What was the committee asked to consider?
On April 30, 2026, the U.S. Food and Drug Administration (FDA) convened the Oncologic Drugs Advisory Committee (ODAC) to consider the benefits and risks of two regimens for treatment of cancer.
The morning session focused on the results of the SERENA-6 trial, which was intended to support a new drug application (NDA) for camizestrant, an oral selective estrogen receptor degrader (SERD), for the treatment of patients with HR+/HER2- metastatic breast cancer. The committee evaluated whether a novel treatment-switching paradigm—where patients receiving an aromatase inhibitor (AI) and CDK4/6 inhibitor switched to camizestrant upon detection of an ESR1 mutation, rather than at radiographic progression—provided adequate evidence of clinically meaningful benefit on camizestrant.
The afternoon session focused on the results of the CAPItello-281 trial, intended to support a supplemental NDA (sNDA) for the addition of capivasertib, a pan-AKT kinase inhibitor, to abiraterone and prednisone. The committee considered whether the trial demonstrated that the benefits outweigh the risks for patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC).
Why does this matter for patients and drug development?
Both sessions highlighted oncology’s shift toward biomarker-driven treatment strategies, including approaches that enable earlier detection of treatment response and therapeutic resistance, as well as biomarker-defined indications. In breast cancer, circulating tumor DNA (ctDNA) testing can detect ESR1 mutations months before disease progression appears on imaging, creating a potential window for intervention before resistance. In prostate cancer, assessing PTEN deficiency can identify patients with aggressive disease who may respond to AKT pathway inhibitors, such as capivasertib. However, the committee’s discussion around the limitations of the SERENA-6 and CAPItello-281 trials highlighted challenges in validating biomarker-driven treatment approaches and defining biomarker subgroups most likely to benefit from targeted therapies. Despite these limitations, committee comments noted the promise of novel treatment-switching approaches. The open public statements and patient-focused considerations raised throughout both the morning and afternoon sessions highlighted how these approaches can provide meaningful patient benefit, in particular for those with no other treatment options. The sessions highlighted how, when validated and implemented reliably, biomarker-driven approaches provide promising tools for accelerating drug development, directing treatment decisions, and ultimately, helping to improve patient outcomes.
What was discussed?
SERENA-6
The SERENA-6 trial met its primary endpoint of progression free survival (PFS), with camizestrant improving PFS by approximately seven months compared to the control arm. Although overall survival (OS) trended favorably, OS data were immature and not statistically significant at the time of analysis. Discussion centered on how to interpret the observed PFS benefit, given that progression was measured from the time of ESR1 mutation detection—a landmark that varied across patients depending on when they were tested, and that does not correspond to any standard clinical benchmark. The FDA and committee members noted that PFS measured from a biomarker event (i.e., ESR1 mutation detection) is a fundamentally different metric than PFS measured from treatment initiation or radiographic progression.
The committee also considered whether SERENA-6 was designed to assess the paradigm-shift in treatment timing, comparing early camizestrant treatment initiation at biomarker detection with later treatment initiation at radiographic progression. Committee members suggested the trial was not designed to distinguish early versus late treatment effects, while also recognizing the challenges of conducting a perfect trial in a rapidly evolving treatment landscape.
Discussion also touched on the increase in cardiac safety events (QTc prolongation and a case of torsades de pointes) due to drug interaction, and the limited data available to assess these toxicities.
CAPItello-281
The CAPItello-281 trial also met its primary endpoint of radiographic PFS (rPFS) and showed that adding capivasertib to abiraterone and prednisone improved rPFS by 7.5 months in patients with PTEN-deficient mHSPC. There was no detriment to OS at the interim analysis; however, the FDA expressed concern that in the absence of large rPFS improvement and considering the toxicity of capivasertib, a statistically significant improvement in OS would be needed to demonstrate a favorable benefit-risk profile. The committee considered the clinical meaningfulness of the observed rPFS improvement, the biomarker definition (i.e., PTEN deficiency defined as ≥90% loss by immunohistochemistry [IHC]), and high rate of treatment-related hyperglycemia, including a fatal case of diabetic ketoacidosis (DKA).
When considering rPFS benefit, the FDA noted that no prior prostate cancer drug has been approved as an add-on therapy at this magnitude of treatment effect. The agency encouraged the committee to consider whether the rPFS improvement justified adding capivasertib to an already-active hormonal therapy, given the associated toxicities and tolerability concerns. The sponsor and clinical perspectives highlighted how close monitoring, including more frequent glucose checks, hemoglobin A1c monitoring, and urinalysis for ketones, could reduce the risk of fatal DKA and the need for long-term insulin after treatment discontinuation.
The patient representative encouraged the FDA to reconsider how it defines “clinically meaningful” benefit, emphasizing that while six to seven months of disease control—while modest on a clinical trial report—can be highly meaningful for patients with aggressive metastatic cancer.
Much of the committee discussion revolved around the biomarker definition and potential need to further refine the companion diagnostic test. Exploratory subgroup analyses suggested stronger PFS and OS in patients with 99-100% PTEN loss than in patients with 90-98% loss (approximately 60% of the enrolled patient population). Although these analyses were hypothesis-generating, one voting member urged the FDA to consider restricting any approval to the 99-100% PTEN loss patient population (approximately 40% of enrolled patients), where the benefit signal was clearest.
What are the outcomes and implications of the meeting?
The committee voted 6-3 that the SERENA-6 trial did not demonstrate clinically meaningful benefit for camizestrant treatment. Those in favor cited the magnitude of PFS improvement, the favorable early OS trend, and plausibility of the early treatment switching approach. Those opposed pointed to the trial’s inability to determine whether earlier treatment switching improves patient outcomes, particularly in the absence of a statistically significant OS benefit or a crossover design to isolate treatment timing. Thus, the committee concluded that, although camizestrant appears active, the trial design could note establish whether the observed PFS gain represents a real, clinically meaningful benefit from the earlier treatment switching.
For the afternoon session, the committee voted (7-1, 1 abstain) that the benefits of adding capivasertib to abiraterone and prednisone treatment outweighed the risks for the proposed indication. Members voting “yes” cited the unmet need in PTEN-deficient aggressive disease, manageable toxicity with appropriate monitoring infrastructure, the importance of patient choice, and the biological plausibility reinforced by the biomarker dose-response signal. The “no” voter cited marginal magnitude of benefit relative to the toxicity burden and duration. The abstaining member expressed confidence in the efficacy signal but concern about real-world toxicity management in non-academic center care settings where coordinated, interdisciplinary care may be more difficult.
The discussions emphasized the need for carefully designed trials and validated biomarker-defined treatment strategies, and to consider what is important to patients when interpreting whether PFS, early OS, and safety demonstrate “clinically meaningful benefit.” These discussions can inform future biomarker-driven trial design and biomarker validation efforts.
Friends has several upcoming meetings on topics discussed during the ODAC. These include a Virtual Hill Briefing on Strengthening FDA’s Biomarker Qualification Program, focused on strengthening regulatory pathways for biomarker development, qualification, and broader adoption of biomarkers and novel endpoints.
A webinar on Interpreting Interim Overall Survival (OS) for Decision-Making will explore challenges interpreting interim OS results, assessing potential treatment-related harm, and simulation-informed frameworks to support these evaluations.