Although data from the phase 3 SERENA-6 trial (NCT04964934) demonstrated progression-free survival (PFS) and quality-of-life (QOL) benefits with switching from first-line aromatase inhibitor (AI) plus CDK4/6 inhibitor therapy to camizestrant upon the detection of an ESR1 mutation in patients with hormone receptor–positive, HER2-negative advanced breast cancer, additional time to second progression (PFS2) and overall survival (OS) data are needed to support the adoption of molecularly-guided treatment switching in clinical practice, according to Laura Huppert, MD.
Additionally, Huppert noted that dhese data, along with ongoing work with other novel endocrine therapies, could provide expanded and improved options for patients following progression on a CDK4/6 inhibitor–based regimen.
Findings presented during the 2025 ASCO Annual Meeting showed that the median investigator-assessed PFS with camizestrant plus CDK4/6 inhibition (n = 157) was 16.0 months (95% CI, 12.7-18.2) vs 9.2 months (95% CI, 7.2-9.5) with continued AI plus CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001). The 12- and 24-month PFS rates with the camizestrant regimen were 60.7% and 29.7%, respectively. Respective rates with continued AI plus CDK4/6 inhibition were 33.4% and 5.4%.
“If [the camizestrant combination] ends up being an approved regimen, it would definitely be a paradigm shift for how we’re treating breast cancer, because we would need to start monitoring circulating tumor DNA [ctDNA] and switching earlier,” Huppert, an assistant professor of medicine at the University of California, San Francisco School of Medicine, stated in an interview with OncLive®. “The PFS difference is very interesting and compelling; we just need a bit more data to know how we’ll ultimately utilize this in clinical practice.”
In the interview, Huppert discussed the mechanistic differences between oral selective estrogen receptor degraders (SERDs) and proteolysis-targeting chimeras (PROTACs); the current post–CDK4/6 inhibitor treatment landscape in hormone receptor–positive breast cancer; the clinical implications of the SERENA-6 trial for early intervention with camizestrant based on molecular progression; and how novel endocrine therapies could help improved outcomes for patients in later lines of therapy.
OncLive: What is the distinction between oral SERDs and PROTACs in the hormone receptor–positive breast cancer space?
Huppert: Both of these [drug classes represent] different ways to target estrogen receptor [ER] signaling. The idea is that if disrupting that signaling can prevent tumor cell growth. Oral SERDs work by binding to the ER and inducing its degradation, [thereby inhibiting] ER signaling. PROTACs are a novel class of molecules that work by using the cell’s own natural protein degradation system. They bring an enzyme in close proximity to the ER, which labels it for degradation, and then the cell’s own ubiquitination system and proteasome degrade it.
At ASCO 2025, we saw the first [readout of] phase 3 data with a PROTAC [with vepdegestrant in the VERITAC-2 trial (NCT05654623)], which was interesting. It’s a first-in-class molecule and will potentially be a novel form of ER blocking that’s slightly different than oral SERDs and other agents we’ve had before.
What are some of the available treatment options after a patient progresses on a frontline CDK4/6 inhibitor–based regimen?
After progression on first-line AI plus CDK4/6 inhibitor therapy, we typically check next-generation sequencing [NGS] to see what mutations the tumor cells either have or have developed over time that might be targetable. For example, approximately 40% of patients develop an ESR1 mutation [during first-line therapy]. In these patients, we have a currently approved therapy, elacestrant [Orserdu], that can be utilized. If a patient has a PIK3CA, AKT, or PTEN mutation, capivasertib [Truqap] plus fulvestrant [Faslodex] is a currently approved option.
If patients have none of these mutations, we have other options as well. We can use fulvestrant and a switch in CDK4/6 inhibitor, or everolimus [Afinitor] is still an option with fulvestrant or exemestane [Aromasin]. Of course, there are many novel therapies in this arena. Some are likely to be approved, and others are still in development. The second- and third-line endocrine therapy space is a rapidly evolving area at the moment.
With SERENA-6 demonstrating a benefit in switching treatment following the emergence of an ESR1 mutation prior to radiographic progression, what could this mean for future treatment strategies in terms of earlier intervention?
SERENA-6 was a phase 3 trial that evaluated whether it would be beneficial for patients on their first-line AI and CDK4/6 inhibitor [who develop an] ESR1 mutation but don’t have evidence of clinical progression by imaging to switch to [treatment with] an oral SERD, camizestrant, in that setting.
It enrolled patients who were already receiving their AI and CDK4/6 inhibitor, and they were monitored every 3 months with ctDNA testing. Patients who developed an ESR1 mutation [without clinical progression were then] randomly assigned to either stay on their AI and CDK4/6 inhibitor with a placebo, or switch to camizestrant and CDK4/6 inhibitor with a placebo. They followed these patients over time, with the primary end point being PFS.
What they saw was that patients who switched to camizestrant had improved PFS [by a] difference of [6.8] months between the 2 arms, which was definitely very interesting, compelling, and statistically significant data. [The results] also showed that there was improved time to deterioration of global health status and QOL [with this approach], which I thought was interesting as well.
In this trial, PFS2 and OS [were also evaluated]. PFS2 [data] favored the switch to camizestrant, but these were not yet statistically significant. The data are not yet mature. OS data are also not mature.
[SERENA-6] was an interesting and compelling study for multiple reasons. Historically, we wanted to keep patients on each treatment as long as possible until we see evidence of progression by scans or symptoms. However, this was looking at whether we should switch [treatment] at the time of molecular progression, rather than progression on scans.
What still needs to be learned about the benefit of earlier treatment switching based on molecular progression in order to support adopting this approach in clinical practice?
It will be important to look at PFS2 more as those data mature. Does this early switch help people do better on their next line of therapy? Ideally, we’re hoping for OS data to show whether switching early ultimately helps people live longer. We need more of follow-up data to know how to employ this [strategy] in the future.
There are also ongoing trials looking at using oral SERDs from the start [of first-line treatment], rather than switching [from an AI to an] oral SERDs [with subsequent treatment]. We’ll have to see what those trials look like as well. All these moving pieces will help us figure out how to employ these data and what to do with them going forward.
How could a potential approval of the SERENA-6 regimen affect clinical practice in terms of second-line treatment decision-making?
If SERENA-6 is approved and a certain percentage of our patients develop the ESR1 mutation and switch to camizestrant, in the second-line setting, we would still want to check NGS and look for any new mutations that might be present, and then we can choose therapy accordingly.
In patients who were on the SERENA-6 regimen and did switch to an oral SERD, it will be important to potentially think about other endocrine backbones or other combinations beyond just an oral SERD in the subsequent line. This is all the more reason we are excited to have novel endocrine therapy backbones, as well as novel targeted therapy partners, to offer more and more options in the second- and third-line settings.
Despite the incorporation of novel endocrine therapies into the treatment paradigm, what unmet needs still exist for patients with hormone receptor–positive breast cancer after progression on a CDK4/6 inhibitor–based regimen?
In general, patients experience the longest PFS on first-line therapy, which is typically an AI plus a CDK4/6 inhibitor. The duration of response generally shortens in the second- and third-line settings. There is hope that with the introduction of novel agents, it may be possible to achieve longer PFS in these later lines of therapy by utilizing new mechanisms of action with the endocrine therapy backbone, as well as novel targeted therapy combinations. Prolonging PFS in the second- and third-line settings remains an area of unmet need.
Typically, patients receive 2 to 3 lines of endocrine therapy before becoming resistant and needing to transition to chemotherapy or antibody-drug conjugates. However, with emerging agents, it may be possible to extend the number of endocrine therapy lines. The goal is to prolong the endocrine-sensitive phase of disease by leveraging these novel agents, which are often oral and better tolerated than chemotherapy. Delaying the need for cytotoxic therapies may enhance both QOL and OS. Therefore, there is significant interest in optimizing treatment options in the second- and third-line settings.
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
