In its first meeting in 9 months, the FDA’s Oncologic Drugs Advisory Committee (ODAC) backed a novel regimen for certain patients with prostate cancer but voted against recommending a new treatment approach with an investigational drug for breast cancer.

Both decisions at the April 30 ODAC meeting hinged largely on whether the respective trials demonstrated effects that were not only statistically significant but also clinically meaningful. And they underscored the difficulty of defining “clinically meaningful” for different patient groups.

ODAC members agreed, in a 7-1 vote with one member abstaining, that based on the results of the CAPitello-281 trial, the benefits of capivasertib (Truqap, AstraZeneca) for certain patients with hormone-sensitive prostate cancer outweigh the risks.

There was less agreement on the separate matter of whether the phase 3 SERENA-6 trial demonstrated a clinically meaningful benefit. In that trial, patients with HER2-negative advanced breast cancer switched to the investigational drug camizestrant (AstraZeneca) plus a CDK4/6 inhibitor when an ESR1 mutation was detected, as opposed to the current practice of changing regimens upon disease progression.

The committee voted 6-3 against recommending approval — with the treatment approach of switching at molecular progression playing heavily into the decision.

The FDA, which accepted a supplemental Drug Application and New Drug Application for capivasertib and camizestrant, respectively, in 2025, is not bound by ODAC votes but strongly considers the committee’s recommendations.

Capivasertib and the CAPitello-281 Trial

The phase 3 CAPitello-281 trial compared capivasertib vs placebo in addition to abiraterone and prednisone in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC). PTEN deficiency is a marker of more aggressive disease and poorer treatment response.

Capivasertib is a potent oral inhibitor of all AKT isoforms and currently approved in combination with fulvestrant for advanced hormone receptor-positive breast cancer. In CAPitello-281, the drug improved patients’ median radiographic progression-free survival vs placebo (33.2 vs 25.7 months). Overall survival data were immature at an interim analysis.

FDA staff noted in briefing documents that the benefit for progression-free survival represents a smaller treatment effect compared with prior approvals in this setting. In the absence of a “large improvement,” they said, a statistically significant improvement in overall survival may be needed to support a clinically meaningful treatment effect.

Staff also cited safety concerns, with one FDA representative saying that “the benefit does not appear to outweigh the substantial toxicity.”

However, trial investigator Daniel J. George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, speaking on behalf of AstraZeneca, had a different take.

“This is the first targeted therapy to delay progression in patients with PTEN-deficient mHSPC,” he said, stressing that for such patients, who have limited treatment options, the risk tolerance associated with this treatment “will be an individual decision.”

For many patients, a 7.5-month improvement in progression-free survival may be clinically meaningful, and “worth the risk of side effects that are recognizable, reversible, and treatable,” added George.

Several patient advocates and representatives of advocacy organizations also implored the committee to vote yes. Toni Choueiri, MD, Dana-Farber Cancer Institute in Boston, was among those who ultimately did, noting that CAPitello-281 trial was “a statistically significant trial.”

But Choueiri said, it was a tough decision. And he and other members stressed the need for careful patient monitoring and for limiting treatment to patients with PTEN expression of at least 99%, who derived the most benefit in the trial.

Neil Vasan, MD, PhD, of NYU Langone Health in New York City, expressed confidence that the treatment side effects were manageable. “I think the conversation we had around toxicities was convincing that this is not only something we can manage but also something that will be tailored for a patient with individual conversations,” he said.

Voting no, Brian Rini, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, cited what he called a “relatively marginal benefit” given the toxicity observed – though he, too, said the decision was difficult.

“It was really close, but there is a lot to work out,” Rini said.

Camizestrant and the SERENA-6 Trial

ODAC was less convinced by the treatment approach studied in the SERENA-6 trial. 

Members voiced concerns about the lack of overall survival benefit. But another key issue extended beyond reported outcomes, with some committee members rejecting what they considered a new treatment and trial paradigm.

Among patients in the study who responded to a CDK 4/5 inhibitor and aromatase inhibitor, switching to camizestrant at the time of an ESR1 mutation detection resulted in a 56% reduction in the risk for disease progression or death.

Median progression-free survival improved from 9.2 to 16 months among those who made the switch.

However, FDA staff argued that there is “no internal evidence from SERENA-6 or external evidence to support this early switch strategy.”

Evidence of benefit would require an adequately designed trial demonstrating that the strategy is beneficial compared with switching at radiographic progression, they noted in the briefing documents.

FDA staff also highlighted the potential for camizestrant to cause life-threatening arrhythmias.

Public comments at the ODAC meeting were mixed. Some speakers lauded the new direction proposed by the trial investigators and the potential for more treatment options for patients, while others agreed with FDA staff on the need for stronger evidence.

Choueiri and Vasan were among the yes votes, noting that the prolonged disease control seen in the trial could delay the need for subsequent lines of therapy, including chemotherapy.

Ultimately, though, the prevailing view was one of caution.

Sarah Colonna, MD, of the Huntsman Cancer Institute, University of Utah in Salt Lake City, said the treatment approach would be “a huge change in clinic and practice for a lot of women with no chance of benefit, given the large number of women who have to be tested.”

“I am hopeful that this is the future,” she added. “But my hopes aren’t enough to make me vote for it.”

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X @SW_MedReporter.