Is the FDA softening their stance on approving drugs using progression radiographic progression-free survival (rPFS) (how long it takes for the disease to progress based on scans) as opposed to only survival? The answer is maybe, under certain circumstances.

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

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

The FDA’s approval was based on the results of the clinical trial (COU-AA-302). It looked at men with asymptomatic or mildly symptomatic, chemotherapy-naïve mCRPC who were randomized to treatment with either abiraterone acetate + prednisone (N = 546) or placebo + prednisone (N = 542). The trial was structured to have two endpoints; radiographic progression-free survival (rPFS) and overall survival (OS).

The trial showed that the median time to rPFS was 8.3 months in the placebo arm and the median time had not yet been reached in the investigational arm at the time the study was stopped by the independent trial monitoring committee

Analysis showed that the pre-specified improvement in OS favoring the abiraterone acetate + prednisone arm compared to the placebo + prednisone arm of the trial (HR = 0.79), did not meet the pre-specified criterion for statistical significance, or there was not adequate evidence of survival, the normally gold standard for the FDA.
Despite the failure of the investigational drug to provide statistically significant OS it was still approved! Does this mean that the FDA will now approve investigational treatments without an improvement in OS? The answer is no, but with certain circumstances maybe. The authors said that the FDA’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 patient reported pain data’.

What we can take away is that for the FDA OS remains important, the best driver for approval. However, if there is a strong indication that OS is approved by looking at prior trials and with other important factors like pain being factored it is possible to obtain FDA approval. This is a small step, but a giant leap forward for us.

Once the pre-chemo data for Xtandi is released, if it shows OS along with rPFS or palliation of pain  it can be arguably considered a superior drug!

Joel T Nowak, M.A., M.S.W.