QOL Data Could Help Support Switch to Camizestrant in HR+ Breast Cancer After Emergence of ESR1 Mutation

Hope S. Rugo, MD

Discussion-generating data from the phase 3 SERENA-6 trial (NCT04964934) showed that the addition of camizestrant to CDK4/6 inhibition significantly improved progression-free survival (PFS) and delayed time to deterioration (TTD), suggesting a potential quality of life (QOL) benefit from the early detection of endocrine resistance and supporting the use of molecular monitoring via circulating tumor DNA (ctDNA) to inform therapy adjustments in patients with hormone receptor–positive breast cancer receiving standard endocrine therapy, according to Hope S. Rugo, MD.

In a presentation of data at the 2025 ASCO Annual Meeting, camizestrant plus continued CDK4/6 inhibition generated a median investigator-assessed progression-free survival (PFS) of 16.0 months (95% CI, 12.7-18.2) among patients with a detected ESR1 mutation prior to radiographic progression on frontline therapy (n = 157) vs 9.2 months (95% CI, 7.2-9.5) with the continuation of an aromatase inhibitor (AI) and CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001).

Moreover, QOL analyses from SERENA-6 showed that the median TTD was 23.0 months (95% CI, 13.8-not calculable) with the camizestrant combination vs 6.4 months (95% CI, 2.8-14.0) in the AI plus CDK4/6 inhibitor arm (HR, 0.53; 95% CI, 0.33-0.82; nominal P < .001).

“[Notably, at ASCO 2025], investigators didn't report on the [QOL] domains; that we hope to see at the ESMO Congress later [in 2025],” Rugo stated in an interview with OncLive®. “[Those data] will be important for understanding the clinical applicability of these findings, [keeping in mind that] camizestrant isn't an approved drug yet. We're waiting to hear what the regulatory [agencies] say, but I assume that this approach will be approved in less than a year.”

In the interview, Rugo discussed the significance of SERENA-6 using molecular markers to guide therapy adjustments in breast cancer; the potential regulatory implications of camizestrant plus CDK4/6 inhibition in endocrine-sensitive disease with emergent ESR1 mutations; and the need for additional data on subsequent therapy sequencing and QOL outcomes to inform the optimal placement of this therapeutic strategy in clinical practice.

Rugo is a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women's Cancers Program at City of Hope in Duarte, California.

OncLive: Why have results from SERENA-6 generated so much discussion regarding the use of molecular markers to guide therapeutic decision-making?

Rugo: The most anticipated and hotly contested results after the presentation at [the 2025] ASCO Annual Meeting in breast cancer were indeed those from the SERENA-6 trial. This is the first trial using a molecular marker to change therapy. [Prior attempts] to use tumor markers or circulating tumor cells (CTCs) failed to improve survival in those patients; [however], it is important to keep in mind that those trials [used] survival end points during [an era with] limited options for sequential therapy. That’s not true at the present time, and there is an enormous disparity in the sequencing of therapy around the world. This affects the results of clinical trial populations where they don't have access to better therapies on the control arm and their cancer progresses.

What are the implications of efficacy and QOL data from the SERENA-6 trial regarding the use and potential regulatory approval of camizestrant plus CDK 4/6 inhibition for patients with HER2-positive breast cancer who develop ESR1 mutations?

SERENA-6 is a very important trial. This trial utilized circulating tumor DNA [ctDNA] to detect emergent ESR1 mutations; this is similar to trials that looked at rising tumor markers, except ctDNA is a much more sensitive indicator. SERENA-6 used a resistance marker—the emergence of ESR1 mutations—to [inform therapeutic decisions].

Notably, [investigators] screened a lot of patients, [and they followed 3266] patients. [They then identified] 548 patients with emergent ESR1 mutations; the median time from the start of AI plus CDK4/6 inhibitor therapy to the detection of an ESR1 mutation was 22 months. Importantly, patients could be screened after 6 months [of therapy]. Even though nearly half of the patients at their first blood draw had ESR1 mutations, many had already been on endocrine therapy plus a CDK4/6 inhibitor for a long time. Some patients developed ESR1 mutations 10 months into treatment, and others had a median time of 23 months, [indicating] a highly endocrine-sensitive population.

What do these findings mean for clinical practice?

When endocrine therapy changed, it was unsurprising that PFS was longer. [The question is whether] these results are enough to change clinical practice. A key data point showed in the presentation [at ASCO] was the delayed TTD [as measured by the European Organization for Research and Treatment of Cancer 30-item QOL questionnaire]. This showed us that changing therapy may [be associated with less] pain emergence. We were all struggling to understand why QOL fell off so rapidly in the control population when it took them 9 months to display evidence of progressive disease. [This could be because] we don't pick up metastatic breast cancer very well on scans in this endocrine-sensitive patient population, so patients were experiencing more pain from arthralgias and early progressive disease that we couldn’t see on scans. When patients switched to camizestrant, that pain improved.

What future subsequent analyses are needed to fully clarify the sequencing of camizestrant in the hormone receptor–positive breast cancer treatment paradigm?

[Understanding] subsequent therapy is essential. In her discussion [of the trial], Angela DeMichele, MD, MSCE, of Penn Medicine, talked about the fact that when [a patient starts] their next therapy, [assessment of time to second progression (PFS2)] begins from the start of randomization to the next progression after change of therapy. For the patients on camizestrant, that [subsequent therapy after the trial is] their third line of treatment. For the patients still on an AI and CDK4/6 inhibitor, that's their second line of treatment. Understanding what PFS2 is [based on] the kinds of treatments patients [on this trial] received and the duration [of treatment] is going to be quite complex.

Whether overall survival is going to be an effective way to evaluate efficacy also remains to be seen. We hope that these patients live a long time. This was a patient group with very endocrine-sensitive disease, where they can receive sequential antibody-drug conjugates and other targeted agents if they have PIK3CA mutations that are acquired or already existent. How does this work in patients who have different mutations?

All of these [questions will be answered by] future results. However, if the QOL data hold up, changing therapy and having an improved time to deterioration of QOL by finding this molecular marker of resistance is going to be very important for patients. Access to [subsequent] therapies [will be] an important evaluation as we move forward.

How could additional clinical trial data provide additional support for the adoption of a dual endocrine therapy and CDK4/6 inhibitor switching strategy, and how might this new approach affect clinical outcomes?

What we would like to [consider] are the [phase 3] EMBER-3 [NCT04975308] results, where patients received imlunestrant and abemaciclib [Verzenio] in the most successful arm of that 3-arm trial. [This combination] was superior to imlunestrant alone, regardless of whether patients had an ESR1 mutation. [Investigators] included patients who had received a CDK4/6 inhibitor and those who had not. That is complex, because we are looking at a subset of patients who did receive a prior CDK4/6 inhibitor. We would expect that if a patient had never received abemaciclib, [it would be more effective] in combination with anything in the second-line setting. However, even in those who had received a prior CDK4/6 inhibitor, data from [the 2025] ESMO Breast Cancer Congress [showed that] it was still better to have abemaciclib [alongside endocrine therapy]. That is consistent with the [phase 3] postMONARCH [NCT05169567] data as well.

If we took this approach to evaluating the molecular development of resistance and switched not only the endocrine therapy to a more effective drug but also switched the CDK4/6 inhibitor to abemaciclib—keeping in mind that three-quarters of the patients in SERENA-6 had received palbociclib [Ibrance] and 15% had received ribociclib [Kisqali]—would that even further improve outcomes? I suspect that it would, and I hope that we will be able to start studying that in the next few months.

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Reference

Turner N, Mayer E, Park YH, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4