Translating Evidence to Clinical Practice: Oral SERDs in HR+/HER2– Metastatic Breast Cancer

Session Overview & Highlights

Therapeutic Significance of ESR1 Mutations and Treatment Decision-Making

There was concordance between the faculty on the timing and method of biomarker testing including for ESR1 mutations. Most centers do not have an established standard operating procedure on testing, but tissue and liquid biopsies are performed at diagnosis, and at least liquid biopsy is done upon disease progression.

Oral SERDs as Monotherapy: EMERALD, EMBER-3, SERENA-2

The faculty agreed that elacestrant is well tolerated and that it offers the added convenience of oral therapy. The response, however, is typically modest; as a single agent, it may be suitable for patients with ESR1 mutation who are experiencing a slow progression or locoregional recurrence after initial endocrine therapy for at least 12 months. Most faculty members were underwhelmed by the EMBER-3 data in which imlunestrant monotherapy demonstrated approximately 1 month of progression-free survival (PFS) benefit compared to the standard-of-care endocrine therapy. For some, the data confirmed that they should use combination therapy rather than monotherapy in this setting. Others mentioned that there still is a role for oral SERD monotherapy for select patient populations.

Based on efficacy data from recent studies, there is no clear preferred option among the different oral SERDs in HR+/HER2– MBC. The different inclusion criteria in these studies add to the complexity of interpreting the data. Key differentiating factors in selecting emerging oral SERDs include provider experience/familiarity, toxicity profile, and the ability to use them in combination with other agents.

Oral SERDs as Combination Therapy: ELEVATE, EMBER-3, SERENA-4, SERENA-6, pionERA, perservERA, evERA

The faculty reported that they do not use serial ESR1 mutation monitoring to guide earlier treatment switches. Instead, they wait for clinical/radiographic progression to test for ESR1 when considering a therapy change. Outcomes of the SERENA-6 trial showed that an early therapy switch to camizestrant in combination with a CDK4/6 inhibitor resulted in a highly significant and clinically meaningful improvement in PFS in the first-line treatment of patients with HR+/HER2– advanced BC whose tumors had an emergent ESR1 mutation. However, most faculty believed that the data are still too premature to change the current sequencing practices.

Management of Treatment-Related Adverse Events

The faculty found the safety data from the EMBER-3 trial involving an imlunestrant-abemaciclib combination encouraging, as mostly low-grade toxicities were noted without any added toxicity from either of the drugs. Diarrhea and nausea were common but manageable. Close monitoring of dyslipidemia will be important. The faculty agreed that the favorable safety profile of the oral SERD combinations motivates continued exploration of their role in the frontline setting for HR+/HER2– MBC before other less tolerable options.

Discussion Themes and Expert Insights

The recent data on the oral SERD–based combinations are encouraging, and the faculty looked forward to having more options for their patients with HR+/HER2– MBC before considering chemotherapy options. Their key takeaways from the trials were that the oral SERD–based combinations are well tolerated, and patients can stay on long-term therapy. The convenience of oral therapy is desirable, but steps for ensuring patient adherence to therapy and appropriate toxicity monitoring should be addressed. Cost may be a barrier, and strategies to mitigate high cost associated with these new therapies should be explored.

Unmet Needs and Recommendations

The key challenge will be determining how to sequence these therapies. The faculty were excited about the oral SERD–based combinations. However, use of a second drug other than a CDK4/6 inhibitor may be helpful, as most patients will receive CDK4/6 inhibitors in the first line in the current treatment landscape. Despite the excitement over having more options, it will be challenging to synthesize all the available data into an optimal treatment algorithm for patients. There is still a lot to learn about optimizing treatment in this patient population.

Conclusion

The discussion highlights the rapidly evolving treatment landscape for HR+/HER2– MBC and the importance of finding therapies with a durable response and favorable toxicity profile. Oral SERD-based combinations provide an exciting new option for patients with HR+/HER2– MBC. The main challenge will be integrating these agents into the current treatment paradigm and individualizing these therapies with thoughtful patient selection to optimize their outcomes and minimize toxicity.

This article was supported in part by Eli Lilly. Content independently developed and published by OncLive.

References

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