Updated SERENA-6 Data Sharpen the Debate on Early ctDNA-Guided Switching in Advanced Breast Cancer

The phase 3 SERENA-6 trial’s (NCT04964934) circulating tumor DNA (ctDNA)–guided strategy of switching to camizestrant upon detection of an emergent ESR1 mutation in hormone receptor–positive, HER2-negative advanced breast cancer was novel and forward-thinking when it was first designed, but the rapid arrival of multiple ESR1-targeted second-line treatment options has complicated the interpretation of the SERENA-6 results and fueled debate over whether intervening early truly improves survival, according to Komal Jhaveri, MD, FACP.

In an interview with OncLive® in light of World Breast Cancer Research Day, which is observed annually on August 18, Jhaveri shared her thoughts on the design of the SERENA-6 trial, larger questions for the breast cancer field that remain after seeing its results, and what research themes she wants to follow to expand on prior advances.

Additionally, she provided insights on the use of CDK4/6 inhibitors in hormone receptor–positive breast cancer, the risk/benefit profile of treatment for patients with PIK3CA-mutated disease, and the evolution of oral selective estrogen receptor degraders (SERDs) in first part of the interview.

Jhaveri is section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive®: How has the design of the SERENA-6 trial added to controversies surrounding the potential FDA approval of a ctDNA-guided treatment approach in advanced breast cancer?

Jhaveri: This is a complicated, convoluted story. We understand the implications of ESR1 mutations. We understand that [ESR1 mutations are] a mechanism of resistance that’s occurring under the selective pressure of aromatase inhibitors, and that is driving the tumor growth in a ligand-independent, estrogen receptor [ER]–dependent way.

Now we have strategies specifically targeting these mutations. ESR1 is a mechanism of resistance to endocrine therapy, and we have novel endocrine agents that work effectively against this resistance target of ESR1 mutations. We have oral SERDs and a PROTAC approved: elacestrant [Orserdu], imlunestrant [Inluriyo], and most recently, vepdegestrant [Veppanu].

When SERENA-6 was designed back in 2020, we did not have all these options available, and the question was: Should we be intervening on this mechanism of resistance early to make an impact? [Intervening on this mechanism of resistance early] logically makes sense. This is a defined mechanism of resistance, and therapies would potentially work if you were to act on [this mutation] quickly. Would you not want to see that? That’s what the trial set out to do.

Since the design of the study and since the conduct, accrual, and reporting of the results, the field has moved and evolved so quickly that the landscape now has 3 [ESR1-targeted] options available. We have options available upon radiological progression in the second-line setting, and not just single agents. Now we also have combinations. We have data from the phase 3 EMBER-3 trial [NCT04975308] for imlunestrant and abemaciclib [Verzenio] that the National Comprehensive Cancer Network endorsed.¹ We’re waiting to hear from the FDA about official approval for that combination from EMBER-3. We have giredestrant (GDC-9545) plus everolimus (Afinitor) now reported out from the phase 3 evERA Breast Cancer trial (NCT05306340), and we are going to hear about the FDA review of that doublet in the second-line setting by December 2026.²

SERENA-6 was so novel, important, and impactful, but knowing what we know about SERDs and ESR1 mutations, the FDA’s Oncologic Drugs Advisory Committee meeting [about the SERENA-6 strategy asked]: Now that we have all these options and we understand [the field] better than we did in 2020, are we saying that a strategy where we would intervene early is going to improve survival? That is not what the study was designed to do, the study had a primary end point of progression-free survival. [The SERENA-6 story is] not that straightforward anymore because it has implications for whether [switching treatment] early or waiting for the second-line setting will improve outcomes, especially because you have second-line options available, which you didn’t back in the day. The study was designed appropriately and was novel and futuristic for its time, using a fancy technology that we’ve been using to identify these mechanisms of resistance and act on them.

What updated data from SERENA-6 were presented at the 2026 ASCO Annual Meeting? How might these data further complicate the picture of this trial?

What was interesting and impactful from the SERENA-6 updated data was that there was not only ESR1-mutation [ctDNA clearance benefit, but also] total ctDNA clearance [benefit] on the camizestrant arm compared with the control arm. In the control arm, the clearance rate was in the single digits, and it was 51.0% in the camizestrant arm.³ That makes [the SERENA-6 strategy] even more meaningful in some ways. The data for patient-reported quality of life were also nice.

From a patient perspective, I can see a patient who will say, ‘I would like to know what’s happening in my tumor early enough and do something soon, and not have it go to the liver or spread [to other sites], even on a scan.’ For such a patient, if [the SERENA-6] option is available, I’d be okay suggesting that because I think it’s an appropriate approach. The conversation is going to be nuanced and complicated in that we have to [remember] that the [evidence] that this might make a patient live longer is not something we know from this dataset and might not know. However, could this be appropriate for an individual patient in clinic? Sure, it can be.

What does the future of breast cancer research look like, and what would you like to see going forward?

We are in an exciting time in that we’re trying to understand tumor biology more. We have novel technologies to help us get that information, but we’re not definitely done with our search for optimal therapies, sequencing, and ways of treating a patient in clinic. There’s a lot more work that needs to be done.

We are in an era where we have multiple treatment options, which we’re grateful to offer to our patients, and many of which have shown survival benefits. However, what we still need to focus on and do more work on is how to best use each strategy. Is one strategy better than the other if both are applicable in the same setting? What do we expect when we do the sequencing strategies? Ultimately, can we continue to further affect outcomes and survival rates for our patients with ER-positive disease? There is more to do, but these are exciting times. I am looking forward to more advances in the field, so we can help our patients better.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2026. July 29, 2026. Accessed August 18, 2026.https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
2. FDA accepts new drug application for Roche’s giredestrant in ESR1-mutated, ER-positive advanced breast cancer. News release. Roche. February 19, 2026. Accessed August 18, 2026. https://www.roche.com/media/releases/med-cor-2026-02-20
3. Bidard F-C, Mayer E, Park YH, et al. First-line camizestrant for emergent ESR1 mutations in advanced breast cancer: final progression-free survival results 2 from the phase III SERENA-6 trial. J Clin Oncol. 2026;44(suppl 17):LBA1007. doi:10.1200/JCO.2026.44.17_suppl.LBA1007