FDA Staff Raises Concerns on Two Cancer Drug Applications

 For the first time since last July the FDA's Oncologic Drugs Advisory Committee (ODAC) will meet on Thursday to evaluate two cancer drugs after FDA staff voiced concerns about benefit-risk assessments, despite positive trial results.

In a morning session, ODAC panelists will discuss a new drug application for the investigational oral selective estrogen receptor degrader (SERD) camizestrant in combination with a CDK4/6 inhibitor to treat patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer upon emergence of an ESR1 mutation during first-line endocrine-based therapy.

In the afternoon, the panel will consider an expanded indication for the AKT inhibitor capivasertib (Truqap) in combination with abiraterone (Zytiga) and prednisone for the treatment of patients with metastatic hormone-sensitive prostate cancer (HSPC) with PTEN deficiency.

Camizestrant in Breast Cancer

Results from the phase III SERENA-6 trial showed that for patients responding to a CDK4/6 inhibitor and an aromatase inhibitor, the strategy of dropping the latter in favor of camizestrant after ESR1 mutations were detected on circulating tumor DNA resulted in a 56% reduction in the risk of disease progression or death, meeting the trial's primary endpoint of progression-free survival (PFS).

Median PFS improved from 9.2 months for those who remained on the aromatase inhibitor to 16 months with the switch to camizestrant.

In a briefing document, FDA staff said that while they agreed the trial achieved a statistically significant result for PFS, as well as time to second progression or death (PFS2), they were "uncertain regarding the clinical meaningfulness of the SERENA-6 results because of lack of evidence that switching at ESR1 mutation detection is better than at radiographic progression, the new PFS starting point."

"There is no internal evidence from SERENA-6 or external evidence to support this early switch strategy," they wrote. "To help establish evidence of benefit for the early treatment-switching strategy, an adequately designed trial would demonstrate that switching treatment at ESR1 mutation detection is beneficial compared to switching at radiographic progression."

FDA staff also said they are concerned about the potential for camizestrant to cause life-threatening arrhythmias, particularly when administered with other drugs that have QT interval-prolonging effects and/or that may increase camizestrant exposure.

"To support approval of a new drug for an intended patient population, clinical benefit must be established, and the benefits must outweigh the risks of treatment," they wrote.

The panel will vote on whether the results of SERENA-6 support a positive benefit-risk assessment.

Capivasertib in Prostate Cancer

Capivasertib was first approved in 2023 in combination with fulvestrant for patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations.

The supplemental new drug application for capivasertib is supported by data from the phase III randomized CAPItello-281 trial in patients with PTEN-deficient metastatic HSPC, which compared capivasertib versus placebo added to abiraterone and prednisone.

Capivasertib plus abiraterone improved radiographic PFS versus placebo plus abiraterone (median 33.2 months vs 25.7 months; HR 0.81, 95% CI 0.66-0.98, P=0.034), meeting the trial's primary endpoint.

No statistically significant overall survival (OS) benefit was observed at the interim analysis and OS results were immature, with a hazard ratio of 0.90 (95% CI 0.71-1.15, P=0.401).

In a briefing document, FDA staff noted that there was no evidence for a detriment in OS.

However, the PFS benefit alone "represents a smaller treatment effect in the context of previous approvals in metastatic HSPC," they observed. "In the absence of a large improvement in PFS, a statistically significant improvement in OS may be needed to support a clinically meaningful treatment effect."

In addition, they said the agency is concerned that the toxicity and tolerability of capivasertib is "poor for an add-on therapy in an early metastatic disease context and when considering the magnitude of the treatment effect."

ODAC panelists will be asked to vote on whether the benefit of adding capivasertib to abiraterone and prednisone outweighs the risk for the proposed indication.

https://www.medpagetoday.com/hematologyoncology/breastcancer/121003