Camizestrant Plus CDK4/6 Inhibitor Demonstrates Sustained Benefit Beyond First Progression in ESR1-Mutated Breast Cancer

For patients with hormone receptor–positive, HER2-negative advanced breast cancer that acquires an ESR1 mutation during first-line therapy, switching endocrine treatment early prior to progression has emerged as a compelling strategy. Final progression-free survival 2 (PFS2) results from the phase 3 SERENA-6 trial (NCT04964934) now reinforce that approach, showing that the benefit of switching to camizestrant (AstraZeneca) extends meaningfully beyond the first progression.¹

“Disease progression on first-line therapy is commonly associated with worsening symptoms and quality of life as well as with greater diversity of resistance mechanisms that may impair the efficacy of subsequent treatments,” said François-Clément Bidard, MD, PhD, a professor of medicine in the Department of Medical Oncology at Curie Institute and the University of Versailles Saint-Quentin-en-Yvelines at Paris-Saclay University in France, at a presentation during the 2026 American Society of Clinical Oncology Annual Meeting. “In SERENA-6, we investigated whether a proactive switch to camizestrant, while continuing the same CDK4/6 upon detection of ESR1 mutation, could address emerging resistance before disease progression and improve PFS and longer-term outcomes.”²

The SERENA-6 Trial and Camizestrant

ESR1 mutations are among the most common mechanisms of acquired resistance to aromatase inhibitor (AI)–based therapy and are detectable in circulating tumor DNA before radiographic progression. The SERENA-6 trial was designed to test whether proactively switching patients to camizestrant—a next-generation selective estrogen receptor degrader and complete estrogen receptor antagonist—upon detection of an ESR1 mutation could improve outcomes compared with continuing the same AI, in both cases alongside a CDK4/6 inhibitor.¹

The trial enrolled patients with hormone receptor–positive, HER2-negative advanced breast cancer receiving a first-line AI plus a CDK4/6 inhibitor who had not yet experienced disease progression. Patients were randomly assigned to switch to camizestrant plus a CDK4/6 inhibitor (n = 157) or continue the AI plus CDK4/6 inhibitor (n = 158). The primary end point was PFS; PFS2—defined as the time from randomization to progression on first subsequent therapy or death—was a key secondary end point, powered to detect an HR of 0.65.¹

Camizestrant Showed Meaningful PFS Benefit

Previously reported data established a striking PFS benefit with camizestrant: an HR of 0.44 (95% CI, 0.31-0.60; P < .0001), with approximately one-third of patients still progression free at 30 months vs just 2.7% in the AI-continuation arm. That benefit held with longer follow-up, with no meaningful attenuation of effect.¹

“With longer [follow-up], we're able to confirm the benefit of the switch to camizestrant triggered by ESR1 mutation,” explained Bidard.¹ “Median PFS was 9.2 months in the AI arm vs 16.8 months in the camizestrant arm—an absolute difference of 7.6 months—with a hazard ratio of 0.45. Of course, there's the early separation of the curves, but now with longer follow-up, you can actually see that, in this analysis, up to 35% of patients were still progression free at 2 years.”²

The final PFS2 analysis, conducted at a median follow-up of approximately 23.5 months, confirmed that the benefit extends beyond the first line of therapy. Median PFS2 was 25.7 months with camizestrant vs 19.1 months with continued AI—a statistically significant improvement (HR, 0.63; 95% CI, 0.46-0.86; P = .00373). Notably, endocrine-based therapy remained the most common first subsequent treatment in both arms, suggesting that switching to camizestrant did not preclude later endocrine options.¹

Camizestrant also significantly prolonged chemotherapy-free and antibody-drug conjugate–free survival (HR, 0.64; P = .00375) and delayed deterioration in global health status and quality of life (HR, 0.48; P < .001)—end points directly relevant to patients' day-to-day experience.¹

The PFS benefit was consistent across key subgroups, including patients with comutations in PIK3CA (present in 41% of patients; HR, 0.44) and TP53 (present in 25%; HR, 0.49). Overall survival data were only 30% mature, yielding an HR of approximately 0.87. Safety was consistent with the established profile of both agents.¹

Clinical Implications

Findings from the SERENA-6 trial make a strong case for routine ESR1 mutation monitoring during first-line therapy and for acting on that information before progression occurs. Switching to camizestrant at the time of mutation emergence—rather than waiting for clinical or radiographic progression—appears to delay not only first progression but also subsequent progression while reducing exposure to chemotherapy and preserving quality of life. These results support the use of camizestrant in combination with a CDK4/6 inhibitor as a new standard of care for this molecular subgroup.¹

“We can confirm the benefits in terms of reduction in the risk of deterioration in patient-reported cancer symptoms and functioning,” said Bidard.¹ “And that reduction was mostly observed in terms of emotional functioning, but also [in] pain and shortness of breath, which are obviously key parameters for our patients. We are also confirming the extension of chemotherapy‑free survival for patients who have been switched to camizestrant.”²

REFERENCES

1. Bidard FC, Mayer EL, Park YH, et al. First-line (1L) camizestrant (CAMI) for emergent ESR1 mutations (ESR1m) in advanced breast cancer (ABC): final progression-free survival 2 (PFS2) from the phase III SERENA-6 trial. Presented at: ASCO 2026; May 28-June 2, 2026; Chicago, IL. Abstract LBA1007

2. Bidard FC. Breast cancer—metastatic. Presented at: ASCO 2026; May 28-June 2, 2026; Chicago, IL. Abstract LBA1007