Dr Cristofanilli on the Next Steps With Camizestrant in HR+/HER2– Breast Cancer

“We need to be able to prevent [disease] recurrence and intervene [with treatment] even earlier before they have recurrence. When disease recurrence occurs, the treatments are primarily palliative, but they can also prolong the time to the use of infusion therapy and chemotherapy.”

Massimo Cristofanilli, MD, an attending physician at NewYork-Presbyterian Hospital and a professor of medicine at Weill Cornell Medical College, discussed future research directions with camizestrant in patients with 

-mutated hormone receptor–positive, HER2-negative advanced breast cancer.

Findings from the phase 3 SERENA-6 trial(NCT04964934) presented during the 

 demonstrated that patients who received camizestrant in combination with a CDK4/6 inhibitor (n = 157) achieved a median investigator-assessed progression-free survival (PFS) of 16.0 months (95% CI, 12.7-18.2) compared with 9.2 months (95% CI, 7.2-9.5) among patients who were treated with an aromatase inhibitor (AI) plus a CDK4/6 inhibitor (n = 158; adjusted HR, 0.44; 95% CI, 0.31-0.60; 

 < .00001). The 12-month PFS rates were 60.7% and 33.4%, respectively, and the 24-month rates were 29.7% and 5.4%, respectively. Notably, patients in the trial were randomly assigned to the investigational or control arm following the detection of an 

 mutation by circulating tumor DNA, which is often an indicator of disease progression, during initial therapy with an AI plus a CDK4/6 inhibitor.

In the future, investigators will look to develop approaches that can be employed before disease recurrence and monitoring strategies to do so, Cristofanilli said. Cristofanilli noted that targeted therapies have shown efficacy in patients with disease that is resistant to endocrine therapy, a setting in which chemotherapy would have been used in the past. Ongoing clinical trials are examining camizestrant and other selective estrogen receptor degraders, as well as novel agents, in the adjuvant setting to delay the time to disease recurrence, he added.

Additionally, disease monitoring techniques such as minimal residual disease (MRD) detection could be further used to intervene as soon as possible, Cristofanilli noted. The development of MRD-informed treatments will be a field of active study in the future, he concluded.

Videos

Massimo Cristofanilli, MD, discusses the next steps with camizestrant in ESR1-mutated HR-positive, HER2-negative advanced breast cancer.

Cristofanilli

"The most important message from [SERENA-6] is that you need to institute a [protocol] for monitoring patient with cell-free DNA very early on in the course of their disease."

Massimo Cristofanilli, MD, director of Breast Medical Oncology and associate director of Precision Oncology at Weill Cornell Medicine/NewYork-Presbyterian, discussed the clinical implications of serial 

 mutation monitoring using circulating tumor DNA (ctDNA) in hormone receptor–positive, HER2-negative advanced breast cancer, based on findings from the 

 demonstrated that adding camizestrant to a CDK4/6 inhibitor after the detection of emerging 

 mutations through serial ctDNA significantly delayed radiographic disease progression in patients receiving frontline CDK4/6 inhibitor–based therapy.

Specifically, patients who transitioned to camizestrant, a next-generation oral selective estrogen receptor degrader (SERD), and continued CDK4/6 inhibition upon detection of an 

 mutation (n = 157) achieved a median progression-free survival (PFS) of 16.0 months (95% CI, 12.7-18.2) compared with 9.2 months (95% CI, 7.2-9.5) in patients who continued an aromatase inhibitor (AI) plus CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; 

Cristofanilli highlighted the dynamic nature of metastatic breast cancer biology and stressed that traditional static biomarker assessments may not always capture evolving resistance mechanisms. He underscored that serial ctDNA monitoring represents a significant shift in clinical practice that could enable early intervention based on molecular progression—before radiographic evidence of disease advancement.

 mutational testing as a predictive biomarker to drive treatment decisions and demonstrates the actionable value of real-time ctDNA surveillance to tailor endocrine-based treatment strategies, he continued. Cristofanilli noted that an early switch to camizestrant led to a meaningfully alteration of disease trajectory in SERENA-6.

Findings from SERENA-6 could pave the way for clinicians to adopt routine serial ctDNA testing in HR-positive/HER2-negative advanced breast cancer, particularly for patients receiving endocrine-based therapies, Cristofanilli concluded.

Massimo Cristofanilli, MD, details the implications of serial ESR1 mutation monitoring using ctDNA in HR-positive/HER2-negative advanced breast cancer.

Dr Cristofanilli on the Potential Role of Serial ESR1 Mutation Monitoring in HR+/HER2-Negative Advanced Breast Cancer

Mayer

"We already have an oral SERD approved for breast cancer—elacestrant as monotherapy— but maybe we really need to be moving toward combinations with SERDS [and] a targeted partner, and that's where we may see the greatest benefit that can extend to a broader population of patients."

Erica L. Mayer, MD, MPH, director of Breast Cancer Clinical rResearch at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, discussed clinical significance of findings from the phase 3 EMBER-3 trial (NCT04975308), which evaluated the oral selective estrogen receptor degrader (SERD) imlunestrant with or without abemaciclib (Verzenio) in patients with hormone receptor–positive, HER2-negative advanced breast cancer who have progressed following prior endocrine therapy.

Mayer explained that EMBER-3 was a 3-arm, randomized trial designed to compare imlunestrant monotherapy and the combination of imlunestrant plus abemaciclib vs physician’s choice of endocrine therapy. All enrolled patients had previously received at least one line of endocrine therapy with an aromatase inhibitor with or without a CDK4/6 inhibitor, either in the advanced setting, or in the adjuvant setting if patients experienced recurrence on or within 12 months of completing treatment.

The primary comparison between imlunestrant and standard endocrine therapy showed a progression-free survival (PFS) benefit in favor of imlunestrant, particularly in patients with detectable 

 mutations. The median PFS among patients with 

 mutations was 5.5 months (95% CI, 3.9-5.5) for imlunestrant (n = 138) vs 3.8 months (95% CI, 3.7-5.5) for the control arm (n = 118; HR, 0.62; 95% CI, 0.46-0.82; 

 < .001). In the overall patient population, imlunestrant plus abemaciclib (n = 213) led to a median PFS of 9.4 months (95% CI, 7.5-11.9) vs 5.5 months (95% CI, 3.8-5.6) for standard-of-care endocrine therapy (n = 213; HR, 0.57; 95% CI, 0.44-0.73; 

Mayer noted that this PFS duration is among the longest reported in the post-endocrine therapy setting, highlighting the potential utility of SERD-based combinations in overcoming resistance.

Updated analyses from EMBER-3 presented at the 2025 ASCO Annual Meeting also showed that 

 in both imlunestrant arms compared with the SOC arm.

Mayer emphasized that although the oral SERD elacestrant (Orserdu) is already FDA approved for patients with 

-mutant tumors, the EMBER-3 findings suggest broader applicability of oral SERDs when used in combination with targeted therapies. The data support a potential shift in treatment strategy from SERD monotherapy to combination regimens to extend this class of drugs to a larger portion of patients, she concluded.

Erica L. Mayer, MD, MPH, discusses the use of imlunestrant in HR+, HER2-negative advanced breast cancer following prior endocrine therapy.

Dr Mayer on Imlunestrant in HR+/HER2-Negative Advanced Breast Cancer Following Prior Endocrine Therapy

The addition of camizestrant to continued therapy with CDK4/6 inhibition significantly improved progression-free survival (PFS) vs continued therapy with an aromatase inhibitor (AI) and CDK4/6 inhibitor in the presence of an 

 mutation ahead of disease progression on frontline therapy in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to findings from the phase 3 SERENA-6 trial (NCT04964934) that were presented in a press briefing at the 

The median investigator-assessed progression-free survival (PFS) was 16.0 months (95% CI, 12.7-18.2) with camizestrant plus CDK4/6 inhibition (n = 157) vs 9.2 months (95% CI, 7.2-9.5) with continued AI/CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; 

 < .00001). The 12- and 24-month PFS rates in the camizestrant arm were 60.7% and 29.7%, respectively, vs 33.4% and 5.4% in the continued AI/CDK4/6 inhibition arm.

“SERENA-6 is the first global registrational phase 3 study to demonstrate the clinical utility of circulating tumor DNA [ctDNA] monitoring to detect and treat emerging resistance ahead of disease progression,” Nicholas C. Turner, MD, PhD, lead study author and director of The Royal Marsden and Institute of Cancer and National Institute for Health and Care Research Biomedical Research Centre in London, United Kingdom, said in the press briefing.

Echoing the significance of these findings, Eleonora Teplinsky, MD, stated, “When patients progress on scans, we’re already behind. We’re switching therapy, and we’ve already lost control [of the disease]. What this study does is [adopt] an early switch approach before we see disease progression on imaging, allowing us to stay ahead of the curve.” Teplinsky is head of Breast and Gynecologic Medical Oncology at Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, and a clinical assistant professor of medicine at The Icahn School of Medicine at Mount Sinai in New York, New York.

Turner started the presentation by acknowledging the present unmet need for patients with 

-mutant, advanced hormone receptor–positive breast cancer. Although rare at diagnosis, comprising less than 5% of advanced cases, 

 mutations will develop in approximately 40% of cases, resulting in disease progression on frontline therapy with an AI and CDK4/6 inhibitor.

 mutations can be isolated in ctDNA approximately 6 months before progression.

Camizestrant is a next-generation oral selective ER degrader and complete ER antagonist that’s designed to inhibit and degrade the mutant and wild-type forms of the ER. Previously, the FDA granted fast track designation to the agent for the population enrolled in SERENA-6.

 By coupling the use of ctDNA with early integration of camizestrant ahead of disease progression, investigators theorized they could prolong the clinical benefit of frontline treatment.

The randomized, double-blind, placebo-controlled SERENA-6 trial enrolled female and male patients with ER-positive, HER2-negative advanced breast cancer who had received at least 6 months of an AI in combination with a CDK4/6 inhibitor as initial endocrine-based therapy for advanced disease. Patients also needed to have a detectable 

 mutation in their ctDNA without evidence of disease progression.

A total of 3,325 patients who were receiving frontline therapy with an AI and CDK4/6 inhibitor for at least 6 months were screened. 

mutation testing (n = 3,256) was evaluated in ctDNA with the Guardant360 CDx assay every 2 to 3 months at the time of routine staging scans. A total of 548 patients had detectable 

 mutations, 51% of whom were positive on the first test, 38% of whom were positive after 2 to 5 tests, and 11% of whom were positive after the fifth test. A total of 233 patients discontinued the study due to screening failure (n = 200) or consent withdrawal, lost follow-up, or other reasons (n = 33).

A total of 315 patients were randomly assigned 1:1 to 75 mg of camizestrant daily plus continued CDK4/6 inhibition and placebo for the AI or continued AI with anastrozole or letrozole plus CDK4/6 inhibition and placebo for camizestrant. Treatment was continued until disease progression, unacceptable toxicity, and patient withdrawal or death.

The primary end point was investigator-assessed PFS by RECIST 1.1 criteria. Secondary end points included time to second disease progression or death, overall survival, safety, and patient-reported outcomes.

Patients were stratified by visceral disease (yes vs no), detection of 

 mutation (mutation detected at first test vs a subsequent test), time from initiation of CDK4/6 inhibition plus an AI to randomization (<18 months vs ≥18 months), and choice of CDK4/6 inhibitor (palbociclib [Ibrance] vs ribociclib [Kisqali] vs abemaciclib [Verzenio]).

Secondary End Points and Trial Significance

Time to deterioration (TTD) in global health status/quality of life (QOL) was also presented. The median TTD according to the European Organization for Research and Treatment of Cancer 30-item QOL questionnaire was 23.0 months (95% CI, 13.8-not calculable) with camizestrant (n = 107) vs 6.4 months (95% CI, 2.8-14.0) with continued AI/CDK4/6 inhibition (n = 95; adjusted HR, 0.53; 95% CI, 0.33-0.82; nominal 

Turner noted that the camizestrant regimen also had a low rate of treatment discontinuations resulting from adverse effects.

“[These data highlight the] potential for a new treatment strategy in oncology to treat developing resistance before it causes progression,” Turner said in conclusion.

Elaborating on the novelty of the study design, Teplinsky explained, “Allowing patients to remain on first-line endocrine therapy for hormone receptor–positive, HER2-negative advanced breast cancer is critical, because we know that outcomes worsen with subsequent lines of therapy. Allowing that longer time on first-line endocrine therapy is significant, and it also improves QOL, as we’ve seen, and that’s a huge part of living with metastatic breast cancer. [The study] uses a technology, [which] is a liquid biopsy, that doesn’t pose risks of surgical biopsies, and it’s something that can be done and is available in our clinic now. Although camizestrant is not yet FDA approved, this likely will pave the way for a new treatment strategy in first-line hormone receptor–positive, HER2-negative metastatic breast cancer in patients with 

Julie Gralow, MD, chief medical officer and executive vice president at ASCO, added, “We are using these liquid biopsies [to detect] ctDNA. We have whole sessions at this meeting, looking at using them in colon cancer, but using them to detect emerging resistance before we see evidence of tumor progression on scans is what’s novel about this study.”

Disclosures: No disclosures were presented for Turner.

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

Camizestrant significantly improved progression-free survival vs faslodex in SERENA-2 phase II trial in advanced ER-positive breast cancer. News release. AstraZeneca. October 26, 2022. Accessed May 31, 2025. https://www.astrazeneca.com/media-centre/press-releases/2022/camizestrant-significantly-improved-progression-free-survival.html

Articles

The SERENA-6 trial demonstrated that adding camizestrant to CDK4/6 inhibitors significantly improved progression-free survival (PFS) in patients with ER-positive, HER2-negative advanced breast cancer with ESR1 mutations, compared to continued therapy with aromatase inhibitors and CDK4/6 inhibitors. The trial utilized ctDNA monitoring to detect resistance before disease progression, allowing for an early switch in therapy. This approach prolonged the clinical benefit of frontline treatment and improved quality of life. The study highlights a potential new treatment strategy for managing resistance in this patient population.

Emergent ESR1-mutant, ER-positive, HER2-negative advanced breast cancer was best treated with camizestrant and continued CDK4/6 inhibition vs SOC therapy.

Early Switch With Camizestrant Plus Continued CDK4/6 Inhibition Nearly Doubles PFS in ESR1-Mutant, ER+/HER2– Advanced Breast Cancer 

Patient-reported outcomes (PROs) were improved with imlunestrant, an oral selective estrogen receptor degrader, with or without abemaciclib (Verzenio), compared with standard-of-care endocrine therapy in patients with estrogen receptor (ER)–positive/HER2-negative advanced breast cancer who experienced disease progression after endocrine therapy, according to data from the phase 3 EMBER-3 trial (NCT04975308) presented at the 

mutation, based on changes in baseline in the EORTC QLQ-C30 global health status (GHS)/quality of life score (QOL), treatment with imlunestrant was favored compared with standard of care endocrine therapy. At treatment cycle 7, the difference between groups was 9.9 points. The GHS/QOL was typically maintained across both treatment arms.

mutation, the median time to deterioration of GHS/QOL with imlunestrant was 5.6 months (95% CI, 3.8-11.1), with 53 events, compared with 3.8 months (95% CI, 3.0-6.5) and 50 events, with endocrine therapy (HR, 0.76; 95% CI, 0.51-1.13; 

= .15). The investigators noted that estimates were limited by a high rate of censoring.

mutation, overall GHS/QOL and functional domains remained consistent. Imlunestrant was superior regarding the physical, role, social, emotional, and cognitive functional domains. Regarding symptom domains, worse scores were observed with endocrine therapy for fatigue, pain, dyspnea, insomnia, and appetite loss; worse scores were observed with imlunestrant for nausea/vomiting, constipation, and diarrhea. It was noted that symptom domains were broadly similar between treatment groups.

In all patients, the overall changes in GHS/QOL and functional domains were typically maintained across all treatment arms. In order from worst to best, the mean change from baseline for GHS/QOL was imlunestrant plus abemaciclib, endocrine therapy, and imlunestrant; for physical function, social function, emotional function, and cognitive function, it was the same, and for role function, it was endocrine therapy, imlunestrant plus abemaciclib, and imlunestrant.

Regarding symptom domains, imlunestrant plus abemaciclib demonstrated clinically meaningful worse scores regarding nausea/vomiting and diarrhea. The average proportion of time with “frequent” or “almost constant” diarrhea was 22% with imlunestrant plus abemaciclib, 3% with imlunestrant, and 2% with endocrine therapy.

“Consistent with the primary results from EMBER-3, these PRO results reinforce the benefit of imlunestrant, as monotherapy or combined with abemaciclib, as an all-oral targeted therapy option after progression on [endocrine therapy] for patients with ER-positive, HER2-negative [advanced breast cancer],” wrote lead study author Giuseppe Curigliano, MD, PhD, a professor of medical oncology at the University of Milano, and of the European Institute of Oncology, National Institute of Hospitalization and Scientific Care in Milano, Italy, and coauthors, in the presentation.

The trial enrolled approximately 859 patients who were randomly assigned, in a 1:1:1 ratio, to receive either imlunestrant monotherapy (n = 327), imlunestrant plus abemaciclib (n = 208), or endocrine therapy (n = 324). Imlunestrant was given at 400 mg every day in both groups, abemaciclib was given at the labeled dose, and endocrine therapy, which was the investigator’s choice between fulvestrant (Faslodex) or exemestane (Aromasin), was also given at the labeled dose.

Eligible patients had ER-positive, HER2-negative advanced disease. Regarding prior therapies, in the adjuvant setting, patients had recurrence on or within 12 months of completion of an aromatase inhibitor with or without a CDK4/6 inhibitor; for advanced breast cancer, patients had progression on a first-line aromatase inhibitor with or without a CDK4/6 inhibitor and no other therapy for advanced breast cancer.

The trial’s primary end points were investigator-assessed progression-free survival across all treatment groups. Secondary end points included overall survival, blinded independent committee review-assessed PFS, overall response rate, and safety; exploratory end points were PROs.

The PRO measures used and their respective schedules are as follows: the EORTC QLQ-C30 GHS/QOL, function domains, and symptom domains were assessed on day 1 and then every 8 weeks after with short-term follow-up; the EORTC IL-19 physical functioning was assessed every 8 weeks opposite the EORTC QLQ-C30; the PRO-CTCAE diarrhea frequency of diarrhea was assessed on day 1 then every week after with short-term follow-up; and the PRO-CTCAE ISR (injection site reaction) occurrence of IJR was assessed every week of cycle 1 then the first 2 weeks of all other cycles.

It was reported that 72% of patients receiving fulvestrant experienced ISR at any time of treatment; 20% of them had an incidence of less than 25%, 32% had an incidence from 25% to 50%, 30% had an incidence from 50% to 75%, and 17% had an incidence of greater than 75%.

The median investigator-assessed PFS, in all patients, was 9.4 months (95% CI, 7.5-11.9) with imlunestrant plus abemaciclib and 5.5 months (95% CI, 3.8-5.6) with imlunestrant alone (HR, 0.57; 95% CI, 0.44-0.73; 

mutation, the median PFS was 5.5 months (95% CI, 3.9-7.4) with imlunestrant alone vs 3.8 months (95% CI, 3.7-5.5) with endocrine therapy (HR, 0.62; 95% CI, 0.46-0.82; 

Regarding safety, treatment-emergent adverse events (TEAEs) of any grade occurred in 83% of patients with imlunestrant, 98% of patients with imlunestrant plus abemaciclib, and 84% of patients with endocrine therapy; of grade 3 or higher, TEAEs occurred in 17%, 49%, and 21%, respectively.

In patients with imlunestrant, dose reductions, treatment discontinuations, and death due to AEs occurred in 2%, 4%, and 2%; in patients with imlunestrant plus abemaciclib, they occurred in 39%, 6%, and 1%, respectively; and in patients with endocrine therapy, they occurred in 0%, 1%, and 1%.

Curigliano G, O’Shaughnessy J, Bidard FC, et al. Patient-reported outcomes (PROs) in patients with ER+, HER2- advanced breast cancer (ABC) treated with imlunestrant, investigator’s choice standard endocrine therapy, or imlunestrant + abemaciclib: Results from the phase III EMBER-3 trial. 

2025;43(suppl_16):1001. doi:10.1200/JCO.2025.43.16_suppl.1001

The phase 3 EMBER-3 trial evaluated patient-reported outcomes (PROs) in patients with ER-positive, HER2-negative advanced breast cancer treated with imlunestrant, with or without abemaciclib, compared to standard endocrine therapy. Imlunestrant showed improved PROs, particularly in patients with ESR1 mutations, with better scores in global health status/quality of life (GHS/QOL) and functional domains. However, imlunestrant plus abemaciclib was associated with higher rates of adverse events, including nausea/vomiting and diarrhea. The trial's primary endpoint was progression-free survival, with imlunestrant plus abemaciclib showing superior results.

Patient-reported outcomes revealed that imulunestrant with or without abemaciclib was favored vs SOC in ER-positive, HER2-negative breast cancer.

Imlunestrant With/Without Abemaciclib Generates Improved PROs in ER+/HER2– Advanced Breast Cancer 

Sponsored in part by AstraZeneca and Daiichi Sankyo. Content produced and independently developed by OncLive.

Unpacking Pivotal Data Updates in Metastatic Breast Cancer Management | Supplements and Featured Publications

Dr Cristofanilli on the Next Steps With Camizestrant in HR+/HER2– Breast Cancer

Dr Cristofanilli on the Potential Role of Serial ESR1 Mutation Monitoring in HR+/HER2-Negative Advanced Breast Cancer

Dr Mayer on Imlunestrant in HR+/HER2-Negative Advanced Breast Cancer Following Prior Endocrine Therapy

Early Switch With Camizestrant Plus Continued CDK4/6 Inhibition Nearly Doubles PFS in ESR1-Mutant, ER+/HER2– Advanced Breast Cancer

Imlunestrant With/Without Abemaciclib Generates Improved PROs in ER+/HER2– Advanced Breast Cancer