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Journal of Clinical Oncology, Vol 22, No 6 (March 15), 2004: pp. 1025-1033 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.06.037 Antiandrogen Withdrawal Alone or in Combination With Ketoconazole in Androgen-Independent Prostate Cancer Patients: A Phase III Trial (CALGB 9583)From the University of California San Francisco, San Francisco, and US Naval Medical Center, University of California San Diego, San Diego, CA; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, and Wake Forest Comprehensive Cancer Center, Winston-Salem, NC; Greenebaum Cancer Center, University of Maryland, Baltimore, MD; University of Chicago Medical Center, Chicago, IL; and Washington University Barnard Cancer Center, St Louis, MO Address reprint requests to Eric J. Small, MD, UCSF Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Room A-718, San Francisco, CA 94115; e-mail: smalle{at}medicine.ucsf.edu
PURPOSE: Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of  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 = 132), or together with K (400 mg orally [po] tid) and hydrocortisone (30 mg po each morning, 10 mg po each evening; n = 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 = .0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P = .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 the time of disease progression. 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.
Prostate cancer is the most common cancer in men and will account for more than 30,000 deaths in 2003 [1]. The vast majority of deaths are due to the development of metastatic disease unresponsive to androgen deprivation. Androgen deprivation, with gonadal androgen suppression with or without antiandrogen, has been the standard of care in patients with metastatic disease since the 1940s [2] and is being increasingly utilized in patients with less advanced disease [3].
The benefits of adding an antiandrogen such as flutamide or bicalutamide to gonadal androgen suppression at the time of initiating androgen deprivation (early use) are modest at best [4]. The late addition of an antiandrogen after initial failure of androgen deprivation (late use) seems to result in prostate-specific antigen (PSA) declines, and in some cases, objective responses [5]. Thus, at one point or another, most patients with advanced prostate cancer will be treated with an antiandrogen. Despite androgen deprivation, including the use of an antiandrogen, most patients will experience disease progression. For patients with progressive disease, despite androgen deprivation, withdrawal of antiandrogen has been reported to result in a decline in PSA level of The duration of decline in PSA observed with antiandrogen withdrawal (AAWD) is brief, with a median duration of 3.5 to 5.0 months [6-8], after which further therapy is generally required. The mechanism by which prostate cancer patients develop disease progression after AAWD is not understood, but it has been postulated that persistence of a clone of cells with partial or full sensitivity to testosterone might be provided a growth advantage by androgen produced by the adrenal glands. If this were the case, it could be anticipated that adrenal androgen suppression would demonstrate some anticancer activity in this setting. An early report suggested that the addition of aminoglutethimide (an adrenal steroid synthesis inhibitor) at the time of AAWD increased the percentage of patients with a decline in PSA over that which would be expected with antiandrogen alone [10].
Ketoconazole is an azole antifungal agent which exerts its clinical effect through the inhibition of cytochrome P450 14a-demethylase, a catalyst of the conversion of lanosterol to cholesterol. Ketoconazole has been in clinical use as an antifungal agent for more than 20 years. In its initial use as an antifungal agent, it was discovered that a proportion of men who used ketoconazole developed painful gynecomastia, which was later found to be due to the suppression of testicular and adrenal androgen production, and it was postulated that this adverse effect could be useful for prostate cancer therapy. Several trials have evaluated the use of ketoconazole in patients with androgen-independent prostate cancer (AiPCa), though most predated the use of PSA or an understanding of the AAWD syndrome [11-14]. Most recently, the use of ketoconazole after AAWD was reported in a trial of 48 patients, 30 (63%) of whom demonstrated a It was hypothesized that the simultaneous addition of ketoconazole to AAWD would have additive anticancer activity, simultaneously targeting the stimulating effects of antiandrogen and adrenal androgens. Hence, the principal goals of this study were to prospectively evaluate and compare the effect of AAWD alone on PSA levels, compared with simultaneous AAWD and ketoconazole therapy. In addition, the effect of ketoconazole used in patients whose cancer had progressed after AAWD was also evaluated.
Patients Eligible patients had histologically confirmed adenocarcinoma of the prostate with progressive metastatic disease, as defined below, despite anorchid testosterone levels (< 50 ng/mL). Androgen deprivation therapy was required to include at least 4 weeks of ongoing therapy with an antiandrogen (flutamide, bicalutamide, or nilutamide). Ongoing gonadal androgen ablation with a luteinizing hormone-releasing hormone analog or orchiectomy was required. For patients with measurable disease, progression was defined as a greater than 25% increase in the sum of the products of the perpendicular diameters of all measurable lesions. For patients with "bone only" disease, a PSA greater than 5 ng/mL, which had risen from baseline on at least two successive occasions at least 4 weeks apart was required. Patients were required to have had metastatic disease demonstrated on imaging at some point during their history, but were not required to have demonstrated metastases on imaging at the time of enrollment. Patients were excluded if they had received prior chemotherapy, immunotherapy, experimental therapy, or prior treatment with ketoconazole, aminoglutethimide, or corticosteroids if they had a Cancer and Leukemia Group B (CALGB) performance status of more than 2, total bilirubin level greater than 1.5x the upper levels of normal (ULN), or serum glutamic-oxaloacetic transaminase level greater than 3x ULN. Because of potential interactions with ketoconazole, no ongoing or concurrent use of terfenadine, astemizole, or cisapride was allowed. All participants signed an institutional review board–approved, protocol-specific, informed consent form in accordance with federal and institutional guidelines.
Treatment Patient registration, subsequent randomization and data collection were managed by the CALGB Statistical Center. Furthermore, data quality was ensured by careful review of all data at the CALGB Statistical Center and by the study chairperson. Patients enrolled on the AAWD + ketoconazole arm received ketoconazole 400 mg tid po plus hydrocortisone 40 mg/d po (30 mg each morning and 10 mg every night) continuously until disease progression or unacceptable toxicity, as described below. Patients randomized to the AAWD-alone arm were required to cross over to treatment with ketoconazole on disease progression (see Response and Progression Criteria). Eligible patients were evaluated with a medical history and physical examination at study entry and monthly thereafter. In addition to a complete medical history and physical examination at each visit, patients were evaluated for adverse events. No formal quality-of-life or pain assessment was undertaken. CBC, PSA, total bilirubin, alkaline phosphatase, asparate transaminase, creatinine, glucose, and lactate dehydrogenase (LDH) were checked at baseline and then monthly. An endocrine panel including androstendione, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and testosterone was obtained at baseline, at 1 month after starting therapy, at 3 months after starting therapy, and at the time of disease progression. Blood samples were obtained between 8:00 AM and 10:00 AM. Plasma was isolated, frozen, and shipped for analysis at a central laboratory to determine androstendione, DHEAS, DHEA, and testosterone levels. A bone scan and computed tomography scan of the abdomen and pelvis were obtained at baseline. If imaging studies were positive at baseline, they were repeated every 3 months. Replacement doses of hydrocortisone were continued as long as the patient was receiving ketoconazole. When the patient was no longer receiving ketoconazole, hydrocortisone was tapered by 5 mg every 3 days until completely discontinued. Antacids, H-2 blockers, and proton pump inhibitors were avoided but not explicitly prohibited. This study did not mandate that ketoconazole be taken on an empty stomach or with acidifying procedures. At each visit, toxicity was graded according to the National Cancer Institute common toxicity criteria (CTC, version 2.0) and recorded. In the event of grade 3 or higher hepatotoxicity or symptomatic peptic ulcer or gastritis, patients were removed from protocol treatment. Antiemetics other than corticosteroids were permitted. If grade 2 or 3 nausea persisted despite these measures, the patient was removed from therapy. Patients developing other grade 3 or higher toxicity had treatment held until toxicity resolved to grade 1 or better. Any patient developing grade 4 toxicity or grade 3 toxicity persisting for longer than 4 weeks, except as outlined previously, was removed from protocol treatment.
Response and Progression Criteria
Statistical Methods
With 119 patients per arm, and a one-sided
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
The relationship between overall survival and 50% decline 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 landmark (eg, 8 weeks). Further, the patients alive at the landmark were classified as responders or nonresponders depending 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 relationship between survival duration, and PSA decline was examined. For the primary end point, a one-sided
Patient Characteristics Two hundred sixty patients were enrolled onto this study. No consistent approach to screening patients for this trial was mandated. One hundred thirty-two were randomized to AAWD alone and 128 were randomized to AAWD and ketoconazole. Patient characteristics, including stratification variables, are summarized in Table 1. With regard to stratification variables, approximately 36% of patients (on both arms) received prior flutamide, 59% had prior bicalutamide, and 4% to 5% had received nilutamide. Approximately 15% of patients had received prior intermittent androgen deprivation, and approximately 60% had received initial combined androgen blockade (luteinizing hormone-releasing hormone analog plus antiandrogen). Imaging studies were positive for metastatic disease in 97% and 94% of patients in the AAWD and AAWD and ketoconazole arms, respectively. The two arms were similar regarding age, sites of disease, requirement for opioid analgesics, and a variety of pretreatment prognostic factors, including performance status, hemoglobin, PSA, alkaline phosphatase, LDH, and creatinine. The median age of patients in both arms was just older than 70 years, and 93% had a performance status of 0 or 1. The median serum PSA levels at study entry was 58 ng/mL. Thirty-one percent of patients in the AAWD arm and 39% of patients in the AAWD and ketoconazole arms had measurable disease. More than 80% in both arms had bone metastases, and approximately one-third had lymph node involvement. Approximately 30% of patients were using opioid analgesics at the time of study entry.
Clinical Outcome Relevant clinical outcomes, including PSA decline, objective response rate, overall survival, and time to PSA progression are summarized in Table 2. Overall, 15 (11%; 95% CI, 7% to 17%) of 132 patients undergoing antiandrogen withdrawal alone experienced a 50% decline in PSA. By contrast, 34 (27%; 95% CI, 20% to 35%) of 128 patients who underwent AAWD and received simultaneous ketoconazole had a 50% decline in PSA (P = .002). In patients with a 50% decline in PSA, the subsequent median time to PSA progression was 5.9 months (95% CI, 5.3 to 10.1 months) and 8.6 months (95% CI, 5.7 to 20.4 months) in the AAWD alone and AAWD and ketoconazole arms, respectively (log-rank P = .063). Figure 1 demonstrates the overall PSA progression-free survival by treatment arm for those patients who had a 50% decline in PSA. Objective responses in measurable disease were observed in 1 (2%; 95% CI, 0.13% to 11%) of 41 of patients treated with AAWD alone, compared with 10 (20%; 95% CI, 11% to 32%) of 50 in the AAWD and ketoconazole arm (P = .02). While no longer currently in use, when the composite end points described were applied, 8 (6%) of 132 of patients treated with AAWD had a response, compared with 22 (17%) of 128 of patients on the AAWD/ketoconazole arm (one-sided P = .004).
Eighty-two percent of patients (108 of 132) treated with AAWD alone ultimately received "deferred" ketoconazole/hydrocortisone therapy. Twenty-four patients assigned to initial AAWD alone never received deferred ketoconazole for a variety of reasons, including disease progression and withdrawal of consent. Of the 108 patients receiving deferred ketoconazole, a decline in PSA of 50% was observed in 35 (32%) of 108 patients. An objective response was seen in 3 (7%) of 41 patients treated with AAWD followed by deferred ketoconazole. Although the study was not designed to compare the aggregate PSA declines and objective responses in patients treated with simultaneous versus sequential AAWD and ketoconazole, there did not seem to be an advantage of either approach over the other. In aggregate, 40 (30%) of 132 patients treated with AAWD followed by ketoconazole had a PSA decline of 50% compared with 34 (27%) of 128 of patients treated with simultaneous AAWD and ketoconazole. The median survival time was 16.7 months (95% CI, 14.3 to 21.5 months) in the AAWD-alone arm, and 15.3 months (95% CI, 13.4 to 19.5 months) in the group of patients who received simultaneous AAWD and ketoconazole therapy (two-sided P = .936; Fig 2).
For those patients receiving sequential AAWD followed by ketoconazole, prior PSA "response" (decline of 50%) after AAWD seemed to be associated with a higher likelihood of PSA response to subsequent ketoconazole. Overall, 35 patients had a PSA response when treated with deferred ketoconazole. Ten of these PSA responses occurred in the group of 15 patients who had obtained a prior PSA response to AAWD (10 of 15; 67%), whereas an additional 25 patients had a response to deferred ketoconazole from among a group of 117 patients (25 of 117; 21%) who had failed to achieve a PSA response after AAWD.
A proportional hazards model was used to identify predictors of overall survival. Pretreatment PSA, alkaline phosphatase, LDH, and hemoglobin levels, each dichotomized at the median; the presence or absence of weight loss at the time of study entry; and prior therapy with flutamide but not treatment arm, were predictors of survival (Table 3). In addition, using a 4-week landmark analysis, a
Toxicity Overall, 7% of patients undergoing AAWD alone had a grade 3 or 4 toxicity (all presumably attributed to causes other than AAWD itself), but no one toxicity occurred in more than 3% of patients. Twenty-one percent of patients receiving ketoconazole had grade 3 and 4 toxicities. The most common toxicities with ketoconazole were neurologic toxicity (4%), which consisted of motor neuropathy and ototoxicity, and malaise or fatigue (3%; Table 4). Grade 3 or 4 hepatic toxicity was observed in 2% of patients receiving ketoconazole, and was not more common than in the AAWD arm.
Adrenal Androgen Levels Baseline plasma adrenal androgen levels are available on 213 patients, 113 in the AAWD-alone arm, and 100 in the AAWD and ketoconazole arm. One hundred sixty-four patients had levels drawn after 1 month of therapy; 81, after 3 months; and 111, at progression, which occurred at a median of 3.1 months after starting therapy (95% CI, 2.1 to 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 testosterone level was 13 ng/mL, and did not change over time in either treatment arm. DHEA, DHEAS, and androstendione levels did not change appreciably over time in the AAWD group (data not shown). By contrast, in the AAWD and ketoconazole group, there was a decline in levels of all three adrenal androgens (DHEA, DHEAS, androstendione), accounting for declines from baseline of 54%, 90%, and 58%, respectively, at 1 month. There was a rise in all three adrenal androgen levels at the time of disease progression, though not back to baseline (Table 5). The difference between DHEAS and androstendione levels at month 1 and at the time of progressive disease are significant (P = .0001).
This prospective, randomized phase III trial has compared changes in PSA levels as well as objective responses in metastatic AiPCa patients treated with either AAWD alone or with AAWD plus simultaneous ketoconazole and hydrocortisone replacement therapy. No difference in survival was observed, though the planned use of deferred ketoconazole in the AAWD-alone arm may have blunted a treatment effect.
This study has demonstrated that PSA declines and objective responses after AAWD are uncommon. A PSA decline of
Ketoconazole seems to have moderate activity in AiPCa patients following AAWD or with concurrent AAWD. PSA decreases of
The percentage of patients with a
While the use of PSA as an intermediate marker of response and outcome remains controversial, an emerging body of literature supports the use of a This is the largest study to evaluate adrenal androgen levels in patients treated with ketoconazole. These data indicate that levels of DHEA, DHEAS, and androstendione all fall with treatment with ketoconazole, but as anticipated, do not fall with AAWD alone. Moreover, it appears that there is a modest increase in median adrenal androgen levels at the time of progression that reached statistical significance (P = .0001) for DHEAS and androstendione. Whether this increase is sufficient to account for disease progression is not known. However, it suggests that at least part of the reason patients develop progressive disease while on ketoconazole is tachyphylaxis to the adrenolytic properties of ketoconazole. The correlation of adrenal androgen levels, both at baseline and over time, with clinical outcomes including response, response duration, and survival, is under way and will be reported elsewhere. In summary, AAWD results in PSA declines and objective responses in patients with metastatic AiPCa only rarely. Second-line ketoconazole, either at the time of AAWD or following AAWD, is a reasonable, well tolerated treatment option with moderate activity in this group of patients.
The following institutions participated in this study: CALGB Statistical Office, Durham, NC —Stephen George, PhD; supported by CA33601, Dartmouth Med School-Norris Cotton Cancer Ctr., Lebanon, NH–Marc S. Ernstoff, MD; supported by CA04326, Georgetown Univ. Medical Center, Washington, DC, Edward Gelmann, MD,, supported by CA77597, Illinois Oncology Research Assoc, Peoria, IL, John W. Kugler, MD, supported by CA35113, Mount Sinai School of Medicine, New York, NY–Lewis R. Silverman, MD; supported by CA04457, Rhode Island Hospital, Providence, RI–Louis A. Leone, MD; supported by CA08025, Roswell Park Cancer Institute, Buffalo, NY–Ellis Levine, MD; supported by CA02599, SUNY Upstate Medical University, Syracuse, NY–Stephen L. Graziano, MD; supported by CA21060, University of California at San Diego, San Diego, CA–Stephen L Seagren, MD; supported by CA11789, University of California at San Francisco, San Francisco, CA–Alan P. Venook, MD; supported by CA60138, University of Chicago Medical Center, Chicago, IL - Gini Fleming, MD, supported by CA41287, University of Illinois MBCCOP, Chicago, IL–Thomas Lad, MD; supported by CA74811, University of Iowa, Iowa City, IA, Gerald Clamon, MD, supported by CA47642, University of Maryland Cancer Center, Baltimore, MD–Martin Edelman, MD; supported by CA31983, Univ. of Massachusetts Medical Center, Worcester, MA, Mary Ellen Taplin, MD, supported by CA37135, University of Minnesota, Minneapolis, MN–Bruce A Peterson, MD; supported by CA16450, Univ. of Missouri/Ellis Fischel Cancer Ctr, Columbia, MO–Michael C Perry, MD; supported by CA12046, University of Nebraska Medical Center, Omaha, NE–Anne Kessinger, MD; supported by CA77298, University of Tennessee Memphis, Memphis, TN–Harvey B. Niell, MD; supported by CA47555, Vermont Cancer Center, Burlington, VT–Hyman B. Muss, MD; supported by CA77406, Wake Forest Univ. School of Medicine, Winston-Salem, NC–David D Hurd, MD; supported by CA03927, Walter Reed Army Medical Center, Washington, DC–Joseph J. Drabeck, MD; supported by CA26806, Washington University School of Medicine, St. Louis, MO, Nancy Bartlett, MD, supported by CA77440, Weill Medical College of Cornell Univ, New York, NY–Michael Schuster, MD; supported by CA07968.
The authors indicated no potential conflicts of interest.
Supported by grants CA60138 (E.J.S. and B.I.R.), CA47577 (S.H. and E.K.), CA31983 (N.A.D.), CA41287 (W.M.S. and N.J.V.), CA77440 (J.P.), CA11789 (P.G.), and CA03927 (F.M.T.). The research for Cancer and Leukemia Group B Trial 9583 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman). The research was also supported by Janssen Pharmaceutica Products, LP. Presented in part at the American Society of Clinical Oncology annual meeting, San Francisco, CA, May 12-15, 2001. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
of .05, the independent two-group binomial test had 80% power to detect a difference in the percentage of patients with a partial or complete (composite) response from 25% in the AAWD group, to 40% in the AAWD + ketoconazole arm. Allowing for a 5% ineligibility rate, the target sample size was 250 patients. 
2 and Fisher's exact test were used to compare the two arms with regard to response rates (composite end point), objective response rates, and 50% decline in PSA [
