As breast cancer experts weigh the FDA's concerns about the design of the phase 3 SERENA-6 trial (NCT04964934) investigating a circulating tumor DNA (ctDNA)–based trigger to switch treatment to camizestrant plus a CDK4/6 inhibitor in patients with hormone receptor–positive, HER2-negative metastatic breast cancer and an emergent ESR1 mutation, the debate underscores a broader question regarding the future role of radiographic progression vs liquid biopsy when considering the timing of therapeutic shifts in individual patients.
“The field has come an enormous way, and we have a whole lot of work ahead of us, but we've made enormous progress, and we can't forget that,” Adam Brufsky, MD, PhD, said in an interview with OncLive®.
Brufsky is a professor of medicine and associate division chief for the Division of Hematology/Oncology in the Department of Medicine at the University of Pittsburgh School of Medicine, as well as the medical director of the Magee-Women's Cancer Program, associate director for clinical investigations, and codirector of the Comprehensive Breast Cancer Center at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania.
What background information on SERENA-6 is important to note?
SERENA-6 evaluated the switch to the oral selective estrogen receptor degrader (SERD) camizestrant plus a continued CDK4/6 inhibitor upon the emergence of an ESR1 mutation detected in ctDNA ahead of radiographic disease progression during treatment with a CDK4/6 inhibitor plus an aromatase inhibitor (AI) vs the continuation of CDK4/6 inhibitor plus an AI \ in patients with hormone receptor–positive, HER2-negative metastatic breast cancer. Findings presented at the 2025 ASCO Annual Meeting demonstrated a progression-free survival (PFS) improvement with the switch (n = 157), meeting the trial’s primary end point, with a median of 16.0 months (95% CI, 12.7-18.2) per investigator assessment vs 9.2 months (95% CI, 7.2-9.5) in the control arm (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001).1 Updated data presented at the 2025 San Antonio Breast Cancer Symposium showed respective median PFS values of 16.6 months (95% CI, 14.7-19.4) vs 9.2 months (95% CI, 7.2-9.7; HR, 0.46; 95% CI, 0.34-0.62; P < .00001).2 Notably, the overall survival (OS) data were not mature at the time of these analyses.1,2
What questions did the FDA’s ODAC meeting raise about the SERENA-6 trial design?
On April 30, 2026, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 6-3 against the clinically meaningful benefit of this camizestrant switch approach ahead of radiographic disease progression.3 No voters cited a request to see OS data, as well as a lack of confidence in the trial’s design, as it did not show the benefit of early vs late treatment with camizestrant in this patient population.
“The trial design brings up a lot of important questions,” Sara M. Tolaney, MD, MPH, stated in another interview with OncLive®. “SERENA-6 has an innovative design, and maybe the way we need to move forward is looking at molecular progression and then switching therapy at that time, rather than waiting for radiographic progression. When you change the way we've practiced for decades, it raises a lot of open questions.”
Tolaney is chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women’s Cancers and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.
“The problem with the criticisms of SERENA-6 is that they're criticizing a trial that wasn't done,” Brufsky added. “This was never an early [treatment]-vs-late [treatment] trial.”
Tolaney further extrapolated on this point, noting that although the questions asked in the ODAC meeting were posed in an effort to determine the long-term efficacy of the SERENA-6 approach, there are nuances to using end points such as OS in a global registrational trial.
“There are differences in levels of drug access with subsequent lines of therapy that will significantly influence OS, where we already have seen imbalances in use of subsequent antibody-drug conjugates [ADCs], for example,” Tolaney explained. “I don't want the takeaway from ODAC [to be] that we need to wait for OS to make these decisions about changing [treatment] with molecular progression. I don't think that's a feasible end point, and [it’s] not really a reflection of what's being evaluated.”
What updated SERENA-6 data were presented at ASCO 2026?
Following the ODAC vote, updated data from SERENA-6 presented at the 2026 ASCO Annual Meeting showed that the time to second progression (PFS2) was extended in the camizestrant arm at a median of 25.7 months (95% CI, 20.4-30.3) vs 19.1 months (95% CI, 16.8-21.0) in the control arm (HR, 0.63; 95% CI, 0.46-0.86; P = .00373).4 Additionally, the ctDNA analysis showed a higher total ctDNA clearance rate in the camizestrant arm (n = 98) at 51.0% compared with 1.9% in the control arm (n = 108).
“I don't know how [these data] will translate in terms of long-term outcomes, but [they are] certainly provocative,” Tolaney explained.
Brufsky added that patient symptom experiences that point toward potential disease progression ahead of radiographic confirmation bolster the argument in favor of using the SERENA-6 strategy in clinical practice.
SERENA-6 Trial Raises Questions Regarding the Future of Metastatic Breast Cancer Management
- SERENA-6 showed that switching to camizestrant plus a CDK4/6 inhibitor upon ctDNA ESR1 mutation emergence ahead of radiographic progression nearly doubled the median PFS vs continuing an AI plus a CDK4/6 inhibitor, meeting the trial's primary end point.
- The FDA's ODAC voted 6-3 against SERENA-6’s clinically meaningful benefit, citing immature OS data and trial design concerns, although experts counter that OS is confounded by uneven global drug access and was never the question SERENA-6 set out to answer.
- Proponents argue that SERENA-6 signals a broader shift toward biomarker-driven treatment decisions, recognizing that radiographic progression, which is particularly hard to capture in bone-predominant disease, should no longer be the sole trigger for changing therapy.
“These were patients who already weren't feeling great, and [the SERENA-6 approach reflects what] we do in practice,” he said. “You're going to do some sort of ctDNA test on them to see what their ESR1 [mutation status] is. We do that anyway, and if [their status changes], we change [their treatment to] fulvestrant. I do that in my practice right now regardless of what the scan shows, because in breast cancer, scans often go slow. This trial would give me permission to use [this strategy] in patients who feel worse. [Although] their scans maybe don't look different, but [if] they now have an ESR1 [mutation in ctDNA], it would give me permission to give them an oral SERD that doubles the median PFS. Can you wait and just give the oral SERD at progression? Sure, but why not give it earlier?”
How might the SERENA-6 design and findings influence future breast cancer research and management strategies?
Brufsky emphasized that the SERENA-6 design represents a potential sea change in the use of biomarker testing for breast cancer management, explaining that radiographic progression is no longer considered the only valid marker of practice-informing disease evolutions.
“[SERENA-6] is the first of many trials like this,” he predicted. “We're realizing in 2026 that radiology isn't everything, especially in metastatic breast cancer or hormone receptor–positive breast cancer, where [metastases are] predominantly [in the bone], and bone metastases are difficult to image progression on a scan. I just thought the ODAC discussion didn't talk about any of this. What's important to the patients is that they feel better for a longer period of time, and that's the most important thing. Patients would like [the SERENA-6 strategy], and doctors would want to give it.”
Brufsky noted that the SERENA-6 strategy would fill an unmet need left by the negative results of the phase 3 persevERA Breast Cancer trial(NCT04546009), which showed that the addition of the oral SERD giredestrant to the CDK4/6 inhibitor palbociclib (Ibrance) did not significantly improve investigator-assessed PFS outcomes compared with letrozole plus palbociclib in patients with estrogen receptor–positive, HER2-negative locally advanced or metastatic breast cancer (HR, 0.89; 95% CI, 0.76-1.05; P = .1553).4
“[The persevERA Breast Cancer regimen is likely] not going to be a standard of care, so we need a subset of patients to whom we can give an oral SERD earlier before frank clinical progression,” he stated. “I feel strongly about this. My colleagues on the other side of the argument feel equally as strongly, and that's fine. It's okay for people to disagree about this, but as someone who treats a lot of [patients with] breast cancer and encounters this all the time in metastatic disease, where [a patient is receiving] a CDK4/6 inhibitor for some amount of time and you start to think they’re progressing, you're deciding with the patient what's going on. [The SERENA-6 strategy would] allow us to have an additional tool that affects the patient's quality of life and probably affects other parameters, as well.”
He bolstered his stance with findings from the phase 3 SONIA trial (NCT03425838), which showed no statistically significant benefit with the use of CDK4/6 inhibitors in the first-line setting vs the second-line setting in patients with hormone receptor–positive, HER2-negative advanced breast cancer (HR, 0.87; 95% CI, 0.74-1.03; P = .10).5
“The other thing people forget about these switch/wait trials is the degree of patients who don't make it to the second-line setting,” he remarked. “In the US, we have a lot of [options], and we'll keep giving [treatments to patients], but outside of the US, sometimes patients just stop [therapy] and don't [receive] anything else, so it may make sense to use the best [treatment] as soon as you can.”
Going forward, Brufsky highlighted that SERENA-6 is just one of many innovative breast cancer trials in the metastatic setting and expressed his optimism that collective research in this area may soon yield actionable insights regarding biomarkers, treatment sequencing, and the incorporation of novel therapies into the treatment paradigm.
“There are a lot of interesting drugs coming out in this post–CDK4/6 inhibitor setting,” he concluded. “CDK4/6 inhibitors have worked well and are a clear step forward for us in metastatic breast cancer, even in the adjuvant setting. The real question now becomes: Just like with ADCs, which are great, what do you do after? We have so many [treatments that] are going to be available for us in the metastatic breast cancer setting. How to use them, when to use them, and what biomarkers to use [are] going to be [areas that will] take us a while to figure out, but it's better to have more choices than less.”
References
- 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
- Bidard FC, Mayer EL, Park YH, et al. Updated results and an exploratory analysis of ESR1m circulating tumor DNA dynamics from SERENA-6, a phase 3 trial of camizestrant + CDK4/6 inhibitor for emergent ESR1m during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF7-03.
- April 30, 2026 meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed April 30, 2026. https://www.youtube.com/live/taCx7enN7hk
- Turner N, et al. Giredestrant (GIRE) + palbociclib (PALBO) vs letrozole (LET) + PALBO as first-line (1L) therapy in patients (pts) with estrogen receptor–positive, HER2-negative locally advanced or metastatic breast cancer (ER+, HER2– LA/mBC): primary analysis of the phase III persevERA BC trial. J Clin Oncol. 2026;44(suppl 17):LBA1006. doi:10.1200/JCO.2026.44.17_suppl.LBA1006
- Sonke GS, van Ommen-Nijhof A, Wortelboer N, et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024;636(8042):474-480. doi:10.1038/s41586-024-08035-2
