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 ESR1 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.

At the 2025 ASCO Annual Meeting, 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 ESR1 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; P < .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.