Dr Huppert on the Implications of SERENA-6 for Second-Line Treatment Strategies in HR+ Breast Cancer

"If [the] SERENA-6 [regimen] is approved and a certain percentage of our patients develop the 

 mutation and switch to camizestrant, [then] in the second-line setting, we would still want to check NGS and look for any new mutations that might be present, and then choose therapy accordingly."

Laura A. Huppert, MD, a breast medical oncologist and assistant professor at the University of California, San Francisco School of Medicine, discussed the potential implications of data from the phase 3 SERENA-6 trial (NCT04964934) for shaping second-line treatment strategies in hormone receptor (HR)–positive, HER2-negative advanced breast cancer.

, results from SERENA-6 demonstrated a significant progression-free survival (PFS) benefit with camizestrant, a next-generation oral selective estrogen receptor degrader (SERD), when used in combination with continued CDK4/6 inhibition following detection of an 

 mutation during first-line therapy prior to clinical progression. Specifically, switching to camizestrant plus CDK4/6 inhibition led to a median PFS of 16.0 months compared with 9.2 months with continued aromatase inhibitor (AI) plus CDK4/6 inhibition (HR, 0.44; 95% CI, 0.31-0.60; 

 < .00001), along with improvements in quality of life.

If the SERENA-6 regimen is incorporated into standard practice, it will introduce a paradigm shift in first-line management by enabling earlier intervention based on molecular progression rather than radiographic or symptomatic progression, Huppert asserted. However, this advancement also necessitates reconsideration of second-line therapeutic sequencing after frontline CDK4/6 inhibition. According to Huppert, patients who transition to camizestrant during first-line treatment will still require next-generation sequencing (NGS) at the time of disease progression to identify newly emergent mutations that may guide subsequent therapy selection.

In this evolving landscape, clinicians will need to look beyond oral SERDs alone in the second-line setting and consider alternative endocrine therapy backbones or novel targeted combinations, she stated. Huppert noted that this development reinforces the enthusiasm around emerging agents that may be better tolerated, more effective, or offer synergistic activity with other classes of therapeutics.

Ultimately, the integration of molecular monitoring and selective treatment switching in the first-line setting would result in a paradigm shift for patients with breast cancer across multiple lines of therapy, she concluded.

Videos

Laura A. Huppert, MD, discusses how the approval of the SERENA-6 regimen could affect second-line treatment decision-making in HR-positive breast cancer.

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 

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.

 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; 

 < .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 

. “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.

: What is the distinction between oral SERDs and PROTACs in the hormone receptor–positive breast cancer space?

 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 

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 

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 

 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] 

 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

 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 

 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.

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. 

. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4

Articles

Laura Huppert, MD, outlines additional information needed to implement the SERENA-6 approach in hormone receptor–positive breast cancer.

Ongoing Research Aims to Alter Management of HR+ Breast Cancer After Frontline CDK4/6 Inhibition

Molecular testing is becoming increasingly important for refining targeted treatment approaches for patients with hormone receptor–positive, HER2-negative metastatic breast cancer, a setting in which several agents have been recently approved and additional promising investigational regimens are poised to rapidly enhance the treatment paradigm, according to Kevin Kalinsky, MD, MS, FASCO. 

“For as long as possible, we want patients to [receive] therapy that is well tolerated [and for which] they don’t have to spend time in infusion centers,” Kalinsky said in an interview with 

In the interview, Kalinsky discussed the importance of optimizing well-tolerated endocrine-based therapies and delaying chemotherapy initiation in patients with hormone receptor–positive, HER2-negative metastatic breast cancer; the critical role of molecular testing in guiding post-CDK4/6 inhibitor treatment decisions; and ongoing challenges regarding treatment sequencing, drug availability, and patient adherence to endocrine therapies.

He highlighted the implications of findings from the final overall survival (OS) analysis of the phase 3 INAVO120 trial (NCT04191499), which were presented at the 

. This study showed that first-line inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex; n = 161) significantly improved OS vs placebo plus palbociclib and fulvestrant (n = 164) in patients with 

-mutated, hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer (HR, 0.67; 95% CI, 0.48-0.94; 

He also cited data that support the emerging treatment strategy of using a CDK4/6 inhibitor following prior progression on another agent in the same class. For instance, the phase 3 postMONARCH trial (NCT05169567) demonstrated that among patients with hormone receptor–positive, HER2-negative advanced breast cancer who had disease progression or recurrence following treatment with a prior CDK4/6 inhibitor (palbociclib, 58.8%; ribociclib [Kisqali], 33.5%; or abemaciclib [Verzenio], 7.7%) plus an aromatase inhibitor (AI), treatment with the CDK4/6 inhibitor abemaciclib in combination with fulvestrant (n = 182) significantly improved progression-free survival (PFS) vs placebo plus fulvestrant (n = 186; HR, 0.73; 95% CI, 0.57-0.95; 

Kalinsky is a professor in and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine; as well as the Louisa and Rand Glenn Family Chair in Breast Cancer Research and the director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

: Although CDK4/6 inhibitor–based regimens have demonstrated efficacy in the frontline setting for hormone receptor–positive breast cancer, what are some of the challenges and limitations of these combinations?

: Some of the challenges we face post-CDK4/6 inhibition are the development of resistance and trying to [offer] options that are endocrine based for patients. We have determined that the median time to the start of chemotherapy is important for our patients, because for estrogen receptor [ER]–positive disease, [treatment] is a marathon. It’s not a sprint. That’s the unmet need where the field is trying to continue to go for ER-positive, HER2-negative metastatic breast cancer.

What is the importance of testing for molecular alterations—including those in 

—at progression, or potentially before progression in the case of 

 mutations [in] patients who’ve had tumors that have progressed on an AI, it is important to check for 

 mutations. We also see that approximately one-third of patients have alterations in the PI3K/AKT pathway. Those include 

. We have approvals of agents like capivasertib [Truqap] and alpelisib [(Piqray) for these patients], though we generally use capivasertib [more often] given its safety profile.

Additionally, we saw data at ASCO 2025 for patients with endocrine-resistant disease that has become newly metastatic. We’ve already seen the approval of inavolisib plus fulvestrant and palbociclib given the PFS advantage in patients who have endocrine-resistant disease, meaning [disease that has] progressed on an AI or within 12 months of completing [therapy with an AI] in the adjuvant setting. However, at ASCO, we saw an OS advantage [with the inavolisib-based combination], which is the first we’ve seen with an agent that targets that pathway. It is important to [see whether] patients have PI3K mutations [following AI progression].

Additionally, there are other targetable alterations, like germline 

 [mutations]. [There is also a] question about [the efficacy of] PARP inhibition in patients with somatic 

 [mutations]. It’s important to think about those considerations as well.

What are the key factors you consider for second-line therapy in patients with hormone receptor–positive breast cancer?

The factors that are important post-progression on an AI and a CDK4/6 inhibitor [include]: How long [was the patient receiving] their prior CDK4/6 inhibitor? Were they receiving it for more than 1 year?

[If a] patient has low-volume, bone-only disease, one may consider elacestrant [Orserdu]. If you have patients who have a PI3K mutation, you can consider fulvestrant plus capivasertib. Sometimes I consider giving doublet therapy in patients who need a bit more of a response. We also have fulvestrant plus everolimus [Afinitor]. Everolimus benefits patients regardless of PI3K mutation status or any alterations in that pathway; just make sure [patients use] the prophylactic oral rinse.

We also have data with [the use of] a CDK4/6 inhibitor [following a different] CDK4/6 inhibitor like abemaciclib plus fulvestrant based on the postMONARCH data [and] the phase 2 MAINTAIN study [NCT02632045] of fulvestrant plus ribociclib [in patients with hormone receptor–positive, HER2-negative advanced breast cancer]. We’ll see if we [gain] approval of other agents that we’ve seen [have] notable data, like imlunestrant plus abemaciclib from the phase 3 EMBER-3 trial [NCT04975308].

Although novel endocrine therapies have entered clinical practice for patients with hormone receptor–positive disease, what challenges still exist regarding the future of this treatment field?

Recently, we’ve seen impressive data with new drugs. Some of these drugs [are not] available at this moment. Regarding the phase 3 SERENA-6 trial [NCT04964934] regimen, for instance, we don’t have camizestrant available in the clinic. Regarding EMBER-3, we don’t have imlunestrant available in the clinic. Vepdegestrant is not available yet. We’re hoping to see whether they get approved. Important questions remain, like: What’s the best sequencing [approach]?

Also, some patients don’t tolerate some of the endocrine therapies we give. We see this in the early-stage setting too. Patients may have arthralgias, and they don’t tolerate these agents. We’ve been emphasizing that patients are not likely to benefit [from therapy] if they’re not taking the drugs. Those are some of the important considerations [based on] where we are post-ASCO 2025.

Turner NC, Im SA, Saura C, et al. INAVO120: phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with 

-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). 

. 2025;43(suppl 16):1003. doi:10.1200/JCO.2025.43.16_suppl.1003

Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the phase III postMONARCH trial. 

. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086

Kevin Kalinsky, MD, MS, FASCO, discusses the importance of optimizing endocrine-based therapies in hormone receptor–positive metastatic breast cancer.

Targeted Therapies Broaden Treatment Options for CDK4/6 Inhibitor–Resistant, HR+ Breast Cancer

Kalinsky

 mutations [in] patients [whose] tumors…have progressed [on] an aromatase inhibitor, it is important to check for 

Kevin Kalinsky, MD, MS, FASCO, director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University and professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, emphasized the importance of biomarker testing in guiding therapeutic decision-making for patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer.

At the time of disease progression—particularly after treatment with aromatase inhibitors—

 mutations commonly emerge and serve as a key mechanism of acquired resistance, Kalinsky explained. Kalinsky further underscored the value of identifying 

 mutations early, given the availability of targeted therapies such as elacestrant (Orserdu) for patients with 

-mutant tumors. He noted that testing for

 mutations can be clinically informative not only at progression but potentially earlier in the disease course.

Kalinsky also highlighted the relevance of alterations in the PI3K/AKT/PTEN pathway, which he noted are detected in approximately one-third of patients with HR-positive, HER2-negative breast cancer. These include mutations in 

. The therapeutic implications of identifying such alterations include the use of pathway-targeted agents such as alpelisib (Piqray) and capivasertib (Truqap), with capivasertib often favored due to its safety and tolerability profile, he explained.

Kalinsky highlighted data presented at the 2025 ASCO Annual Meeting, including findings from the phase 3 INAVO120 trial (NCT04191499), which showed the first overall survival benefit with inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex) vs placebo plus palbociclib and fulvestrant in patients with 

-mutant, HR-positive, HER2-negative, endocrine-resistant advanced breast cancer. These results underscore the clinical value of molecular profiling to detect actionable alterations and support the use of PI3K/AKT pathway inhibitors in appropriately selected patients, he explained.

 and PI3K pathway mutations, Kalinsky also emphasized the importance of germline and somatic testing for 

 mutations, which may inform the use of PARP inhibitors. Although PARP inhibitors are approved for patients with germline 

 mutations, there is growing interest in their role in patients with somatic mutations as well, Kalinsky concluded.

Kevin Kalinsky, MD, discusses the importance of biomarker testing in guiding therapeutic decision-making in HR-positive, HER2-negative breast cancer.

Navigating Novel Endocrine Therapies in ER+ Breast Cancer | Supplements and Featured Publications

Dr Huppert on the Implications of SERENA-6 for Second-Line Treatment Strategies in HR+ Breast Cancer

Ongoing Research Aims to Alter Management of HR+ Breast Cancer After Frontline CDK4/6 Inhibition

Targeted Therapies Broaden Treatment Options for CDK4/6 Inhibitor–Resistant, HR+ Breast Cancer

Dr Kalinsky on the Importance of Biomarker Testing in HR+/HER2-Negative Advanced Breast Cancer