oozzs347/s7/1574-1204$03.00/0
`THE JOURNAL OF UROLOOY
`Copyright @ 1997 by AMERICAN UmmlcAL ASSOCIATION, h c
`
`Vol. 157, 1204-1207, April 1997
`Printed in U . S . 4
`
`Original Articles
`
`KETOCONAZOLE RETAINS ACTIVITY IN ADVANCED PROSTATE
`CANCER PATIENTS WITH PROGRESSION DESPITE FLUTAMIDE
`WITHDRAWAL
`ERIC J. SMALL,* ARI D. BARON, LINDA FIPPIN AND DAN APODACA
`From the Departments of Medicine, Urology and Nursing, and Urologic Oncology Progmm, University of California, San Francisco
`Cancer Center, San Francisco, California
`
`ABSTRACT
`Purpose: We tested the hypothesis that certain patients with hormone refractory prostate
`cancer retain hormonal sensitivity even after progression following antiandrogen withdrawal.
`The efficacy of ketoconazole and hydrocortisone in this patient population was evaluated.
`Materials and Methods: A total of 50 consecutive patients with advanced prostate cancer
`received ketoconazole and hydrocortisone at progression aRer antiandrogen withdrawal. Pros-
`tate specific antigen (PSA) response was defined as greater than a 50% decrease in PSA from
`baseline that was maintained for at least 8 weeks.
`Results: Overall, of 48 evaluable patients 30 (62.5%, 95% confidence interval 47.3 to 76.1%) had
`greater than a 50% decrease in PSA, while 23 (48%) had greater than an 80% decrease. The
`median duration of response was 3.5 months but 23 of 48 patients continue to exhibit a response,
`ranging from 3.25 to 12.75 or more months. The ketoconazole response rate in patients with no
`response to prior antiandrogen withdrawal was not different from that in patients with such
`a response (65 versus 40%, p = 0.35). Toxicity was mild. Grade 1 or 2 nausea, fatigue, edema,
`hepatotoxicity and rash occurred in 10.4 (5 of 48), 6.25, 6.25, 4.2 and 4.2% of patients, respec-
`tively, and anorexia occurred in 2%.
`Conclusions: Failure to respond to antiandrogen withdrawal does not identify patients with
`truly hormone refractory disease. Ketoconazole retains significant activity in this setting and is
`extremely well tolerated.
`KEY WORDS: prostate-specific antigen, prostatic neoplasms, ketoconazole, flutamide, neoplasm metastasis
`Until recently patients with advanced prostate cancer and
`prostate cancer after combined androgen blockade, and fol-
`failure of combined androgen blockade therapy were consid-
`lowing flutamide withdrawal with ketoconazole and hydro-
`ered to have hormone refractory disease. A common belief
`cortisone. To our knowledge this is the first report of the use
`of ketoconazole in patients previously treated with an anti-
`was that secondary hormonal maneuvers, particularly those
`aimed at adrenal androgen deprivation, while of use in pa-
`androgen and after antiandrogen withdrawal.
`tients treated only with gonadal androgen deprivation, were
`unlikely to be efficacious for those already on combined an-
`drogen blockade.1.2 However, the unexpected antitumori-
`genic activity manifested by the withdrawal of antiandro-
`gens3-6 has prompted a reexamination of the prior belief that
`other hormonal maneuvers done after combined androgen
`blockade are not likely to be of use. It is now apparent that
`tremendous heterogeneity exists in the population with hor-
`mone refractory prostate cancer, and that some cases previ-
`ously labeled as resistant to hormonal therapy may, in fact,
`retain a certain degree of hormonal sensitivity.7 To test the
`hypothesis that certain hormone refractory cases retain hor-
`monal sensitivity even after progression following antiandro-
`gen withdrawal, we treated 50 patients with progressive
`Acce ted for publication October 11, 1996.
`Reafat annual meeting of American Urologicd Association, ~ r
`lando, Florida, May 4-9,1996.
`* Requests for reprints: Urologic Oncology Program, UCSF Cancer
`Center, 2356 Sutter St., 5th Floor, San Francisco, California 94115.
`Editor'. Note: This article is the firet of 5 published in this
`issue for which category 1 CME credits cam be earned. In-
`structionn for obtainmg credits are given with the questions
`on pages 1478 and 1479.
`
`PATIENTS AND METHODS
`A total of 50 consecutive patients with histologically con-
`firmed metastatic prostate cancer that had become hormone
`refractory received treatment with ketoconazole and hydro-
`cortisone. To be considered for this therapy patients had to
`have progressive disease on combined androgen blockade,
`undergone antiandrogen withdrawal and have progressive
`disease after antiandrogen withdrawal. Progressive disease
`was defined by objective evidence of disease progression on
`any imaging study or at least 2 consecutive prostate specific
`antigen (PSA) levels at least 2 weeks apart, each of which
`demonstrated greater than a 50% increase above the nadir
`level achieved with the most recent hormonal manipulation.
`In addition to a 50% increase in PSA level, an arbitrary
`-
`
`minimum PSA increase of 2 ng./ml. was required to diagnose
`progressive disease. Prior therapy with aminoglutethimide,
`ketoconazole or any investigational agent, chemotherapy or
`immunotherapy was not permitted.
`On day 1 of treatment a serum PSA (Tandem-Rt assay)
`t Hybritech Inc., San Diego, California.
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`1205
`KETOCONAZOLE FORPROSTATECANCER
`bicalutamide in 1. All 48 patients subsequently underwent
`and baseline liver function tests (aspartate aminotransfer-
`ase, alanine aminotransferase and bilirubin) were obtained.
`antiandrogen withdrawal because of progressive disease.
`Five of the 48 patients had obtained a prior response to
`m e n appropriate, imaging studies were performed before
`therapy. Treatment consisted of 400 mg. oral ketoconazole
`antiandrogen withdrawal, which was somewhat less than
`every 8 hours, and 20 mg. oral hydrocortisone each morning
`our prior experience."
`and 10 mg. orally each evening. Patients were encouraged to
`Overall, 30 of 48 patients (62.5%, 95% confidence interval
`47.3 to 76.1%) obtained a PSA response (greater than 50%
`take the medications on an empty stomach unless this re-
`decrease in PSA for at least 8 weeks measured a t least twice
`sulted in nausea or gastrointestinal upset, in which case the
`ketoconazole was taken at mealtime. Antacids and hydrogen
`on 2 separate occasions at least 4 weeks apart), while 37
`(77%) experienced a decrease of 50% or more for at least 4
`blockers were discouraged but not prohibited, and an effort
`weeks in duration and 23 (48%, 95% confidence interval 33.3
`was made to have patients time the ketoconazole dosage so
`to 62.8%) had an 80% or greater decrease for a t least 8 weeks.
`that it was taken several hours before the next antacid or
`Serum PSA decreased to 0.3 ng./ml. or less in 5 patients
`hydrogen blocker dose. Because of potential adverse drug
`(10%) for 3+, 3.5, 4.5+, 7+ and 10+ months, respectively.
`interactions with ketoconazole, concurrent treatment with
`These patients had pre-ketoconazole PSA values of 22,47.4,
`astemizole, terfenadine or cisapride was prohibited. PSA,
`15, 488 and 6.7 ng./ml., respectively. For all patients the
`alanine aminotransferase, aspartate aminotransferase and
`median PSA decrease was 79.5% (range 0 to 99). Median PSA
`bilirubin were measured once a month. Patients remained on
`response duration was 3.5 months, although the range was
`this therapy until there was evidence of progressive disease
`wide (2 to 12+). Median PSA progression-free survival for all
`or toxicity precluded further treatment. When appropriate,
`patients was 4 months (see figure) and median survival of
`imaging studies were repeated. However, since the majority
`all patients had not been reached at 6+ months. Routine
`of patients were asymptomatic, in an effort to contain unnec-
`followup imaging studies, formal quality of life assessment or
`essary costs routine imaging studies were not obtained un-
`pain assessment was not done, since most patients were
`less warranted by symptoms or rapid PSA progression. A
`asymptomatic. Of 16 patients (33%) with bone pain attribut-
`PSA response to ketoconazole and hydrocortisone therapy
`able to prostate cancer before therapy 8 (50%) experienced
`was defined as greater than a 50% decrease in PSA from
`improvement in pain with therapy, although this was by
`baseline that lasted for at least 8 weeks (a minimum of 2
`patient self-report without use of a formal pain assessment
`consecutive determinations at least 4 weeks apart).
`instrument. In the absence of a randomized trial the impact
`The duration of PSA response was measured from the first
`PSA that decreased to less than 50% of baseline to the first PSA
`of a placebo effect on improvement in subjective symptoms
`that increased to greater than 50% above the nadir value.
`cannot be determined.
`Of the 48 patients 25 remained on therapy 3.25 to 12.75
`Actuarial survival and freedom from PSA progression curves
`months after treatment initiation, while 23 discontinued
`were calculated with the method of Kaplan and Meier. The
`therapy with ketoconazole due to progressive disease (16)
`effect of prior response to antiandrogen withdrawal on the like-
`and toxicity (7). Two of 5 patients (40%) with a response to
`lihood of response to ketoconazole was analyzed with the log
`prior antiandrogen withdrawal subsequently obtained a PSA
`rank test.
`response to ketoconazole, compared to 28 of 43 (65%) with
`no response to prior antiandrogen withdrawal. The propor-
`tions of responses were not statistically significant (p = 0.35).
`Toxicity was moderate. The most common toxicity was
`gastrointestinal upset and, more specifically, nausea. Grade
`1 or 2 nausea occurred in 5 of 48 patients (10.4%). Other
`toxicities included grade 1 or 2 fatigue, edema, hepatotoxicity
`and rash in 6.25,6.25,4.2 (2 of 48) and 4.2% of the patients,
`respectively, and anorexia in 2%. One episode of grade 4
`congestive heart failure was observed but a causal relation-
`ship with ketoconazole therapy could not be determined. The
`patients who withdrew from treatment because of toxicity
`
`RESULTS
`Patient characteristics are listed in the table. Median age
`was 74 years (range 51 to 87) and median serum PSA before
`initiating therapy was 62 ng./ml. (range 6.7 to 3,190). Of the
`50 patients 48 had sufficient followup after initiation of treat-
`ment with ketoconazole to be considered evaluable (that is
`they received 8 weeks of therapy to allow a minimum of 2
`PSA measurements at least 4 weeks apart) and they are the
`basis of this report. Patients who withdrew from treatment
`before receiving 8 weeks of therapy because of rapid disease
`progression (1) or early toxicity (3) were not censored and
`were considered evaluable. Of the 48 evaluable patients 45
`had undergone prior androgen deprivation for advanced
`prostate cancer (positive nodes andlor metastatic disease),
`while 3 had received hormonal therapy for serological (PSA)
`progression after definitive local therapy. Prior combined
`androgen blockade included flutamide in 47 patients and
`
`Patient characteristics
`
`No. evaluable pts.
`Median (range):
`Age (yrs.)
`Pretreatment PSA (ng./ml.)
`Alkaline phoaphatase
`Hemoglobin
`Creatinine
`Lactic dehydrogenase
`No. extent of disease:
`N+MO
`M t
`PSA only (NOMO)
`No. prior therapy:
`Flutamide
`Bicalutamide
`Prior response to antiandrogen
`withdrawal
`
`48
`
`(51-87)
`74
`79 (6.7-3,190)
`131
`(59-3,090)
`12.6 (4.8-15.1)
`1.05 (O.Gl.9)
`193
`(124-5063
`
`11
`34
`3
`
`47
`1
`5
`
`8
`
`0
`
`5
`10
`Duration of Ketomnazole Response (MonmS)
`Actuarial Kaplan-Meier plot of probability of freedom from PSA
`progression after treatment with ketoconazole and hydrocortisone.
`
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`1206
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`had hepatocicity (21, nausea and/or anorexia (3), congestive
`heart failure (1) and rash with edema (1).
`
`KETOCONAZOLE FOR PROSTATE CANCER
`prior antiandrogen withdrawal might result in a clinical
`benefit. Indeed, this was the case when our patients were
`treated with ketoconazole and hydrocortisone.
`In addition to ketoconazole, adrenal androgen suppression
`can be achieved with other agents, including aminogluh
`thimide and perhaps glucocorticoids. While many previous
`reports detailed the use of these agents, to our knowledge
`their use during or after antiandrogen withdrawal has only
`recently been reported. In the first such study adrenal an-
`drogen deprivation consisted of aminoglutethimide and hy-
`drocortisone therapy with a reported 48% PSA response
`rate,17 which was considerably greater than that reported for
`flutamide withdrawal alone.
`It is noteworthy that in our series patients with no re-
`sponse initially to the discontinuation of antiandrogen were
`just as likely to respond to subsequent therapy with ketocon-
`azole as those who had a prior response. This finding sug-
`gests that failure to respond to antiandrogen withdrawal
`does not reliably identify patients with true hormonal resis-
`tance, although the small number of patients involved makes
`it impossible to draw definitive conclusions. In addition, com-
`pared to our previous series: a considerably smaller percent-
`age of patients had previously responded to antiandrogen
`withdrawal (10 versus 15%), raising the possibility of inad-
`vertent patient selection bias. Furthermore, none of our cases
`was primarily refractory to androgen deprivation. It could be
`postulated that such patients, while relatively rare, have
`truly hormonal refractory disease and it is possible that they
`would be unlikely to respond to ketoconazole.
`We are encouraged by the relatively high proportion of our
`patients who obtained a PSA response and by the duration of
`PSA decrease that we observed, since a decrease in PSA has
`been advocated as a surrogate marker for survival in patients
`with hormone refractory prostate cancer.ls. l9 Nonetheless,
`while it seems clear that greater than a 50% (or in some
`series 75%) decrease in PSA appears to define patients with
`improved survival, controversy remains as to the validity of
`PSA decrease as a surrogate marker of response or surviv-
`a1.20 In our patients the median survival of responders com-
`pared to nonresponders was not statistically different, al-
`though our short followup and small number of events (7)
`compounded with innumerable permutations for subsequent
`therapies make survival difficult to evaluate. A recently ac-
`tivated multicenter phase I11 trial addressing the impact of
`ketoconazole and hydrocortisone after antiandrogen with-
`drawal may shed further light on the mechanisms of re-
`sponse and define more precisely the efficacy of this regimen.
`Ketoconazole is particularly attractive because of its favor-
`able toxicity profile and ease of use. All medications are given
`orally and patients need only monthly laboratory followup.
`The most frequent toxicity was nausea, which was generally
`mild and occurred in 10% of the patients. The remaining
`toxicities were primarily grades 1 and 2 , and in all cases
`occurred in 6% or fewer patients. For these reasons, while
`there is no evidence that there is a survival advantage to
`treatment with ketoconazole, this regimen is nonetheless
`well suited for patients with progressive prostate cancer
`(generally by PSA criteria) who are asymptomatic, and un-
`willing or not eligible to be treated with protocol therapy or
`more aggressive means. The ease and efficacy (as measured
`by PSA decreases) of this regimen must be balanced with a
`lack of survival data and the relatively high cost of ketocon-
`azole.
`
`DISCUSSION
`We demonstrated a surprisingly high PSA response rate
`(62.5%) when patients with progressive prostate cancer after
`combined androgen blockade and antiandrogen withdrawal
`were subsequently treated with adrenal androgen suppres-
`sion with ketoconazole and hydrocortisone. Unlike any prior
`study with ketoconazole to our knowledge, we showed that
`sensitivity to this agent is retained in patients previously
`treated with adrenal androgen blockade with an antiandro-
`gen.
`Ketoconazole is a substituted imidazole that suppresses
`testicular and adrenal steroidogenesis by inhibition of the
`conversion of cholesterol to pregnenolone. Because ketocon-
`azole is a potent inhibitor of all adrenal steroid synthetic
`pathways, replacement doses of hydrocortisone may be re-
`quired. The efficacy of corticosteroids in the treatment of
`advanced prostate cancer has long been appreciated and was
`recently reviewed.7 These data indicate that the impact of
`steroids on PSA response rate, measures of quality of life
`and, possibly, objective responses must be remembered when
`considering regimens, such as ketoconazole, that include cor-
`ticosteroids, even at replacement (physiological) doses. How-
`ever, it is unlikely that our results with ketoconazole and
`hydrocortisone can be explained by the effect of steroids
`alone, since use of corticosteroids as a single agent in pa-
`tients with progression after antiandrogen withdrawal has
`been reported to yield a PSA response rate of only 20%.7
`Regardless of the relative contribution of hydrocortisone to
`our results, we believe that our relatively high response rate
`is provocative and warrants confirmatory studies.
`The efficacy of ketoconazole in patients with advanced
`prostate cancer has long been appreciated. Overall, objective
`partial responses have been reported in 16% of patients, with
`stable disease (National Prostatic Cancer Project criteria)
`noted in 30%’ Our response rate is considerably greater than
`that previously reported with ketoconazole, although in some
`earlier studies corticosteroids were not used.8-11 However, it
`must be emphasized that many prior reports did not use PSA
`response criteria, and most contemporary series on any treat-
`ment of hormone refractory prostate cancer have noted
`PSA response rates that were considerably greater than ob-
`jective response rates. While nearly all of our patients had
`advanced (nodal or metastatic) disease, only a small percent-
`age were symptomatic, so that routine imaging studies, qual-
`ity of life assessments and pain assessment were not formally
`done.
`Limited data on PSA responsiveness to ketoconazole ex-
`ist.12-14 Other than our series, to our knowledge none of these
`trials has included patients who had been previously treated
`with an antiandrogen, let alone with antiandrogen with-
`drawal. Gerber and Chodak observed a PSA decrease (of any
`magnitude) in 12 of 15 patients (80%), with a median PSA
`decrease of 49% in those with a response.12 Trump et a1
`observed objective responses in 5 of 36 patients (14%), with a
`PSA decrease of greater than 80% in 4.13 Seven of 21 patients
`(33%) reported on by Muscato et a1 had greater than a 90%
`decrease in PSA.I4
`The mechanism of the antiandrogen withdrawal syndrome
`is not fully understood but it is hypothesized that a mutation
`in the hormonal binding domain of the androgen receptor is
`responsible for the capacity of antiandrogens to act as partial
`agonists.15.16 However, in vitro some mutant androgen re-
`CONCLUSIONS
`ceptors continue to demonstrate androgen sensitivity as well.
`During the last 3 to 4 years dramatic changes in the ap-
`We postulated that it is likely that a population of androgen
`proach to patients with hormone refractory prostate cancer
`receptors (wild type or mutant) remains in vivo that retain
`have occurred. It is clear that individuals who have been
`sensitivity to androgenic stimulation, so that suppression of
`treated with combined androgen blockade and antiandrogen
`adrenal androgen production in patients who had undergone withdrawal can benefit from additional hormonal maneu-
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`1207
`KETOCONAZOLE FOR PROSTATE CANCER
`vers, such as ketoconazole and hydrocortisone, although the
`11. Williams, G., Kerle, D. J., Ware, H., Doble, A.. Dunlop, H.,
`impact of these therapies on survival remains unknown. The
`Smith, C., Allen, J., Yeo, T. and Bloom, S. R.: Objective re-
`high PSA response rate observed with ketoconazole and re-
`sponses to ketoconazole therapy in patients with relapsed
`progressive prostatic cancer. Brit. J. Urol., 68: 45, 1986.
`placement doses of hydrocortisone, coupled with the ex-
`12. Gerber, G. S. and Chodak, G. W.: E'rostate specific antigen for
`tremely favorable toxicity profile make this an attractive
`assessing response to ketoconazole and prednieone in patients
`regimen. Whether a given patient will respond to subsequent
`with hormone refractory metastatic prostate cancer. J. Urol.,
`hormonal maneuvers cannot be predicted but a reasonable
`144: 1177, 1990.
`approach is to consider more aggressive therapy for those
`13. Trump, D. L., Havlin, K. H., Messing, E. M., Cummings, K. B.,
`with apparently primarily hormone refractory disease and
`Lange, P. H. and Jordan, V. C.: High-dose ketoconazole in
`those with a rapidly growing tumor burden or progressive
`advanced hormone-refractory prostate cancer: endoninologic
`symptomatology .
`and clinical effects. J . Clin. Oncol., 7: 1093, 1989.
`14. Muscato, J. J., Ahmann, T. A. and Johnson, K M.: Optimal
`dosing of ketoconazole (keto) and hydrocortisone (HC) leads to
`long responses in hormone refractory prostate cancer. Roc.
`Amer. Soc. Clin. Oncol., 13:229, 1994.
`15. Veldscholte, J., Berrevoets, C. A, Brinkmann, A. O., Grootegoed,
`J. A. and Mulder, E.: Anti-androgens and the mutated andro-
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`16. Taplin, M. E., Bubley, G. J., Shuster, T. D., Frantz, M. E.,
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