FDA's ODAC Votes Against Camizestrant in Advanced Breast Cancer

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 6-3 that the benefit-risk assessment is not favorable for the novel agent camizestrant in combination with a CDK4/6 inhibitor in hormone receptor–positive (HR+)/HER2-negative advanced breast cancer upon detection of an ESR1 mutation.¹

The ultimate sticking point for those who voted no was the potential for the SERENA-6 trial (NCT04964934), which evaluated a novel design, to create an unfavorable precedent. While there was a notable progression-free survival (PFS) benefit, the study is likely underpowered to assess overall survival (OS).

“I think the data for changing the paradigm just [aren’t] there,” said Stanley Lipkowitz, MD, ODAC member who voted no. “There is a PFS benefit. There was no OS benefit. I think if there was, I would have voted yes for sure.”

“The bar should be high here, because it’s changing fundamentally the way we do business. I agree with the FDA’s concern that all the next trials will do exactly this, with no evidence that it’s improving outcomes,” Lipkowitz added.

Scientific Rationale of Camizestrant

The proposed indication is the use of camizestrant in combination with a CDK4/6 inhibitor for patients with HR+/HER2-negative advanced breast cancer upon emergence of an ESR1 mutation during first-line therapy, prior to radiographic progression.¹

Mutations in the ESR1 gene represent a specific marker of resistance to aromatase inhibitors (AIs). These mutations lead to constitutive, estrogen-independent activation of the estrogen receptor, rendering AIs ineffective.ESR1 mutations are found in approximately 4% of patients at initial advanced breast cancer diagnosis but rises to roughly 40% at the end of first-line AI and CDK4/6 inhibitor therapy. By intercepting resistance early, before the tumor develops greater genetic diversity and heterogeneity, the use of the oral selective estrogen receptor degrader (SERD) camizestrant maximizes the duration of endocrine-based treatment and delays the need for chemotherapy.

SERENA-6 Background

The primary evidence supporting camizestrant stems from the phase 3 SERENA-6 trial, which evaluated an "early switch" strategy: changing endocrine therapy from an AI to camizestrant at the first molecular sign of resistance ESR1 mutation detection in circulating tumor DNA (ctDNA) rather than waiting for radiographic progression.

Study Design

SERENA-6 is a randomized, double-blind, placebo-controlled, 2-step phase 3 trial.

• Step 1 (Surveillance): Patients on first-line AI plus CDK4/6 inhibitor for ≥6 months underwent ctDNA testing every 2 to 3 months using the Guardant360® CDx assay.
• Step 2 (Randomization): 315 patients with detected ESR1 mutation and no radiographic progression were randomized 1:1 to:

1. Camizestrant 75 mg daily with continued CDK4/6 inhibitor plus AI-placebo.
2. Continued AI with continued CDK4/6 inhibitor plus camizestrant-placebo.

Trial Results

Data presented at the 2025 ASCO Annual Meeting showed that the trial met its primary end point of PFS. Patients switching to camizestrant had a median PFS of 16.0 months compared with 9.2 months for those continuing AI (HR 0.44; P <.00001).²

FDA’s Perspective

The FDA expressed significant reservations regarding the clinical meaningfulness of these results.¹ Key concerns include the lack of evidence that switching at ESR1 mutation detection is superior to switching at radiographic progression, the use of a nonstandard PFS starting point, and immature OS data. The nontraditional study design also raised flags.

“…The treatment paradigm evaluated in SERENA-6 is experimental and does not represent standard of care for patients with [HR+] metastatic breast cancer,” said Mirat Shah, MD, clinical team leader, Division of Oncology 1, Office of Oncologic Diseases, Office of New Drugs, FDA.

“The biggest concern with the SERENA-6 trial is that approving the drug camizestrant would include an endorsement of a treatment paradigm that does not have established clinical benefit. It is unknown whether changing therapy at detection of an ESR1 mutation rather than waiting until radiography progression to start a new treatment improves long-term outcomes like [OS] for patients,” Shah added.

Cardiac Safety

Camizestrant is associated with unique toxicities, specifically visual disturbances (photopsia) and cardiotoxicity (bradycardia and QT prolongation). One nonfatal case of Torsade de Pointes occurred in a phase 1 trial when camizestrant was combined with ribociclib (Kisqali).¹

While the FDA granted fast track and breakthrough therapy designations, these do not constitute a final favorable benefit-risk assessment.

AstraZeneca’s Perspective

While the applicant presentations acknowledged that the design of SERENA-6 challenges the present clinical trial approaches, they maintained the benefits of camizestrant, primarily in allowing patients to remain on well-tolerated endocrine therapy for longer, delaying symptomatic progression and worsening quality of life.

Safety Analysis

Andrew Walding, MSc, global safety head of camizestrant at AstraZeneca, delivered the safety presentation and brought special attention to the FDA’s concerns of cardiac toxicity.

“The data show that the combination of camizestrant and ribociclib is safe and well tolerated. Camizestrant monotherapy has no clinically significant QT prolongation at all clinically relevant and that includes the camizestrant exposure seen in in combination with ribociclib,” Walding explained.

A QT study was conducted in SERENA-1 (NCT03616587) where patients were observed with 24-hour HOLTER monitors and generated over 80,000 data points per patient. This study was conducted in line with international guidelines and an FDA-co-authored white paper. According to Walding, the study did not find any clinically significant QT effect, contrary to the FDA’s presentation.

“The mechanisms of commiserate mediated bradycardia and ribociclib-mediated QT prolongation are distinct,” Walding explained. Regarding the patient in SERENA-1 who experienced grade 4 QT prolongation with camizestrant and 600 mg of ribociclib, Walding said, “This case was heavily confounded by concomitant medications and electrolyte abnormalities. Critically, when the patient had a QCF of over 550 milliseconds, ribociclib was not interrupted, contrary to ribociclib indications.”

Clinical Perspective

Kevin Kalinsky, MD, division director of Medical Oncology at Emory University, delivered the clinical perspective during the applicant presentation.

“Since I was in training, patients have wanted an actionable blood marker to inform whether a treatment is working. With ESR1 mutations, we finally have such a marker and, with camizestrant, a way to effectively target it,” Kalinsky said. “In my view, SERENA-6 offers a novel biomarker-driven approach that provides a positive benefit-risk ratio. It extends the clinical benefit of frontline endocrine therapy and CDK4/6 inhibition, delaying progression in deterioration and quality of life, and maximizes time on well-tolerated therapy and delays the need for chemotherapy or antibody-drug conjugates. It is straightforward to use in the clinic, empowering patients to adjust treatment before worsening symptoms and disease progression.”

ODAC’s Discussion

During the discussion section of the meeting, the ODAC discussed the choice of end points evaluated in SERENA-6, ideal trial design, and how to operationalize this treatment paradigm in the real world. Opinions were split among committee members, with many expressing skepticism in the study design.

“I think that it has not been proven that if you treat at the time of a mutation, you get the most benefit vs waiting until radiographic progression,” said ODAC member Karla Ballman, PhD, Mayo Clinic. “This hasn't been shown to be a predictive biomarker at this point. We know it's prognostic, we know patients do worse, but we don't know that if you treat that actual biomarker you're going to get benefit above not treating it.”

“It’s something that, as a breast oncologist, gives me a lot of pause,” said Neil Vasan, MD, PhD, acting chairperson of the ODAC and breast medical oncologist at NYU Langone Health. “I struggle to understand what the ideal trial design would be, because I think there’s a theoretical ideal trial, but that would also introduce challenges that would make [it]…hard to interpret [later on].”

ODAC Meetings Under Makary’s FDA

This convening of the ODAC marks the first of 2026. Since FDA commissioner Marty Makary, MD, MPH, was sworn into office in April 2025, there have been fewer advisory committee meetings per year. In 2024, the ODAC convened 6 times, compared with only twice in 2025.³ While the FDA is not required to vote in concordance with ODAC, it often does.

REFERENCES

1. April 30, 2026 Meeting of the Oncologic Drugs Advisory Committee (ODAC). US FDA. Accessed April 30, 2026. https://tinyurl.com/yk8k3yws

2. 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. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4

3. Oncologic Drugs Advisory Committee. US FDA. Accessed April 30, 2026. https://tinyurl.com/yk8k3yws