The FDA has released briefing documents detailing its concerns for AstraZeneca’s cancer drugs camizestrant and Truqap ahead of an upcoming advisory committee meeting, the first such gathering in about nine months.
For AZ’s application for its oral SERD camizestrant, the FDA argued (PDF) that the company’s trial design cannot discern whether the switching strategy is beneficial compared with a treat-upon-progression approach, where oral SERDs are becoming standards of care. AZ’s med is under review in combination with a CDK4/6 inhibitor as a switch first-line therapy among patients with HR-positive, HER2-negative breast cancer who’ve developed ESR1 mutations while receiving endocrine-based therapy.
As for Truqap, AZ is asking the FDA to approve the AKT inhibitor in combination with Jonson & Johnson’s Zytiga in metastatic hormone-sensitive prostate cancer (mHSPC) that is PTEN-deficient. While a phase 3 trial showed a statistically significant improvement in radiographic progression-free survival (PFS), the FDA suggested the treatment effect may be too small, according to a briefing document (PDF).
Between the two meds, camizestrant bears bigger ambitions, with AZ projecting peak sales of over $5 billion. Truqap’s value has diminished after several setbacks, including in metastatic castration-resistant prostate cancer.
The FDA’s issues with camizestrant are also more nuanced, although not unexpected.
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AZ’s Serena-6 trial showed that, compared with remaining on a combination of a CDK4/6 inhibitor and an aromatase inhibitor, switching to camizestrant and the CDK4/6 drug upon emergence of ESR1 mutations led to a 56% improvement in PFS.
The trial design could not answer whether this switch strategy is better compared to the standard approach of receiving new therapy upon disease progression, the FDA noted. Besides, no crossover to camizestrant was allowed at disease progression for patients in the study’s control arm.
“By switching therapy early, patients may not be maximizing the benefit of each line of treatment,” FDA staffers wrote in the briefing document.
AstraZeneca will present updated PFS2 data at the upcoming American Society of Clinical Oncology annual meeting. This endpoint, by measuring time from randomization to progression on a subsequent-line treatment, would have offered some information on whether earlier use of camizestrant is better than waiting for progression.
However, with no camizestrant crossover allowed and only about 14% of patients having received an oral SERD as their subsequent therapy, Serena-6’s PFS2 result would not help AZ make its case, even though it’s statistically powered for formal analysis. Further, as the FDA noted, the agency “does not typically use PFS2 for regulatory decision-making as it does not isolate the effect of the experimental drug.”
As part of its argument, AZ said that ESR1-mutated HR+/HER2- breast cancer becomes difficult to treat after progression on first-line therapy as “tumor genomic complexity increases.”
In second-line treatment, AZ noted that two rival FDA-approved oral SERDs, Menarini Group’s Orserdu and Eli Lilly’s Inluriyo, only showed about 3.8 months and 3.9 months of median PFS, respectively.
But the FDA argued that these are not fair comparisons to AZ’s Serena-6 because the starting points for PFS calculation are different, as AZ’s begins with ESR1 mutation detection rather than at radiographic progression on first-line treatment.
“Because of the new PFS starting point, the clinical meaningfulness of a PFS improvement measured from this new starting point is uncertain,” the FDA said.
With interpretation of the PFS data in question and PFS2 “inadequate to show evidence of clinical benefit,” the FDA further flagged that Serena-6’s overall survival data remain immature and may not read out its final analysis until about 2028. Given the trial is not adequately powered for OS, “FDA is concerned that Serena-6 may not reach statistical significance for OS,” the agency said.
The FDA also raised a heart safety risk of QT prolongation associated with camizestrant.
As trial design is central to the FDA’s concern, AZ cited meeting minutes with the agency dating back to pre-phase 3 discussions in 2021, saying that the agency “generally agreed with” the overall study plan and concurred that the data may support a filing.
The FDA, however, said it “cautioned the Applicant that the strategy of switching treatment at detection of ESR1m prior to radiographic progression would need justification.” And while the data supported a filing, “whether the results supported approval would be determined during the review.”
In comparison to camizestrant, the issue with Truqap is much simpler. In the phase 3 CAPItello-281 trial, Truqap only lowered the risk of progression or death by 19% when added to Zytiga and prednisone.
While the PFS result is statistically significant and there’s no evidence for detriment in OS, the FDA is concerned that the treatment effect is nevertheless too small in the context of previous approvals in mHSPC.
“In the absence of a large improvement in rPFS, a statistically significant improvement in OS may be needed to support a clinically meaningful treatment effect,” the agency said, adding later that this position had already been communicated to AZ at the end-of-phase 2 meeting in 2020.
Although the trial selected patients with PTEN loss, the majority of participants had no or mild symptoms at baseline and less than 10% had progression of pain while on trial.
“The toxicity tolerance for this population is different compared to patients with more advanced, symptomatic, and/or rapidly progressive disease,” the FDA said.
External advisors to the FDA will convene April 30 to discuss the two applications.
