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Hormone Refractory Prostate Cancer
Understanding
Treating Maintaining Quality of Life
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Ketoconazole (Nizoral) Summary Table
Introduction
There are 3 different dosing versions of ketoconazole when used as a 2nd line hormone therapy. These are High
Dose Ketoconazole (HDK, 1200mg/day), Intermediate Dose Ketoconazole (IDK,
900mg/day) and Low Dose
Ketoconazole (LDK, 600mg/day). Furthermore, there have been
several phase II clinical trials testing HDK with other drugs to see if
there is an enhanced response rate. Drugs tested in combination
with ketoconazole include leukine (gm-csf), lenalidomide
(Revlimid), alendronate (Fosamax), and
dutasteride (Avodart.) The results of the various trials are summarized in
the table below as well as single agent ketoconazole results for
comparison.
Discussion The table below summarizes 11 different studies of
ketoconazole -- LDK, HDK and HDK+. Reference 11, a meta analysis with
559 patients came up with a summary PSA RR of 43.6% and a MDR 7.8 months
and median survival of 22.1 months. LDK trials reported 46% and 47% PSA
RR. HDK trials reported 27% to 62.5%. The HDK+ trial that looks
the most promising is the HDK/HC plus Leukine study 75% PSA RR. Which
one of the HDK+ combinations is best isn't clear, but adding leukine is
an easy approach that one could take. What isn't answered here? One thing is that these trials were
all in the mode of second line hormone therapy. It would be very
worthwhile to know the PSA RR, etc. when used as a between chemotherapy
treatment. Another area of interest in the combination trials is whether
or not one could have been on ketoconazole, failed it and then added any
of the different drugs to see if there was a new response. This table is not a comprehensive listing of all trials
with ketoconazole, but does contain what seem to be some basic trials
and studies. Updates will be made if other studies come to light. Ketoconazole Clinical Trials No. of Patients PSA Response Rate of
Combination Median Progression Free
Survival of the combination (PFS)
and Median Duration of Response (MDR) PSA declined > 50% in
30/57 (53%), > 80% in 24/57
and > 90% in 14/57. - PSA RR (≥ 50%
decrease) 55% (10/18). 4 of 18 pts (74%)
have experienced some reduction in PSA. - 12 PSA
Only, 37 with metastases. - II, 72 pts.
Randomized to HDK/HC/AL VS HDK/HC HDK/HC
47% - PFS: HDK/HC/AL 4.6 mos.
HDK/HC 3.8 mos.
MDR: HDK/HC/AL 8.9 mos.
HDK/HC 6.3 mos. (f) Small EJ et al, Cancer 1997 (7) (b) 11 of 20 (55%) - Median survival 19
months. AAWD plus HDK, HC: 27%
AAWD Only then HDK, HC: 32% AAWD plus HDK, HC: 20%. AAWD Only, then HDK,HC:7%. MDR PSA AAWD Only 5.9 mos. 33 of 70 (47%) 12 of 34 (35%) Harris KA, et al
(10), J. Urol 2002 (e) 13 of 28 (46%) (95%
confidence interval 27.5% to 66.1%) -
Ketoconazole: 43.6% (95% CI: 33.4-54.4%)
LDK and IDK:
41.9% (95% CI: 25.1-60.8%)
HDK:
45.0 % (95% CI: 30.-60.2%) for high dose. - LDK
± HC --> 55/138 (39.9%) patients HDK+HC 7 of 55 (12.7%)
had 50% PSA decline. For LDK responders, MDR 9.5 months
(range, 2.6–61 months) and in nonresponders, (h) (i) (a) No significant difference in overall survival
between HDK/HC/AL and HDK/HC. However, a trend was seen in the HDK/HC
arm toward improved survival. (b) Grade 1 and 2 nausea and emesis in 15% of patients,
Grade 1 fatigue in 10% of patients, and reversible Grade 1 or 2
hepatotoxicity in 10% of patients. Mild skin toxicity was observed in
20% of patients. (c) Patients who developed
progressive disease after AAWD alone could cross over to ketoconazole.
The authors found that "Adrenal androgen levels fall with treatment with
K and
and then climb at the time of progression, suggesting that progressive
disease
while on K may be due to tachyphylaxis to the adrenolytic properties of
K." No survival difference was seen between different arms. (d) They concluded that LDK effective and well-tolerated
in HRPC and should be considered for pts with low-volume disease and a
rising PSA despite androgen deprivation therapy. (e) Grade 4 toxicity: none; Grade 3 1pt liver and 2pts
depression. Most common nausea in 29% at grade 1 and 2, dry skin of
grade 1 in 18% and fatigue at grade 1 in 14%. 14% discontinued LDK due
to toxicities. 16 pts moved to HDK/HC when LDK failed. None responded to
HDK and 3 of the 16 were removed due to toxicity. (f)
Prostate specific
antigen (PSA) response was defined as greater than a 50% decrease in PSA
from baseline that was maintained for at least 8 weeks. Toxicity: no
grade 3 or 4 events. Grade 1 or 2 events included nausea, fatigue,
edema, hepatotoxicity and rash in 10.4 (5 of 48), 6.25, 6.25, 4.2 and
4.2% of patients, respectively, and anorexia occurred in 2%. Response to
ketoconazole was no different between pts who were non-responders to
AAWD and pts who did respond to AAWD (65% vs 40%, p=.35). (g) There was no significant difference in PSA
response rate between LDK + IDK and HDK groups. 12-month survival rate
was 64.5% (95% CI: 47.1- 78.7%) and 24- month survival rate was 36.2%
(95% CI: 21.5-43.9%). (h) Dose escalation
patients (55 pts) 39.9% MDR on HDK was only 1.7 mos (range .13 mos -
30.4+ mos.) 2.9 months in LDK responders and 1.3 months in those who did
not respond to LDK. The authors also noted that the addition of steriod
replacement therapy was not associated with the response to HDK (LDK, no
HC to HDK with HC). (i) 21 of 34 patients
(61.8%) with established metastatic disease had a PSA RR(≥
50% decrease.) Overall (all pts), the median time to progression
was 5 months (range 0-27 months) and the median survival was 12 months
(range 3-48 months). Toxicity: nausea(13.2%), fatigue (10.6%), diarrhea
(2.6%), visual disturbance (2.6%), and abnormal liver function tests
(2.6%). 6 pts (15.8%) discontinued keto due to intolerable side effects.
It is interesting to note that patients having a PSA > 40ng/ml when
starting IDK had PSA RR (≥ 50%
decrease) of 72% vs those whose PSA was below 40 having a PSA RR of 40%.
The odds of having a response if over 40 was 3.9x greater than the PSA
below 40 group. (1)
Small EJ, et al, "Ketoconazole Retains Activity in
Advanced Prostate Cancer Patients with Progression Despite Flutamide
Withdrawal," The Journal of Urology, Vol. 157, 1204-1207, April 1997. (2) M. Taplin, Y. Ko, M. M. Regan,
T. M. Beer, M. A. Carducci, P. Mathew, G. Bubley, W. K. Oh, P. W.
Kantoff, S. P. Balk, Phase II trial of ketoconazole, hydrocortisone, and
dutasteride (KHAD) for castration resistant prostate cancer (CRPC),
Abstract No: 5068, J Clin Oncol 26: 2008 (May 20 suppl; abstr 5068). (3) J. A. Garcia, P. Triozzi, P. Elson, M. M. Cooney, A.
Tyler, T. Gilligan, R. Dreicer, Clinical activity of ketoconazole and
lenalidomide in castrate progressive prostate carcinoma (CPPCA):
Preliminary results of a phase II trial, Meeting: 2008 ASCO Annual
Meeting, Abstract No: 5143, J Clin Oncol 26: 2008 (May 20 suppl; abstr
5143). Low-dose aspirin was required for DVT
prophylaxis. (4) Charles J.
Ryan, Vivian Weinberg, Jonathan Rosenberg, Lawrence Fong, Amy Lin,
Jennifer Kim, Eric J. Small, Phase II Study of Ketoconazole Plus
Granulocyte-Macrophage Colony-Stimulating Factor for Prostate Cancer:
Effect of Extent of Disease on Outcome, Volume 178, Issue 6, Pages
2372-2377 (December 2007). (5) WD Figg et
al, A Randomized, Phase II Trial of Ketoconazole Plus Alendronate versus
Ketoconazole Alone In Patients With Androgen Independent Prostate Cancer
and Bone Metastases, J. Urology, Volume
173, Issue 3, Pages 790-796 (March 2005). (6)
Small EJ, Baron AD, Fippin L, Apodaca D, Ketoconazole retains activity
in advanced prostate cancer patients with progression despite flutamide
withdrawal, J Urol. 1997 Apr;157(4):1204-7. (8) Small EJ,
Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, (9) C. Coronado,
D. Castellano, L. Garcia Rodriguez, I. Garcia Escobar, I. Diaz-Padilla,
J. Sepulveda, A. Rodriguez Antolin, H. Cortes-Funes, 625P EFFICACY OF
LOW-DOSE KETOCONAZOLE IN HORMONE REFRACTORY PROSTATE CANCER PATIENTS (HRPC).
A (10) Harris KA,
Weinberg V, Bok RA, Kakefuda M, Small EJ, Low dose ketoconazole with
replacement doses of hydrocortisone in patients with progressive
androgen independent prostate cancer, J Urol. 2002 Aug;168(2):542-5. (12) Nakabayashi
M, Xie W, Regan MM, Jackman DM, Kantoff PW, Oh WK,
Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in
patients with androgen-independent prostate cancer, Cancer. 2006 Sep
1;107(5):975-81. Author:
Howard Hansen (12/8/08)
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