Long-Term Data Expand the Horizon of Hormone Receptor+ Breast Cancer Therapies

Modern hormone receptor–positive breast cancer management is being redefined by the sustained relapse protection of adjuvant CDK4/6 inhibitors, the move toward molecular-driven treatment switches informed by circulating tumor DNA (ctDNA), and the potential for oral selective estrogen receptor degrader (SERD) combinations to benefit a wider patient population, according to Rena D. Callahan, MD.

In an interview with OncLive® following a State of the Science Summit™ on breast cancer, which Callahan co-chaired, she discussed clinical considerations based on the 4-year update of the phase 3 NATALEE trial (NCT03701334), which confirmed the efficacy of adding the adjuvant CDK4/6 inhibitor ribociclib (Kisqali) to endocrine therapy in patients with early-stage hormone receptor–positive breast cancer. At a median follow-up of 44.2 months (range, 0-63 months), the 4-year invasive disease–free survival rate was 88.5% with ribociclib plus a nonsteroidal aromatase inhibitor (NSAI; n = 2549) vs 83.6% with an NSAI alone (n = 2552; difference, 4.9%; 95% CI, 2.7-7.1).¹

She also explained the potential clinical utility of switching therapy based on the detection of an emergent ESR1 mutation ahead of progression on first-line therapy in patients with hormone receptor–positive, HER2-negative advanced breast cancer. Updated data from the phase 3 SERENA-6 trial (NCT04964934) presented at the 2025 San Antonio Breast Cancer Symposium demonstrated a median progression-free survival (PFS) of 16.6 months (95% CI, 14.7-19.4) with a switch to camizestrant plus continued CDK4/6 inhibition (n = 157) vs 9.2 months (95% CI, 7.2-9.7) with continued aromatase inhibition and CDK4/6 inhibition (n = 158; HR, 0.46; 95% CI, 0.34-0.62; P < .00001).² Additionally, she highlighted the benefits of oral SERDs for the treatment of patients with ESR1-mutated disease.

Callahan is a breast medical oncologist at UCLA Health and an associate clinical professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, California.

OncLive: How do the 4-year results of the NATALEE trial inform the optimization of adjuvant CDK4/6 inhibitor selection for hormone receptor–positive breast cancer?

Callahan: The 4-year results provide extra confidence for using the approach of adding adjuvant CDK4/6 inhibitors to endocrine therapy. Now there are 2 adjuvant CDK4/6 inhibitors [FDA approved in this setting]. We had the phase 3 monarchE trial [NCT03155997] with abemaciclib [Verzenio], and we had the NATALEE trial with ribociclib.

There is a consistent story here, which is that when you add a CDK4/6 inhibitor to a patient who has early-stage hormone receptor–positive breast cancer with some high-risk features, over time, you see a bigger difference in relapses. The further out [from treatment] you go, the greater the differences are in the group that received endocrine therapy alone vs the group that received endocrine therapy plus the CDK4/6 inhibitor. That's why, especially for trials like these, it's important to have longer-term data to see whether this [PFS benefit was] just was protective during therapy.

In the NATALEE trial, the duration of the therapy with ribociclib was 3 years.¹ We wanted to get beyond that time point to establish that this was an intervention with longer-term benefit that went beyond the time a patient was receiving therapy. [These data] build confidence for using this approach. The NATALEE trial included patients with node-negative breast cancer, so that is a large treatment population that can benefit from this therapy.

How might the data from the SERENA-6 trial investigating a switch in therapy once an ESR1 mutation is detected but before radiological progression influence your practice, especially if this approach were to become FDA approved?

That trial is interesting because it's potentially paradigm shifting. For years, and I teach my fellows and residents this and have conversations with patients about this, [have thought that] blood tests are [helpful], but that scans are gold standard upon which we make our treatment decisions. We don't change therapy unless we see disease progression on a scan, and in SERENA-6, this was not the case. [When] there was molecular progression, or evidence that there would soon be molecular progression, [shown through] findings in ctDNA associated with ESR1 mutations, that prompted a change in therapy. Patients who underwent the switch based on these molecular findings had a longer PFS [compared with those who did not switch therapy].

What we don't know is, at the end of the day, are patients going to live longer? We don't have that information. There was an analysis of time to second progression [PFS2], which was difficult to interpret, given that 1 of the treatment arms [consisted of patients who had received] 3 different treatments, and the other arm [consisted of patients who had received] 2 [different treatments]. But [the PFS2 data] provide some rationale to make [treatment] changes based on molecular findings or blood tests.

The phase 3 EMERALD (NCT03778931) and EMBER-3 (NCT04975308) trials have assessed oral SERDs in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer following first-line CDK4/6 inhibition. Based on these readouts, how does clinical trial design and patient selection affect or complicate outcomes with this approach?

So far, we have, based on [data from] EMERALD and EMBER-3, 2 FDA-approved oral SERDs that we can use for appropriate patients. ‘Appropriate patients’ is the operative phrase. The FDA approvals for elacestrant [Orserdu] and imlunestrant [Inluriyo] are restrictive in that they are for patients whose tumors have developed an ESR1 mutation in the ER. Those are acquired mutations that tumors accumulate after being under the selective pressure of prior endocrine therapy, specifically an aromatase inhibitor.

When we look at those [pivotal] trials, we see that the benefit with single-agent oral SERDs in patients with metastatic hormone receptor–positive disease was driven by the population that had ESR1 mutations, so there is rationale for why FDA was so restrictive in those approvals. [However,] interestingly from these trials, including another trial—the phase 1/2ELEVATE trial [NCT05563220] with elacestrant in combination with other targeted therapies—[we see] that when combining the oral SERDs with another targeted agent, there does not seem to be the same requirement for an ESR1 mutation for a patient to benefit. If there is an FDA approval of a combination of an oral SERD and a targeted agent, many of us would be excited to use [that regimen], and it would apply to a much broader patient population.

References

1. Fasching PA, Stroyakovskiy D, Yardley DA, et al. Ribociclib plus endocrine therapy in hormone receptor-positive/ERBB2-negative early breast cancer: 4-year outcomes from the NATALEE randomized clinical trial. JAMA Oncol. 2025;11(11):1364-1372. doi:10.1001/jamaoncol.2025.3700
2. 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.