we just kind of know that they might be progressing soon. The SERENA-6 strategy is a really great option for those patients, but it might not be a great fit for everyone, so here's really going to be a lot of shared decision-making here.

For patients who don't take the SERENA-6 approach, patients who maybe right now they've been on their first-line therapy for a long time and we're not going to rock the boat and change the testing, we're going to just continue to monitor for radiographic disease progression. We now have really great oral SERD options to choose from in the second line setting. 

The big question is, should we do a SERD monotherapy or what about a SERD combination therapy? We now have FDA approval for imlunestrant combined with abemaciclib. That combination we've had in the NCCN guidelines as a great option to consider for patients who had not been treated with a CDK4/6 inhibitor in the first-line setting, it makes perfect sense for those patients. Maybe patients who didn't get abemaciclib in the first-line, maybe who got palbociclib, which was the majority of patients in that EMBER-3 trial, or maybe who got ribociclib in the first-line setting, would not be unreasonable to consider that combination in the second-line, especially if a patient wants to be really aggressive.

But I think a SERD monotherapy is still a really great option for patients who have a slower pace of disease, lower disease burden, bone only disease. We have a lot of options now to tailor to our patients based on their disease course and their goals. 

Still have a lot of questions about what is going to be the best way to sequence these options that we're going to be teasing out with future trials hopefully and more real-world data. But as of right now, we have a lot of oral SERD options, we'll have more oral SERD combination therapies coming, so it's an area that is ever evolving right now for metastatic HR-positive disease.