Ketoconazole plus dutasteride(Avodart®)

Introduction

Recently, Sartor O et al(1)) presented a paper at the 2007 ASCO Prostate Cancer Symposium on preliminary data from a clinical trial where patients with progression on ketoconazole alone were given ketoconazole plus dutasteride with some benefit in terms of progression delay. We first review some information on dutasteride alone and then more on this paper and its implications for HRPC patients.

Dutasteride (Avodart®)

Dustasteride (Avodart) is a dual 5 alpha-reductase inhibitor(e.g., it inhibits Type 1 and Type 2 5 alpha-reductase) is prescribed for men with symptomatic benign prostatic hyperplasia (enlarging prostate) and it suppresses DHT (dihydrotesterone).

Dutasteride was able to decrease DHT by 91% after a month of treatment. See the paper by Wurzel R et al for more information.  This decrease, was of course, in BPH patients, not HRPC patients who would have had a castrate level of testosterone and with ketoconazole, suppression of adrenal androgen precursors -- hence a much lower starting DHT.

The manufacturer's website is www.avodart.com where more information on its normal use can be located.

Finasteride (Proscar) is also a 5 alpha-reductase inhibitor but inhibits Type 2 5 alpha-reductase only.  See www.proscar.com.

Some oncologists will prescribe triple hormone blockade which consists of an LH-RH agonist such as Lupron or Zoladex or one of several other brands, an antiandrogen of which casodex and flutamide are examples and also a third drug which is one or the other 5-alpha reductase inhibitors.

Here, we are not concerned with the use for BPH or the use in treating hormone sensitive disease, but focus on use in HRPC patients.  A recent paper on dutasteride was presented the the February 2007 ASCO Prostate Cancer Symposium which describes it use as a part of second-line hormone therapy for HRPC patients. 

Why Dutasteride and not Proscar?

There are two papers that Sartor mentions in the abstract which provide the rationale for this approach(2,3).

Titus, MA et al(2) concludes: "Expression levels and isozyme activity shifts from S5RII toward S5RI in recurrent prostate cancer. Dual inhibition of S5RI and S5RII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer."  In other words, since proscar affects type II and dutasteride affects both I and II 5-alpha reductase inhibitors, then dutasteride is the appropriate drug to use in this study.  Stanbrough et al(3) discusses AIPC samples from bone metastases and again finds that the lesions over-express type I, but not type II 5-alpha reductase.

The additional fact stated is that many HRPC cancer cells are hypersensitive to androgens and hence inhibition of 5-alpha reductase enzyes along with ketoconazole might affect progression positively.

The preliminary Clinical Trial Results

Number of patients: 10 (but there is an ongoing prospective multicenter, phase II trial with the goal of 57 patients.) (Ten is a very small sample size.)

Patient status: PSA was progressing after 600-1200mg/day ketoconazole. 70% (7/10) of these patients had documented metastatic disease and had been on ketoconazole for 3.7-24.2 months.  Their PSA ranged from .5 to 80.7 at the time dutasteride was added (median 5.3ng/dl).

Dose of dutasteride ADDED: .5mg orally every day. (note this is the standard dose for this drug -- would .5mg twice a day be better or safe? -- see below on precautions).

Results: Eighty percent (8/10) has some amount of PSA decline, but the declines in PSA were all less than 50%. The PSA decline range was 0 to 39.8% (median 16.5%.)  Progression-free survival ranged from 2.7+ months to 9.8 months (median 4.9 months.)  7 patients progressed by rising PSA and one patient progressed by radiographic evaluation.

NET: Getting an additional length of time out of ketoconazole by adding dutasteride is a real plus given the statement that there was "No significant adverse events were encountered.) It is interesting that there were no radiographic responses seen, but the time interval may not have been long enough for this to be observed. We can hope that the on-going clinical trial will provide additional details. 

Some Questions and a Caution

1) Did they measure DHT before and after starting dutasteride? Would this be a useful piece of knowledge?

2) Did they try higher doses of dutasteride, say .5mg twice a day? Since dutasteride is metabolized by the CYP3A4 enzyme which ketoconazole blocks, the effective dose may well have been higher anyway.  Grapefruit should also be avoided in this case.

Anyone who has already taken dutasteride in combination with ketoconazole (as opposed to adding it after PSA failure) is probably out of luck and they might have extended their time on ketoconazole by having it earlier (this hasn't been tested, however.)

Author: Howard Hansen 3/27/07

References

(1) A. O. Sartor, M. Nakabayashi, M. E. Taplin, R. Ross, P. Kantoff, S. Balk, W. K. Oh, Activity of dustasteride plus ketoconazole in hormone-refractory prostate cancer (HRPC) after progression on ketoconzole alone,  ASCO February 2007 Prostate Cancer Symposium, abstract # 257.

(2) Mark A. Titus, Christopher W. Gregory, O. Harris Ford, III, Michael J. Schell, Susan J. Maygarden and James L. Mohler, Steroid 5-Reductase Isozymes I and II in Recurrent Prostate Cancer, Clinical Cancer Research Vol. 11, 4365-4371, June 15, 2005.

(3) Michael Stanbrough, Glenn J. Bubley Kenneth Ross, Todd R. Golub, Mark A. Rubin, Trevor M. Penning, Phillip G. Febbo and Steven P. Balk, Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer,  Cancer Research 66, 2815-2825, March 1, 2006.

(4) Here's an additional reference on the long term use of dutasteride:

Debruyne F, Barkin J, van Erps P, Reis M, Tammela TL, Roehrborn C, and the ARIA3001, ARIA3002 and ARIB3003 Study Investigators. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia,  Euro Urol. 2004;46:488-495.