Baseline serum androgen levels key to clinical responses to ...

A retrospective evaluation of data from the multinational Phase III clinical trial of abiraterone has suggested that a subset of the patients in the trial? had significantly better clinical responses than others.

Ryan et al. have re-analyzed the responses of all patients in both arms of the Phase III trial while categorizing the patients on the basis of their baseline levels of androgens in serum. Their data suggest that the men with higher levels of serum androgens at baseline ? and most particularly higher levels of adrenal androgens ? were more responsive to therapy, regardless of whether they received abiraterone acetate + prednisone or whether they received a placebo + prednisone. For more details see the abstract of the presentation by Ryan et al. and the media release issued by the American Association for Cancer Research

Remember that this trial (COU-AA-301) was limited to men who had metastatic, castration-resistant prostate cancer (mCRPC) and had already received at least one cycle of docetaxel-based chemotherapy. Ryan and his colleagues determined the baseline serum levels of testosterone (T), androstenedione (A4), and dehydroepiandrostenedione (DHEA) in all men at the time they were entered into the trial.

They stratified the patients according to their ECOG performance score (0-1 vs 2), their pain levels (pain 4-10 [present] vs pain 0-3 [absent]), whether they had been given one or two previous chemotherapy regimens, and their progression type (PSA only vs radiographic). They then categorized the patients into two groups:

• A higher than median hormone level group (HH) and
• A lower than median hormone level group (LH)

The results of their analysis then showed the following basic results:

• In men treated with abiraterone acetate + prednisone, overall survival times were about twice as long among men in the HH group as they were among men in the LH group.
• In men treated with placebo + prednisone, overall survival times were nearly 50 percent longer in men in the HH group than they were among men in the LH group.
• Men receiving abiraterone + prednisone as opposed to placebo + prednisone had longer survival regardless of their baseline serum androgen levels.

What does this analysis suggest? Well, it appears to suggest a number of things:

• That predisone itself has a significant clinical effect on men with mCRPC who have higher levels of serum androgens (which confirms earlier information)
• That men with mCRPC and lower levels of serum androgens are less likely to get good responses to prednisone alone or to abiraterone acetate + prednisone than men with higher levels of serum androgens
• That baseline levels of serum androgens may be a prognostic and predictive marker for response to abiraterone acetate + prednisone (or indeed to prednisone alone)
• That in future clinical trials, baseline levels of serum androgens may be a key factor in determining who is an appropriate candidate for trial entry for certain types of drug

Clearly there is a good deal more work to be done before we know how to apply this new knowledge in clinical practice. It is not an entirely surprising result, because ? if you think about it ? a drug that is intended to block the effects of peripheral androgens like T4 and DHEA is likely to work better if levels of these particular androgens are high.

It will be interesting to see if a similar analysis of data from the completed trial of enzalutamide (MDV3100) vs. a placebo can also demonstrate similar effects. The data reported here does tell us that a significant component of the overall response to abiraterone acetate + prednisone is actually being contributed by prednisone alone in the men in the HH group.

What this trial does also do, however, is clearly show us just how important it really is to be monitoring the levels of serum androgens during the course of hormonal therapy. It has long been known that men with lower levels of serum T (i.e., < 20 ng/dl) tend to do better than men with higher serum T levels (e.g., 20-50 ng/dl) while on standard forms of androgen deprivation therapy (ADT) with an LHRH agonist ? an antiandrogen like flutamide or bicalutamide. (Men who have serum T levels > 50 ng/dl while on therapy are not considered to be effective responders to standard forms of ADT.) It may well be that, by carefully monitoring serum T levels and serum levels of T4 and DHEA as well as PSA, we can become much better at appreciating when it is appropriate to take aggressive action with drugs like abiraterone acetate, enzalutamide, and others in the development pipeline.

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Filed under: Drugs in development, Management, Treatment

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