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Antiandrogen Withdrawal Alone or in CombinationWith Ketoconazole in Androgen-Independent ProstateCancer Patients: A Phase III Trial (CALGB 9583)Eric J. Small, Susan Halabi, Nancy A. Dawson, Walter M. Stadler, Brian I. Rini, Joel Picus,Preston Gable, Frank M. Torti, Ellen Kaplan, and Nicholas J. Vogelzang Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of Ն 50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy.
Patients and Methods
AiPCa patients were randomized to undergo AAWD alone (n ϭ 132), or together with K (400 mg orally [po] tid) and hydrocortisone (30 mg po each morning, 10 mg po each evening; n ϭ 128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K.
Results
Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients
who underwent AAWD and simultaneous K (P ϭ .0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P ϭ .02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response.
Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at Conclusion
K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K 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.
nadal androgen suppression at the time of INTRODUCTION
initiating androgen deprivation (early use) Prostate cancer is the most common cancer in are modest at best [4]. The late addition of men and will account for more than 30,000 an antiandrogen after initial failure of an- deaths in 2003 [1]. The vast majority of deaths drogen deprivation (late use) seems to result are due to the development of metastatic dis- in prostate-specific antigen (PSA) declines, ease unresponsive to androgen deprivation.
and in some cases, objective responses [5].
flicts of interest are found at the end of Androgen deprivation, with gonadal andro- Thus, at one point or another, most patients gen suppression with or without antiandro- gen, has been the standard of care in pa- treated with an antiandrogen. Despite an- drogen deprivation, including the use of an 1940s [2] and is being increasingly utilized antiandrogen, most patients will experience in patients with less advanced disease [3].
disease progression. For patients with pro- gressive disease, despite androgen depriva- tion, withdrawal of antiandrogen has been Information downloaded from jco.ascopubs.org and provided by at ASCO on April 5, 2011 from 206.205.123.242 Copyright 2004 American Society of Clinical Oncology. All rights reserved.
Small et al
reported to result in a decline in PSA level of Ն 50% in 15% PATIENTS AND METHODS
to 30% of patients [6-8]. The mechanism of this phenome-non has been attributed to alterations in the androgen sig- Patients
naling cascade, including mutations in the androgen recep- Eligible patients had histologically confirmed adeno- tor (AR), resulting in the antiandrogen behaving as an carcinoma of the prostate with progressive metastatic dis- activator, not inhibitor, of the AR [9].
ease, as defined below, despite anorchid testosterone levels The duration of decline in PSA observed with antian- (Ͻ 50 ng/mL). Androgen deprivation therapy was required drogen withdrawal (AAWD) is brief, with a median dura- to include at least 4 weeks of ongoing therapy with an tion of 3.5 to 5.0 months [6-8], after which further therapy antiandrogen (flutamide, bicalutamide, or nilutamide).
is generally required. The mechanism by which prostate Ongoing gonadal androgen ablation with a luteinizing cancer patients develop disease progression after AAWD is hormone-releasing hormone analog or orchiectomy was not understood, but it has been postulated that persistence required. For patients with measurable disease, progression of a clone of cells with partial or full sensitivity to testoster- was defined as a greater than 25% increase in the sum of the one might be provided a growth advantage by androgen products of the perpendicular diameters of all measurable produced by the adrenal glands. If this were the case, it could be lesions. For patients with “bone only” disease, a PSA greater anticipated that adrenal androgen suppression would demon- than 5 ng/mL, which had risen from baseline on at least two strate some anticancer activity in this setting. An early report successive occasions at least 4 weeks apart was required.
suggested that the addition of aminoglutethimide (an adrenal Patients were required to have had metastatic disease dem- steroid synthesis inhibitor) at the time of AAWD increased the onstrated on imaging at some point during their history, percentage of patients with a decline in PSA over that which but were not required to have demonstrated metastases on would be expected with antiandrogen alone [10].
imaging at the time of enrollment. Patients were excluded ifthey had received prior chemotherapy, immunotherapy, Ketoconazole is an azole antifungal agent which exerts experimental therapy, or prior treatment with ketocon- its clinical effect through the inhibition of cytochrome P450 azole, aminoglutethimide, or corticosteroids if they had a 14a-demethylase, a catalyst of the conversion of lanosterol Cancer and Leukemia Group B (CALGB) performance to cholesterol. Ketoconazole has been in clinical use as an status of more than 2, total bilirubin level greater than 1.5ϫ antifungal agent for more than 20 years. In its initial use as the upper levels of normal (ULN), or serum glutamic- an antifungal agent, it was discovered that a proportion of oxaloacetic transaminase level greater than 3ϫ ULN. Be- men who used ketoconazole developed painful gynecomas- cause of potential interactions with ketoconazole, no ongo- tia, which was later found to be due to the suppression of ing or concurrent use of terfenadine, astemizole, or testicular and adrenal androgen production, and it was cisapride was allowed. All participants signed an institu- postulated that this adverse effect could be useful for pros- tional review board–approved, protocol-specific, informed tate cancer therapy. Several trials have evaluated the use of consent form in accordance with federal and institutional ketoconazole in patients with androgen-independent pros- tate cancer (AiPCa), though most predated the use of PSAor an understanding of the AAWD syndrome [11-14]. Most Treatment
recently, the use of ketoconazole after AAWD was reported After registration, patients were randomized to AAWD alone or AAWD ϩ ketoconazole by the CALGB Statistical in a trial of 48 patients, 30 (63%) of whom demonstrated aՆ Center. This study was neither blinded nor placebo con- 50% decline in PSA response. The decline of Ն 50% in trolled. A conventional stratified random blocks design was PSA was comparable in patients who had initially re- used [16]. That is, within each stratum, patients were as- sponded to AAWD and in those who had not initially re- signed to the available two treatments in blocks of treatment sponded to AAWD at 65% v 40%, respectively. Toxicity was assignments so that an equal number of patients was as- largely mild in these patients, consisting of grade 1 or 2 signed to each of the two treatment arms within each block.
nausea, fatigue, edema, hepatoxicity, and rash [15].
Randomization was stratified by four features that could It was hypothesized that the simultaneous addition of potentially affect the likelihood of response, both to AAWD ketoconazole to AAWD would have additive anticancer and/or ketoconazole therapy: (1) prior therapy with flut- activity, simultaneously targeting the stimulating effects of amide, bicalutamide, or nilutamide; (2) continuous or in- antiandrogen and adrenal androgens. Hence, the principal termittent treatment; (3) initial or delayed antiandrogen goals of this study were to prospectively evaluate and com- therapy; and (4) imaging studies positive or negative for pare the effect of AAWD alone on PSA levels, compared with simultaneous AAWD and ketoconazole therapy. In Patient registration, subsequent randomization and addition, the effect of ketoconazole used in patients whose data collection were managed by the CALGB Statistical cancer had progressed after AAWD was also evaluated.
Center. Furthermore, data quality was ensured by careful Information downloaded from jco.ascopubs.org and provided by at ASCO on April 5, 2011 from 206.205.123.242 Copyright 2004 American Society of Clinical Oncology. All rights reserved.
AAWD and Ketoconazole for Prostate Cancer
review of all data at the CALGB Statistical Center and by the combining PSA changes with imaging changes was utilized.
study chairperson. Patients enrolled on the AAWD ϩ keto- Therefore, for patients with measurable disease, a partial conazole arm received ketoconazole 400 mg tid po plus response was defined as a Ն 50% decrease in the sum of the hydrocortisone 40 mg/d po (30 mg each morning and 10 products of the perpendicular diameters of all measurable mg every night) continuously until disease progression or lesions, together with a decline in PSA of Ն 75%, measured unacceptable toxicity, as described below. Patients random- at least twice at least 2 weeks apart, whereas a complete ized to the AAWD-alone arm were required to cross over to response was complete resolution of all visible disease, and treatment with ketoconazole on disease progression (see normalization of PSA on at least two occasions at least 2 weeks apart. A complete response in patients with bone- Eligible patients were evaluated with a medical history only disease was defined as complete normalization of bone and physical examination at study entry and monthly there- scan, again with a normalization of PSA, while a partial after. In addition to a complete medical history and physical response in bone-only patients requires a greater than 75% examination at each visit, patients were evaluated for ad- decline in PSA with no new lesions on bone scan. Addition- verse events. No formal quality-of-life or pain assessment ally, all patients had monitoring of PSA levels, and the was undertaken. CBC, PSA, total bilirubin, alkaline phos- percentage of patients with a decline in PSA of Ն 50%, phatase, asparate transaminase, creatinine, glucose, and lac- documented on at least two successive occasions, at least 4 tate dehydrogenase (LDH) were checked at baseline and weeks apart, was calculated per the PSA Consensus Criteria then monthly. An endocrine panel including androstendi- [17]. An intent-to-treat analysis was utilized. Patients who one, dehydroepiandrosterone sulfate (DHEAS), dehydro- received less than 2 months of therapy for any reason (in- epiandrosterone (DHEA), and testosterone was obtained at cluding progressive disease, toxicity, or withdrawal of con- baseline, at 1 month after starting therapy, at 3 months after sent) and who therefore did not have two sequential PSA starting therapy, and at the time of disease progression.
values for response assessment, were nevertheless consid- Blood samples were obtained between 8:00 AM and 10:00 AM.
ered to be nonresponders. Progressive disease was defined Plasma was isolated, frozen, and shipped for analysis at a by a PSA increase of Ն 50% above nadir, on at least two central laboratory to determine androstendione, DHEAS, successive occasions at least 1 month apart, with a mini- DHEA, and testosterone levels. A bone scan and computed mum rise of 5 ng/mL [17]. Disease progression was also tomography scan of the abdomen and pelvis were obtained defined by new lesions on bone or computed tomography at baseline. If imaging studies were positive at baseline, they scan, or for patients with pre-existing measurable disease, a greater than 25% increase in the sum of the products of the Replacement doses of hydrocortisone were continued perpendicular diameters of all measurable lesions. Survival as long as the patient was receiving ketoconazole. When the was measured from the time of randomization to the time patient was no longer receiving ketoconazole, hydrocorti- of death, and time to PSA progression was measured per sone was tapered by 5 mg every 3 days until completely discontinued. Antacids, H-2 blockers, and proton pumpinhibitors were avoided but not explicitly prohibited. This Statistical Methods
study did not mandate that ketoconazole be taken on an The primary objective of this trial was to compare the empty stomach or with acidifying procedures. At each visit, response rates (composite end point, as defined above) of toxicity was graded according to the National Cancer Insti- AAWD alone versus AAWD combined with ketoconazole tute common toxicity criteria (CTC, version 2.0) and re- and hydrocortisone. However, secondary objectives were to corded. In the event of grade 3 or higher hepatotoxicity or compare the percent of patients with a posttherapy decline symptomatic peptic ulcer or gastritis, patients were re- in PSA of Ն 50%, documented on at least two successive moved from protocol treatment. Antiemetics other than occasions, at least 4 weeks apart, per the PSA Consensus corticosteroids were permitted. If grade 2 or 3 nausea per- Criteria [17]. Secondary objectives were also to evaluate the sisted despite these measures, the patient was removed from posttherapy PSA decline in patients who received ketocon- therapy. Patients developing other grade 3 or higher toxicity azole and hydrocortisone after developing progressive dis- had treatment held until toxicity resolved to grade 1 or ease despite AAWD. The study also sought to correlate better. Any patient developing grade 4 toxicity or grade 3 posttherapy decline in PSA of Ն 50% PSA with survival, as toxicity persisting for longer than 4 weeks, except as out- well as to evaluate the prognostic value of several pretreat- lined previously, was removed from protocol treatment.
ment patient characteristics. Finally, the study evaluated therelationship of pretreatment adrenal androgen levels, and Response and Progression Criteria
changes in adrenal androgen levels with response to therapy This study was launched before publication of the Re- sponse Evaluation Criteria in Solid Tumors criteria or the With 119 patients per arm, and a one-sided ␣ of .05, the PSA Consensus Criteria [17], so that a composite end point independent two-group binomial test had 80% power to Information downloaded from jco.ascopubs.org and provided by at ASCO on April 5, 2011 from 206.205.123.242 Copyright 2004 American Society of Clinical Oncology. All rights reserved.
Small et al
detect a difference in the percentage of patients with a Table 1. Baseline Characteristics
partial or complete (composite) response from 25% in theAAWD group, to 40% in the AAWD ϩ ketoconazole arm.
Allowing for a 5% ineligibility rate, the target sample size The study was monitored by the CALGB Data Safety and Monitoring Board. Planned interim analysis used the Lan-DeMets analog of the O’Brien-Fleming sequential boundary to maintain the overall level of significance of .05 [18]. The Lans-DeMets stopping rule was applied to the composite response end point. At the final analysis, the ␣ level was .045. An intent-to-treat approach was used in the analysis. Pearson ␹2 and Fisher’s exact test were used to compare the two arms with regard to response rates (com- posite end point), objective response rates, and 50% decline in PSA [19]. Exact confidence intervals based on the bino- mial distribution were used to estimate 95% CIs for the response rates. The Kaplan-Meier product-limit method was used to estimate overall survival and PSA progression- free survival by the two arms [20], and the log-rank test was used to compare the two arms on these outcomes (overall survival and PSA progression-free survival). The proportional hazards model was used to assess important factors for predicting survival time adjusting on the The relationship between overall survival and 50% de- cline in PSA from baseline was explored. To minimize “lead time bias,” landmark analyses were performed at 4, 8, 12, and 16 weeks postrandomization [21]. This method selects a fixed time point after initiation of therapy as a “landmark” and excludes patients who died before reaching the land- mark (eg, 8 weeks). Further, the patients alive at the land- mark were classified as responders or nonresponders de- pending on their 50% decline in PSA before the landmark.
In these analyses, survival duration was defined as the time between the landmark (eg, 8 weeks) and death. The rela- tionship between survival duration, and PSA decline was examined. For the primary end point, a one-sided ␣ ϭ .05 Abbreviations: AAWD, antiandrogen withdrawal; PSA prostate-specific antigen; LDH, lactate dehydrogenase; CAB, combined androgen blockade.
was used to compute the 95% CI and the P value. For the ءPatients may have more than one metastasis.
secondary objectives and analyses, tests were performedusing a two-sided ␣ ϭ .05.
proximately 15% of patients had received prior intermittentandrogen deprivation, and approximately 60% had re- Patient Characteristics
ceived initial combined androgen blockade (luteinizing Two hundred sixty patients were enrolled onto this hormone-releasing hormone analog plus antiandrogen).
study. No consistent approach to screening patients for this Imaging studies were positive for metastatic disease in 97% trial was mandated. One hundred thirty-two were random- and 94% of patients in the AAWD and AAWD and keto- ized to AAWD alone and 128 were randomized to AAWD conazole arms, respectively. The two arms were similar and ketoconazole. Patient characteristics, including strati- regarding age, sites of disease, requirement for opioid anal- fication variables, are summarized in Table 1. With regard gesics, and a variety of pretreatment prognostic factors, to stratification variables, approximately 36% of patients including performance status, hemoglobin, PSA, alkaline (on both arms) received prior flutamide, 59% had prior phosphatase, LDH, and creatinine. The median age of pa- bicalutamide, and 4% to 5% had received nilutamide. Ap- tients in both arms was just older than 70 years, and 93% Information downloaded from jco.ascopubs.org and provided by at ASCO on April 5, 2011 from 206.205.123.242 Copyright 2004 American Society of Clinical Oncology. All rights reserved.
AAWD and Ketoconazole for Prostate Cancer
Table 2. Summary of Clinical Outcome
Fig 1. Overall prostate-specific antigen (PSA) progression-free survival by
treatment arm in patients with 50% decline in PSA. AAWD, antiandrogenwithdrawal.
(17%) of 128 of patients on the AAWD/ketoconazole arm Abbreviations: AAWD, antiandrogen withdrawal; PSA, prostate- Eighty-two percent of patients (108 of 132) treated with AAWD alone ultimately received “deferred” ketocon-azole/hydrocortisone therapy. Twenty-four patients as- had a performance status of 0 or 1. The median serum PSA signed to initial AAWD alone never received deferred keto- levels at study entry was 58 ng/mL. Thirty-one percent of conazole for a variety of reasons, including disease patients in the AAWD arm and 39% of patients in the progression and withdrawal of consent. Of the 108 patients AAWD and ketoconazole arms had measurable disease.
receiving deferred ketoconazole, a decline in PSA of Ն 50% More than 80% in both arms had bone metastases, and was observed in 35 (32%) of 108 patients. An objective approximately one-third had lymph node involvement.
response was seen in 3 (7%) of 41 patients treated with Approximately 30% of patients were using opioid analge- AAWD followed by deferred ketoconazole. Although the study was not designed to compare the aggregate PSA de- Clinical Outcome
clines and objective responses in patients treated with si- Relevant clinical outcomes, including PSA decline, ob- multaneous versus sequential AAWD and ketoconazole, jective response rate, overall survival, and time to PSA pro- there did not seem to be an advantage of either approach gression are summarized in Table 2. Overall, 15 (11%; 95% over the other. In aggregate, 40 (30%) of 132 patients CI, 7% to 17%) of 132 patients undergoing antiandrogen treated with AAWD followed by ketoconazole had a PSA withdrawal alone experienced a Ն 50% decline in PSA. By decline of Ն 50% compared with 34 (27%) of 128 of pa- contrast, 34 (27%; 95% CI, 20% to 35%) of 128 patients tients treated with simultaneous AAWD and ketoconazole.
who underwent AAWD and received simultaneous keto- The median survival time was 16.7 months (95% CI, 14.3 to conazole had a Ն 50% decline in PSA (P ϭ .002). In patients 21.5 months) in the AAWD-alone arm, and 15.3 months with a Ն 50% decline in PSA, the subsequent median time (95% CI, 13.4 to 19.5 months) in the group of patients who to PSA progression was 5.9 months (95% CI, 5.3 to 10.1 received simultaneous AAWD and ketoconazole therapy months) and 8.6 months (95% CI, 5.7 to 20.4 months) in (two-sided P ϭ .936; Fig 2).
the AAWD alone and AAWD and ketoconazole arms, re- For those patients receiving sequential AAWD fol- spectively (log-rank P ϭ .063). Figure 1 demonstrates the lowed by ketoconazole, prior PSA “response” (decline of Ն overall PSA progression-free survival by treatment arm for 50%) after AAWD seemed to be associated with a higher those patients who had a 50% decline in PSA. Objective likelihood of PSA response to subsequent ketoconazole.
responses in measurable disease were observed in 1 (2%; Overall, 35 patients had a PSA response when treated with 95% CI, 0.13% to 11%) of 41 of patients treated with deferred ketoconazole. Ten of these PSA responses oc- AAWD alone, compared with 10 (20%; 95% CI, 11% to curred in the group of 15 patients who had obtained a prior 32%) of 50 in the AAWD and ketoconazole arm (P ϭ .02).
PSA response to AAWD (10 of 15; 67%), whereas an addi- While no longer currently in use, when the composite end tional 25 patients had a response to deferred ketoconazole points described were applied, 8 (6%) of 132 of patients from among a group of 117 patients (25 of 117; 21%) who treated with AAWD had a response, compared with 22 had failed to achieve a PSA response after AAWD.
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Small et al
Fig 3. Kaplan-Meier plot of overall survival as a function of Ն 50% decline
in prostate-specific antigen (PSA), using a 1-month landmark analysis.
other than AAWD itself), but no one toxicity occurred in A proportional hazards model was used to identify more than 3% of patients. Twenty-one percent of patients predictors of overall survival. Pretreatment PSA, alkaline receiving ketoconazole had grade 3 and 4 toxicities. The phosphatase, LDH, and hemoglobin levels, each dichoto- most common toxicities with ketoconazole were neurologic mized at the median; the presence or absence of weight loss toxicity (4%), which consisted of motor neuropathy and at the time of study entry; and prior therapy with flutamide ototoxicity, and malaise or fatigue (3%; Table 4). Grade 3 or but not treatment arm, were predictors of survival (Table 4 hepatic toxicity was observed in 2% of patients receiving 3). In addition, using a 4-week landmark analysis, a Ն 50% ketoconazole, and was not more common than in the decline in PSA was a strong predictor of survival— 41 months in patients with a Ն 50% PSA decline versus 13 Adrenal Androgen Levels
months in patients without a PSA decline (P Ͻ .0001; Fig 3).
Baseline plasma adrenal androgen levels are available Toxicity
on 213 patients, 113 in the AAWD-alone arm, and 100 in Overall, 7% of patients undergoing AAWD alone had a the AAWD and ketoconazole arm. One hundred sixty-four grade 3 or 4 toxicity (all presumably attributed to causes patients had levels drawn after 1 month of therapy; 81, after3 months; and 111, at progression, which occurred at amedian of 3.1 months after starting therapy (95% CI, 2.1 to Table 3. Predictors of Survival Time in Proportional Hazards Model
4.9 months). Baseline median DHEAS and androstendione levels were within the normal range, while baseline DHEA levels were slightly elevated (Table 5). Baseline median DHEA, DHEAS, and androstendione levels were similar in both arms (data not shown). The median baseline testoster- Table 4. Treatment-Related Grade 3 and 4 Toxicities
Androgen deprivation, continuous v Abbreviations: PSA, prostate specific antigen; LDH, lactate dehydroge- nase; CAB, combined androgen blockade; AAWD, antiandrogen with-drawal.
Abbreviation: AAWD, antiandrogen withdrawal.
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AAWD and Ketoconazole for Prostate Cancer
Table 5. Median Adrenal Androgen Levels in AAWD Plus Ketoconazole-Treated Patients
Abbreviations: AAWD, antiandrogen withdrawal; DHEA, dehydroeplandrosterone; DHEAS, DHEA sulfate.
ءDifference between levels at month 1 and levels at progression are significant at P ϭ .0001.
one level was 13 ng/mL, and did not change over time in and 32% of patients had a PSA decline of Ն 50% when either treatment arm. DHEA, DHEAS, and androstendione treated with ketoconazole after AAWD. The median time to levels did not change appreciably over time in the AAWD PSA progression was 8.6 months in patients treated with group (data not shown). By contrast, in the AAWD and simultaneous AAWD and ketoconazole. The objective re- ketoconazole group, there was a decline in levels of all three sponse proportion was 20% in patients treated with AAWD adrenal androgens (DHEA, DHEAS, androstendione), ac- and ketoconazole. However, ketoconazole therapy requires counting for declines from baseline of 54%, 90%, and 58%, hydrocortisone replacement therapy, and a large phase III respectively, at 1 month. There was a rise in all three adrenal trial demonstrated that 16% of patients treated with the androgen levels at the time of disease progression, though same dose of hydrocortisone as used in this trial (40 mg/d) not back to baseline (Table 5). The difference between had a Ն 50% drop in PSA [23]. Thus, at least part of the DHEAS and androstendione levels at month 1 and at the activity observed with ketoconazole can be attributed to the time of progressive disease are significant (P ϭ .0001).
requirement for concurrent corticosteroids.
The percentage of patients with a Ն 50% decline in PSA DISCUSSION
as observed in this trial is considerably lower than thatwhich has been previously reported from single-center This prospective, randomized phase III trial has compared studies reporting PSA decreases in 55% to 63% of patients changes in PSA levels as well as objective responses in met- treated with ketoconazole [15,24]. The explanation for this astatic AiPCa patients treated with either AAWD alone or discrepancy may lie in the selection bias and treatment bias with AAWD plus simultaneous ketoconazole and hydrocorti- introduced in single center studies. However, an equally sone replacement therapy. No difference in survival was ob- plausible explanation is that the conduct of the present trial served, though the planned use of deferred ketoconazole in the resulted in suboptimal ketoconazole bioavailability. Prior AAWD-alone arm may have blunted a treatment effect.
studies [25] have suggested that the absorption of ketocon- This study has demonstrated that PSA declines and azole is maximized in an acid gastric environment. This objective responses after AAWD are uncommon. A PSA study did not mandate that the ketoconazole be taken on an decline of Ն 50% was observed in 11% of patients under- empty stomach, or with acidifying procedures. While anti- going AAWD, while an objective response proportion of acids, H2 blockers, or proton pump inhibitors were dis- 2% was noted. The median time to PSA progression was couraged, they were not expressly forbidden, and it is pos- brief, at 5.9 months. The AAWD phenomenon has been sible that the use of these agents could be confounding.
appreciated for many years [6-8], though there are few Regardless of explanation, ketoconazole ϩ hydrocortisone prospective trials carefully assessing its frequency. To our has demonstrated only moderate activity as a second-line knowledge, this is the single largest prospective study of hormonal manipulation. However, its favorable toxicity AAWD. These data indicate that an AAWD response is a profile makes it a reasonable option for patients with met- rare event. It was previously thought that the mechanism of astatic AiPCa. The overall percentage of patients with a Ն AAWD could be explained by the presence of mutations in 50% decline in PSA was not different in those patients the AR [9]. However, as reported elsewhere, only 10% of treated with sequential AAWD and ketoconazole compared surveyed samples from this series harbored AR mutations, with patients receiving concurrent AAWD and ketocon- and there was no correlation in this study between AR azole (30% v 27%), and overall, no survival difference was mutations and an AAWD response [22].
observed; however, this study was not designed to compare Ketoconazole seems to have moderate activity in early versus late use of ketoconazole. Nevertheless, in the AiPCa patients following AAWD or with concurrent absence of fulminant disease mandating more rapid inter- AAWD. PSA decreases of Ն 50% were observed in 27% of vention, it is reasonable to treat these patients first with patients treated with concurrent AAWD and ketoconazole, AAWD, and on subsequent disease progression, to consider Information downloaded from jco.ascopubs.org and provided by at ASCO on April 5, 2011 from 206.205.123.242 Copyright 2004 American Society of Clinical Oncology. All rights reserved.
Small et al
ketoconazole. For patients who have undergone AAWD, it levels at the time of progression that reached statistical is of interest to note that prior PSA response to AAWD was significance (P ϭ .0001) for DHEAS and androstendione.
associated with a higher likelihood of subsequent PSA re- Whether this increase is sufficient to account for disease sponse to ketoconazole therapy (67% v 21%).
progression is not known. However, it suggests that at least While the use of PSA as an intermediate marker of part of the reason patients develop progressive disease while response and outcome remains controversial, an emerging on ketoconazole is tachyphylaxis to the adrenolytic proper- body of literature supports the use of a Ն 50% decline in ties of ketoconazole. The correlation of adrenal androgen PSA as an intermediate marker of survival in patients with levels, both at baseline and over time, with clinical out- AiPCa treated with secondary hormones, cytotoxic agents, comes including response, response duration, and survival, or suramin [26-31]. This study adds to that body of evi- is under way and will be reported elsewhere.
dence. A PSA decline of Ն 50% was strongly correlated with In summary, AAWD results in PSA declines and objec- survival (41 months versus 13 months, P ϭ .0001). How- tive responses in patients with metastatic AiPCa only rarely.
ever, a PSA decline of more than 50% represents a post- Second-line ketoconazole, either at the time of AAWD or treatment variable. In order to determine predictors of sur- following AAWD, is a reasonable, well tolerated treatment vival based on pretreatment variables, a proportional option with moderate activity in this group of patients.
hazards model was used, which identified alkaline phospha- tase, PSA, LDH, hemoglobin, and weight loss as predictors Appendix
of survival, confirming similar prior analyses [32].
The appendix is included in the full-text version of this This is the largest study to evaluate adrenal androgen article, available on-line at www.jco.org. It is not included levels in patients treated with ketoconazole. These data in the PDF (via Adobe® Acrobat Reader®) version.
indicate that levels of DHEA, DHEAS, and androstendioneall fall with treatment with ketoconazole, but as anticipated, Authors’ Disclosures of Potential
do not fall with AAWD alone. Moreover, it appears that Conflicts of Interest
there is a modest increase in median adrenal androgen The authors indicated no potential conflicts of interest.
static androgen-independent prostate cancer.
18. Lan KK, DeMets DL: Discrete sequential
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