Camizestrant Combo Therapy Supports First-Line Use in AstraZeneca’s Breast Cancer Trial

In a breakthrough for advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer treatment, AstraZeneca’s SERENA-6 Phase III trial showed that camizestrant, a next-gen oral therapy, combined with a cyclin-dependent kinase (CDK) 4/6 inhibitor, significantly extends the time patients live without disease progression.

The trial was conducted on patients whose tumors have developed mutations in the estrogen receptor 1 (ESR1) gene, a known contributor to endocrine therapy resistance that leads to relapses and rapid disease progression, limiting treatment options and worsening survival prospects.

With 200,000 patients in the first-line setting receiving endocrine therapy and CDK4/6 inhibitors, ESR1 mutation-driven resistance is a persistent obstacle.

SERENA-6 is unique as the first global, double-blind study to use circulating tumor DNA (ctDNA) monitoring — a blood-based approach — to detect early signs of endocrine resistance. By tracking small fragments of tumor DNA in the bloodstream, researchers identified the emergence of ESR1 mutations before clinical progression appeared.

This early detection allowed for a timely switch in therapy from standard aromatase inhibitors to camizestrant while patients continued receiving a widely approved CDK4/6 inhibitor such as Pfizer’s Ibrance (palbociclib), Novartis’ Kisqali (ribociclib) or Eli Lilly’s Verzenio (abemaciclib).

XTALKS WEBINAR: Redefining Women’s Cancer Care: Delivering Smarter, Safer Clinical Trials

Live and On-Demand: Thursday, April 10, 2025, at 11am EDT (5pm CEST/EU-Central)

Register for this free webinar to explore innovative approaches to enhancing clinical trials for breast and gynecological cancers.

Key findings from the trial demonstrated a highly statistically significant improvement in progression-free survival (PFS) — the period during which patients experience no worsening of their disease — when treated with camizestrant plus a CDK4/6 inhibitor compared to the combination of an aromatase inhibitor with the same inhibitors.

Although data on overall survival (OS) and time to second disease progression (PFS2) are still emerging, early trends suggest that the benefits of camizestrant may extend further, offering hope for longer-term disease control.

The safety profile was consistent with prior findings, with no new safety concerns or unexpected side effects.

Camizestrant works as both a selective estrogen receptor degrader (SERD) and a complete estrogen receptor (ER) antagonist, meaning it not only targets the receptor driving cancer cell growth but also depletes it from the cells.

This dual action makes it particularly effective against ESR1 mutations — a major challenge in HR-positive breast cancer, which accounts for 70% of all breast cancer cases. About 30% of these tumors develop ESR1 mutations during first-line treatment, leading to resistance.

Related: Iovebi (Inavolisib) Gains FDA Nod for PIK3CA-Mutated HR-Positive, HER2-Negative Breast Cancer

Given the role of ESR1, Bio-Techne launched a highly sensitive ESR1 mutation monitoring assay in December 2024 to track these mutations in ctDNA and exosomal RNA, helping to catch signs of resistance early on.

AstraZeneca’s development program also includes SERENA-4, CAMBRIA-1 and CAMBRIA-2 studies, evaluating camizestrant’s use as monotherapy or in combination to address unmet needs. Preclinical models show strong anticancer activity, even in tumors with ER-activating mutations.

In the SERENA-2 Phase II trial, camizestrant improved PFS versus fulvestrant irrespective of ESR1 status or prior CDK4/6 inhibitor use, while SERENA-1 Phase I confirmed its tolerability and anti-tumor profile with CDK4/6 inhibitors.

AstraZeneca plans to present the full dataset at an upcoming medical meeting and engage with global regulators. If approved, camizestrant could offer a proactive approach to managing resistance, shaping the future of HR-positive breast cancer treatment.