The FDA released a briefing document detailing its concerns about AstraZeneca cancer drug distributor and Tolcap ahead of an upcoming advisory committee meeting, its first in nearly nine months.
Regarding AZ’s application for an oral SERD treatment, the FDA asserted that the company’s clinical trial plan does not allow it to determine whether a switch strategy would be beneficial compared to a progression-based treatment approach, where oral SERD is becoming the standard of care (PDF). AZ’s drug is being investigated in combination with a CDK4/6 inhibitor as a switch first-line therapy for patients with HR-positive, HER2-negative breast cancer who develop an ESR1 mutation while receiving endocrine-based therapy.
Regarding Torcap, Arizona is asking the FDA to approve the combination of an AKT inhibitor and Johnson & Johnson’s Zytiga for PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC). Although the Phase 3 trial showed a statistically significant improvement in radiographic progression-free survival (PFS), the FDA suggested that the treatment effect may be too small, according to a briefing document (PDF).
Of the two drugs, Kamizetrand has bigger ambitions, with AZ predicting peak sales of more than $5 billion. After several setbacks, including metastatic castration-resistant prostate cancer, Turcap’s value declined.
The FDA’s questions about Kamiztrant are also more nuanced, although not unexpected.
AZ’s Serena-6 trial showed that switching to camizetrant and a CDK4/6 drug at the onset of an ESR1 mutation improved PFS by 56% compared with continuing combination therapy with a CDK4/6 inhibitor and an aromatase inhibitor.
The FDA noted that the trial design could not answer whether this switching strategy is better than the standard approach of receiving new treatments as the disease progresses. Furthermore, patients in the control arm of the study did not see crossover to Camisetterant at the time of disease progression.
“Switching between treatments too early may prevent patients from taking advantage of the full benefits of each treatment,” FDA staff wrote in a briefing.
AstraZeneca will present updated PFS2 data at the upcoming American Society of Clinical Oncology Annual Meeting. This endpoint, by measuring the time from randomization to progression on subsequent treatment, would have provided some information on whether early use of camimistant is better than waiting for progression.
However, Serena-6’s PFS2 results would not help the AZ claim, even if statistically supported for formal analysis, as no cross-over of cammistant was observed and only about 14% of patients received oral SERD as subsequent therapy. Additionally, as the FDA noted, the agency “generally does not use PFS2 in regulatory decision-making because it does not isolate the effects of experimental drugs.”
As part of its argument, AZ said that ESR1-mutated HR+/HER2- breast cancers become more difficult to treat once they progress on first-line therapy due to the “increased complexity of the tumor genome.”
In second-line therapy, AZ noted that two competing FDA-approved oral SERDs, Menarini Group’s Orceldu and Eli Lilly’s Inluliyo, demonstrated median PFS of only about 3.8 months and 3.9 months, respectively.
However, the FDA argued that these are not fair comparisons to AZ’s Selena-6 because the starting point for PFS calculations is different because AZ begins with detection of an ESR1 mutation rather than first-line radiographic progression.
“Due to the new PFS starting point, the clinical significance of PFS improvements measured from this new starting point is uncertain,” the FDA said.
Given the interpretation of the PFS data in question and PFS2 being “insufficient to demonstrate evidence of clinical benefit,” the FDA further cautioned that Serena-6’s overall survival data remains immature and a final analysis may not be published until around 2028. Given the trial’s lack of sufficient power for OS, “FDA is concerned that Serena-6 may not reach statistical significance with respect to OS,” the agency said.
The FDA also raised the cardiac safety risk of QT prolongation associated with Camistant.
As the study design is at the center of the FDA’s concerns, AZ cited meeting minutes with the FDA dating back to pre-Phase 3 discussions in 2021, saying the FDA was “generally in agreement” with the overall study plan and agreed that the data could support the application.
However, the FDA said it “warned applicants that strategies for switching treatment upon detection of ESR1m prior to radiographic progression require justification.” And while the data supported the application, “whether the results support approval will be determined during review.”
Compared to Camizestrant, the problem with Truqap is much simpler. In the phase 3 CAPItello-281 trial, adding Truqap to Zytiga and prednisone reduced the risk of progression or death by just 19%.
Although the PFS results are statistically significant and there is no evidence of a negative impact on OS, the FDA is nevertheless concerned that the therapeutic effect is too small given previous approvals in mHSPC.
“If there is no significant improvement in rPFS, a statistically significant improvement in OS may be required to support a clinically meaningful treatment effect,” the agency said, adding that this view had already been communicated to AZ at its 2020 Phase 2 termination meeting.
Although this study selected patients with PTEN loss, the majority of participants had no or mild symptoms at baseline, and less than 10% had pain progression during the study.
“Toxicity tolerance in this population is different when compared to patients with more advanced, symptomatic, and/or rapidly progressive disease,” the FDA said.
FDA’s external advisors are expected to convene on April 30 to discuss the two applications.
