ODAC meeting Part 1: FDA’s advisors unconvinced of ctDNA strategy for metastatic breast cancer

The FDA’s Oncologic Drugs Advisory Committee voted 6-3 against the demonstrated benefit of AstraZeneca’s camizestrant, proposed to extend the duration of first-line therapy for a subset of metastatic breast cancer patients. The trial leveraged circulating tumor DNA technology to identify an emerging, resistance-associated mutation and trigger a treatment change – a paradigm shift that the committee found unsupported by the data.

By Amanda Conti | May 5, 2026 4:39 PM EDT

Background: ctDNA for oncology development

• Circulating tumor DNA, or ctDNA, is fragmented genetic material of cancer cells found in the bloodstream, as explained by the National Cancer Institute. As dying cancer cells degrade, their cell contents are released into the patient’s circulation. This allows fragments of DNA that are unique to the cancer to be detected. A major advantage is that the blood-draw technique is less invasive than conventional biopsies.
• The technology has applications in both diagnostic and development spaces. ctDNA can be measured as a biomarker to detect and predict the presence and stage of some cancers. The technique can also provide information about tumor genetics, helping to select directed therapies. In product development, ctDNA is being assessed as a tool to understand therapeutic effectiveness based on the amount and makeup of tumor DNA found in the blood before, during or following treatment.
• ctDNA approaches have been explored in blood and solid tumor trials. Much of the work to bring the technology from research to clinical development has been led by Friends of Cancer Research’s multi-stakeholder initiative called ctDNA for Monitoring Treatment Response, or ctMoniTR. For certain hematological malignancies such as multiple myeloma, stakeholders have leveraged minimal residual disease measured by ctDNA. On the solid tumor side, the FDA finalized guidance in November 2024 for sponsors of “curative-intent” treatments that intend to use ctDNA for patient selection or enrichment, or to measure response. The guidance made it clear that FDA was not ready to recognize ctDNA itself as a validated surrogate endpoint. The scope of this document excluded advanced and metastatic indications. [Read full AgencyIQ analysis here.]
• During the morning session of the April 30, 2026, meeting of the FDA’s Oncologic Drugs Advisory Committee, the advisors considered an application that relied on a trial design with a ctDNA component. AstraZeneca’s investigational drug camizestrant is proposed for use “in combination with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer upon emergence of ESR1 mutation during first-line endocrine-based therapy, based on an FDA approved test.”
• The application relies on the Phase 3 SERENA-6 trial (NCT04964934), which employed a novel design. “In our trial, we performed ctDNA monitoring to identify a drug-induced acquired resistance mutation before the detection of clinical progression, a finding that we then used as a basis for a change in therapy,” study investigators summarized.

The meeting explored the results of a study design that represented uncharted territory

• AstraZeneca’s Global Clinical Strategy Head INGRID MAYER described the unmet need in this metastatic population, saying, “For the vast majority of patients with advanced hormone receptor-positive, HER2-negative breast cancer, first-line treatment with an aromatase inhibitor and the CDK4/6 inhibitor extend survival with great tolerability. However, disease progression is inevitable and ultimately leads to a more aggressive phenotype.” This progression can be driven by mutations in the estrogen receptor gene, or ESR1, which “drive tumor growth independent of estrogen, rendering aromatase inhibitors ineffective in those clones.”
• The sponsor built a scientific case for the treatment paradigm employed in SERENA-6. According to Mayer, camizestrant is “a complete estrogen receptor antagonist” with activity against wild type and mutant ESR1. She added, “This pioneering biomarker-guided approach aims to maximize camizestrant benefit when endocrine dependency is greatest.” CYNTHIA HUANG-BARTLETT, global clinical head for camizestrant, said, “This novel design, replacing the failing aromatase inhibitor by maintaining the CDK4/6 inhibitor, aimed to extend the duration of well-tolerated first-line therapy and preserve quality of life.” Emory University oncologist KEVIN KALINSKY described a clinical role for the approach, saying, it “maximizes time on well-tolerated therapy and delays the need for chemotherapy or antibody drug conjugates,” and “encourages active patient engagement and shared decision-making with individualized care.”
• The FDA, on the other hand, raised concerns with the absence of hard data supporting this scientific rationale. “SERENA-6 was not designed to assess the benefit of the experimental strategy of switching to camizestrant after detecting an ESR1 mutation rather than switching at radiographic progression. There’s also no other prospective trial to support the investigative switch strategy,” said clinical reviewer JOSHUA DONALDSON. In other words, “Since the trial did not randomize patients to switching at biomarker detection versus radiographic progression, we cannot assess whether the experimental strategy provided a clinical benefit compared to standard of care,” he said. Further, the FDA flagged that patients on the control arm were able to unblind their treatment assignment after radiographic progression.
• The meeting offered a window into the regulatory interactions that led to the meeting. AstraZeneca’s Mayer said, “In 2021 we aligned with the FDA on the SERENA-6 study design and primary endpoint.” The FDA on the other hand, maintained that it “asked the applicant in preliminary comments to a meeting request to justify the biomarker surveillance and therapy switch strategy,” Donaldson said. “At a minimum, the FDA asked that patients be consented that they may be foregoing a therapy for which they were benefiting by switching before radiographic progression.”
• Mayer concluded the sponsor presentation by saying, “I ask you to consider that a push toward personalized medicine requires rethinking practice. We recognize that SERENA-6’s innovative design challenges current norms, but what gives us confidence in this approach is the consistent benefit across primary, secondary and exploratory endpoints.”
• Digging into the clinical trial results, the sponsor and FDA agreed that the study met its primary endpoint of investigator-assessed progression-free survival, measured as the period from randomization after ESR1 detection by ctDNA until progression assessed by Response Evaluation Criteria in Solid Tumors, or RECIST, criteria. The FDA calculated a hazard ratio of 0.44 (95% confidence interval: 0.31, 0.60; p < .00001) and estimated median PFS of 16.0 vs. 9.2 months, representing a statistically significant improvement in the group that switched to camizestrant. Donaldson provided the FDA’s perspective, saying, “The clinical meaningfulness of a given PFS improvement is uncertain because randomization starts at ESR1 mutation detection. For most oncology trials, randomization is at metastatic diagnosis for radiographic progressive disease – time points when a new therapy is clearly needed.” This was coupled with statistically significant improvement in the secondary endpoint of PFS2 at the latest data cutoff, though the FDA flagged multiple limitations for its regulatory use.
• The data on secondary endpoint overall survival were immature at the time of data cutoff. According to AstraZeneca’s Huang-Bartlett, “While the study was not adequately powered for assessing overall survival for statistical significance, it is sufficiently sized to assess no detrimental effect.” From the FDA’s standpoint, statistically significant OS findings “could overcome our uncertainties in the new switch strategy as to whether it demonstrates long-term benefit,” Donaldson said. In practice, demonstrating improved OS in this metastatic population could be challenging to parse because patients may receive multiple subsequent therapies.
• The FDA, sponsor and panel considered the safety findings of SERENA-6, which included signals for bradycardia and QTc interval prolongation. AstraZeneca’s ANDREW WALDING said the tolerability is supported by a “very low discontinuation rate” and few dose reductions. He said that a higher rate of Grade 3 or higher adverse events in the camizestrant arm was driven by the increased duration of exposure in that group, which also had a longer duration of exposure to the CDK4/6 inhibitors. According to the FDA’s Donaldson, these signals complicate risk-benefit evaluation in “the setting of an uncertain clinical benefit.”

The discussion and the vote

• ODAC members sought additional detail on numerous aspects of the SERENA-6 trial, including more details on specific safety findings and the technical and practical aspects of the ctDNA assays. Prior the vote, committee chair and NYU breast oncologist NEIL VASAN summarized, “We’ve had a lot of discussions on what this trial would look like in an ideal world, and tensions between the sort of academic answering the question versus what would be best for our patients and what subsequent lines of therapy would be best for our patients.”
• The voting question: “Based on the results of SERENA-6, has clinically meaningful benefit for camizestrant been demonstrated for the treatment of patients with HR+/HER2- metastatic breast cancer with a tumor ESR1 mutation detected while on aromatase inhibitor and CDK4/6 inhibitor treatment, prior to radiographic progression?”
• The committee voted 6-3 against the SERENA-6 trial showing a clinically meaningful benefit. University of Utah cancer geneticist SARAH COLONNA challenged the scientific justification of the paradigm, saying, “I don’t think that we know detection of a mutation should serve as our gold standard marker for progression at this point.” The National Cancer Institute’s STAN LIPKOWITZ added, “I agree that the bar should be high here because it’s changing fundamentally the way we do business.”
• Multiple “no” voters explained that their thinking would change if an OS benefit was observed. Mayo Clinic biostatistician KARLA BALLMAN raised concerns with the PFS findings alone, saying, “It’s a different definition of PFS. It’s PFS from a biomarker change, not PFS from our standard sort of benchmarks, and so I don’t know how to interpret that.” She continued, “I’m hesitant to endorse something just because it’s exciting.”
• On the other hand, Vasan voted yes, citing the statistically significant PFS results and “directionally favorable” OS findings. “The FDA is correct that this trial does not define an optimal sequence, but the field itself has not defined one. In ER-positive metastatic breast cancer, second-line therapy is not a single standard, it’s a plurality of options shaped by biomarkers, toxicities, access, timing,” he said. Vasan added: “A perfect trial, defined in retrospect, would likely have required mandating therapies that were either unavailable at the time or are now outdated. And that is the fundamental tension. A design that maximizes interpretability might sacrifice relevance.” Northwestern University breast oncologist BILL GRADISHAR also voted in favor of the clinical meaningfulness in the real-world setting, saying, “I think that the sentiment of keeping a patient on a particular kind of therapy for an extended period of time with metastatic disease is ultimately the goal we have for all our patients with metastatic breast cancer, particularly those with ER-positive disease, before we have to pivot to something that’s more toxic.”

Analysis

• For AstraZeneca’s camizestrant application, the ODAC’s negative vote may not bode well. A company press release following the meeting stated, “The FDA is not bound by the Committee’s guidance but takes its advice into consideration. AstraZeneca will continue to work with the FDA as it completes its review of the application.” The release also states, “Regulatory applications for camizestrant in this setting are also under review in the EU, Japan and several other countries.”
• During the discussion portion of the meeting, Chair Vasan asked the FDA about its plans for policy development in this area: “The FDA has really clear guidance on MRD testing in the early stage cancers and a white paper on this. Is there discussion in the future about making a similar guidance for ctDNA in the metastatic setting? I mean, every trial is collecting blood, and you know, we don’t really know as a field what to be doing with all these data.”
• The Oncology Center of Excellence’s R. ANGELO DE CLARO responded that the issue is on the agency’s radar. “Yes, certainly we are very aware of the advancement of field in regards to ctDNA testing, and we certainly look forward to working with several members of academia, with the industry and professional societies, of how we integrate these testing to our diagnostic and treatment paradigms.” He got more granular, “So, yes, we are in a process of looking to possibly issue disease-specific guidances or broader guidance. But that’s all a work in progress.” AgencyIQ notes that OCE released a guidance agenda for calendar year 2025 but has yet to do so for 2026. That said, de Claro’s profile webpage was recently updated to shift his title from acting to official director of OCE, which could pave the way for more action.
• In many ways, this ODAC session appeared to represent “business as usual” for one of the agency’s most prominent advisory committees. The committee assessed regulatory and scientific implications of a unique trial design, balancing positive results and limitations in interpretability. The FDA has historically used ODAC meetings as a mechanism for transparency into its thinking on these issues, but the relative importance of the FDA’s advisory committee system has waned under Commissioner MARTIN MAKARY’s leadership. One of his initial actions as commissioner was to institute a new conflict-of-interest policy for the panels that “limits individuals employed at companies regulated by the U.S. Food and Drug Administration, such as pharmaceutical companies, from serving as official members on FDA advisory committees, where statutorily allowed.” In the meantime, multiple ODAC meetings, including the April 30 meeting, have still included active participation from industry representatives.
• What’s next? At the time of writing, the FDA had not scheduled any additional ODAC meetings this year. In 2025, the committee convened in May and July, potentially indicating that another meeting could be in the works for this summer.
• Look for Part 2 of our coverage of the April 30 ODAC meeting soon. In the afternoon session, the committee considered AstraZeneca’s Truqap (capivasertib) tablets, with a proposed indication in combination with abiraterone for the treatment of adult patients with metastatic hormone-sensitive prostate cancer that is PTEN-deficient as detected by an FDA-approved test.

To contact the author of this item, please email Amanda Conti ( aconti@agencyiq.com).
To contact the editor of this item, please email Jason Wermers ( jwermers@agencyiq.com).

Key documents and dates

• April 30, 2026: Meeting of the Oncologic Drugs Advisory Committee
• FDA Docket No.: FDA-2026-N-1867 (comments closed April 29, 2026)