The FDA’s “take” on pre-chemo approval of abiraterone in mCRPC


A new article in Clinical Cancer Research offers us insights into the US Food and Drug Administration’s thinking about the approval of abiraterone acetate for the treatment of chemotherapy-naive patients with metastatic, castration-resistant prostate cancer (mCRPC).

The article by Kleutz et al., tellingly entitled “Abiraterone shows radiographic improvement in PFS for metastatic castration-resistant prostate cancer; survival benefit uncertain,” looks at factors affecting the FDA’s decision to approve abiraterone acetate + prednisone for the treatment of men with chemotherapy-naive mCRPC in December 2012.

Here is a summary of some of the key points made by FDA staff in the new article:

  • The approval was based on data from a clinical trial (COU-AA-302), in which patients with asymptomatic or mildly symptomatic, chemotherapy-naïve mCRPC were randomized to treatment with either abiraterone acetate + prednisone (N = 546) or placebo + prednisone (N = 542).
  • The two co-primary trial endpoints were radiographic progression-free survival (rPFS) and overall survival (OS).
  • The median time to rPFS was 8.3 months in the placebo arm and had not yet been reached in the abiraterone acetate arm at the time the study was stopped by the independent trial monitoring committee (hazard ratio [HR] = 0.43)
  • Although the pre-specified interim analysis showed an improvement in OS favoring the abiraterone acetate  + prednisone arm compared to the placebo + prednisone arm of the trial (HR = 0.79), this improvement in OS did not meet the pre-specified criterion for statistical significance.
  • Analysis of safety data was in line with the established adverse reaction profile of abiraterone acetate + prednisone.

The paper’s authors explain the agency’s decision to approve abiraterone + prednisone for treatment of men with chemotherapy-naive mCRPC as follows:

Full approval was granted on the basis of a large magnitude of effect on rPFS, a favorable trend in OS, and internal consistency across multiple secondary endpoints and exploratory patient-reported pain data.

However, they go on to make the following additional points:

  • That abiraterone acetate is the first drug to be approved for treatment of mCRPC on the basis of rPFS as the primary endpoint.
  • That this approval needs to be seen “in the context of a prior statistically significant OS benefit” that formed the basis of the approval (back in April 2011) of abiraterone acetate for patients with mCRPC who had received prior docetaxel-based chemotherapy.

There is a clear message here from the FDA for the future … that a statistically significant improvement in rPFS should not necessarily be considered as a sufficiently significant finding, on its own, to lead to approval of new drugs in the treatment of metastatic prostate cancer. The rationale behind the publication of this paper appears to us the be a very clear attempt on the part of the FDA to “manage expectations” (of drug developers, the investor community, and clinical trial specialists)

One Response

  1. And Thank You, FDA, for the approval. Zytiga/abiraterone acetate has been effective for me for 27 months and still counting.

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