Abiraterone acetate + dutasteride in treatment of mCRPC


Does adding dutasteride (Avodart) to abiraterone acetate (Zytiga) make any difference in the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC)? There is no clear answer to this question from a small, Phase II, pilot study, the results of which have just been published in Clinical Cancer Research.

Taplin et al. report data from a cohort of just 40 patients enrolled in this pilot study. And to be fair to all concerned, the study was never designed or intended to show whether adding dutasteride to abiraterone acetate would be “better” for the treatment of mCRPC.

The study was a simple one. Patients were initially treated with abiraterone acetate + prednisone for 2 months. They were then treated with abiraterone + prednisone + dutasteride (at 3.5 mg/d) in 28-day cycles until either symptomatic or radiographic progression (or both together). The sole, necessary inclusion criteria were that the patients must have mCRPC with normal organ and bone marrow function.

Here are the study findings:

  • 24/40 patients (60 percent) had a reduction in their PSA level ≥ 50 percent.
  • The average (median) time to radiographic progression was 11 months.
  • 29/30 men tested (97 percent) were positive for nuclear expression of the androgen receptor at baseline.
  • 16/16 men tested (100 percent) were positive for nuclear expression of the androgen receptor post-treatment.
  • 10/21 men tested (48 percent) were positive for expression of the ARV7 gene at baseline
  • 5/12 men tested (42 percent) were positive for expression of the ARV7 gene in post-treatment tumor specimens.
  • Compared to patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens.

The authors are very clear that, “The non-comparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride”, but they also conclude that:

  • “Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression.”
  • “We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance.”

 

6 Responses

  1. For the less knowledgeable among us, can someone interpret what this might mean for the benefits of dutasteride?

  2. Dear Fred:

    Frankly, at present, there is no good evidence that adding dutasteride to abiraterone acetate has any real clinical benefit. To discover that we would need data from at least a small, randomized, double-blind trial that compared treatment with abiraterone acetate + prednisone + dutasteride to treatment with abiraterone acetate + prednisone + a placebo (a sugar pill). I can’t even tell you whether anyone would be willing to provide funding for such a trial.

  3. Dear Sitemaster,

    I have two observations that need clarification, if possible. The first is that they used a dose of 3.5 mg of dutasteride when 0.5 mg is the normal dose. The second is that while “10/21 men tested (48 percent) were positive for expression of the ARV7 gene at baseline,” only “5/12 men tested (42 percent) were positive for expression of the ARV7 gene in post-treatment tumor specimens.” It seems counter-intuitive that a lower percentage of men would be positive for ARV7 expression after treatment with abiraterone, since this drug is known to “select” for higher percentages of ARV7 after treatment. Thank you.

  4. Dear Len:

    I suspect that the only people who could give sensible answers to those two issues are the researchers who did the study.

    You could try e-mailing Dr. Taplin and asking her nicely if she would be kind enough to send you a PDF copy of the full text of the paper. That might give you additional insight. Alternatively, you could scroll to the bottom of the abstract on this page and use the AACR patient access system, through which you could get a copy for about $3.50.

  5. What an unhelpful abstract! Hard to find any useful information in it. My thought is that if they are looking for “more complete androgen synthesis inhibition” they should be adding Lupron, not dutasteride, to the abiraterone therapy. It seems to me that some of these men are progressing simply because their dosage of abiraterone was not enough to give good testosterone control.

  6. Dear Tom:

    I think you may be misunderstanding this study. The men in this study all had mCRPC. There is a 99.9% probability that they were all progressing on an LHRH agonist already (and had probably also progressed again after the addition of an antiandrogen and subsequent androgen withdrawal). So when they became castration-resistant, they were then being started, in addition to the LHRH agonist, on a standard dose of abiraterone acetate (at 1000 mg/dy) + prednisone (5 mg/d) for 2 months, which was then followed by treatment with abiraterone acetate (1000 mg/d)+ prednisone (5 mg/d) + dutasteride (3.5 mg/d) in 28-day cycles until symptomatic or radiographic progression. That is a very high dose of dutasteride.

    In other words, this was almost certainly an experimental pilot study of an LHRH agonist + abiraterone acetate + prednisone + high-dose dutasteride as an initial treatment for mCRPC.

    If they were not going to be on an LHRH agonist, the trial protocol would clearly have excluded anyone who was taking an LHRH agonist — and it doesn’t say that.

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