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Phase II Trial of Docetaxel With Rapid Androgen Cycling for Progressive Noncastrate Prostate Cancer

Dana Rathkopf, Michael A. Carducci, Michael J. Morris, Susan F. Slovin, Mario A. Eisenberger, Roberto Pili, Samuel R. Denmeade, Moshe Kelsen, Tracy Curley, Melinda Halter, Connie Collins, Martin Fleisher, Glenn Heller, Sharyn D. Baker, Howard I. Scher

From the Genitourinary Oncology Service, Department of Medicine, Department of Epidemiology and Biostatistics, and the Department of Clinical Chemistry, Memorial Sloan-Kettering Cancer Center; Department of Medicine, Joan and Sanford Weill College of Medicine, New York, NY; Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; and Pharmaceutical Sciences Department, St Jude Children's Research Hospital, Memphis, TN

Corresponding author: Howard I. Scher, MD, Sidney Kimmel Center for Prostate and Urologic Cancers, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, New York 10021; e-mail: scherh{at}mskcc.org

	ABSTRACT

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Purpose We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers.

Patients and Methods Noncastrate patients with 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m²), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m²), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; 0.05, 0.5, or 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated.

Results A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% v 0%). The 16% incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles.

Conclusion The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.

	INTRODUCTION

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Hormone manipulations alone do not cure prostate cancer because cells that can resist and or survive the effects of androgen depletion are present when the disease is first manifest. Even when the sole manifestation of progression is a rising prostate-specific antigen (PSA) and overall tumor burden is low, hormone manipulations are not curative. Serial histologic studies of prostate cancer xenografts and human prostate cancers show that as early as 1 week after androgen depletion, the surviving cells are nonproliferating and there is little evidence of apoptosis.^1,2 These arrested cells resume proliferating after testosterone is administered,^1,3 or when testosterone levels are allowed to increase using an intermittent androgen depletion approach. Previously, in an effort to increase apoptotic rates, we explored a strategy of rapid androgen depletion and repletion in 28-day cycles in the clinic. While the results showed that repetitive apoptotic cycles could be induced, the overall response rate was not increased.⁴

Chemotherapy in combination with androgen depletion has also been explored in the states of rising PSA and clinical metastases noncastrate⁵ as a way to enhance the efficacy of androgen depletion. Unfortunately, the results to date have been inconclusive, as no trial has been shown to improve outcomes or prolong life relative to androgen depletion alone.^6-12 A drawback to this approach is that at a time of cell cycle arrest chemotherapy may be of limited benefit. This trial is based on the hypothesis that prostate cancer cells will be more sensitive to docetaxel when they are proliferating during the androgen repletion phases of rapid androgen cycling (Fig 1).

View larger version (47K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Idealized patient outcome on docetaxel (Doc) and rapid androgen cycling with leuprolide (GNRH) and testosterone repletion (T). The dotted line represents peak and trough testosterone levels in response to testosterone depletion and repletion. The solid line represents successive declines in peak and trough prostate-specific antigen (PSA) values in response to each cycle of treatment.

	PATIENTS AND METHODS

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This was an institutional review board–approved study including Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (JHU; Baltimore, MD). All patients signed an institutional review board–approved informed consent.

Patient Eligibility
Eligible patients had prostate cancer histologically confirmed at their treating institution, noncastrate testosterone levels (> 150 ng/dL), and progressive metastatic disease or rising PSA. Rising PSA was defined as a minimum baseline of 2 ng/mL with at least three determinations obtained more than 2 weeks apart demonstrating a 50% or greater increase in value. Additional eligibility requirements included: 6 months of prior hormone therapy; Karnofsky performance status of 70%; and adequate organ function.

Study Design
In cohort 1, patients received six 4-week cycles consisting of once per month leuprolide (7.5 mg intramuscularly [IM]) and docetaxel (75 mg/m²) on day 1 of each cycle, with testosterone repletion (AndroGel 1%, 5 g topical daily; Souvay Pharmacueticals, Marietta, GA) for 7 days before initiation of each subsequent cycle. In cohort 2, patients received nine 3-week cycles of 3-month depot leuprolide (22.5 mg IM) on day 1 of cycles 1, 5, and 9, docetaxel (70 mg/m²) on day 1, and testosterone repletion (AndroGel 1%, 5 g topical daily) for 3 days before initiation of each subsequent cycle. The total duration of leuprolide therapy was 24 weeks in cohort 1 and 36 weeks in cohort 2.

Patient Evaluation
Patients were examined and assessed for adverse events monthly while receiving treatment. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria, version 2.0. Patients were required to submit a drug diary for recording testosterone gel administration and toxicities during the cycling phase. Patients who had metastatic disease evident on baseline imaging (computed tomography scan, magnetic resonance imaging, or bone scan) had follow-up studies at 3-month intervals. Patients with no radiographic abnormalities received imaging every 6 months.

PSA and Testosterone Measurements
Blood for PSA and testosterone measurements was collected twice during each cycle: peak samples before docetaxel on day 1 and trough samples before androgen repletion (day 22 in cohort 1 and day 19 in cohort 2). PSA was determined by a two-site immunoenzymometric assay using the Nexia analytic system (Tosoh Medics, South San Francisco, CA). Total testosterone concentrations at MSKCC were determined by a solid-phase radioimmunoassay (Diagnostic Products Corp, Los Angeles, CA) with an analytic sensitivity of 10 ng/dL. For patients at JHU, a chemiluminescence immunoassay with an analytic sensitivity of 20 ng/dL was used.

CYP3A4 Activity
CYP3A4 activity was assessed using the erythromycin breath test as previously described.¹⁴ The test was administered to 12 cohort 1 patients before cycles 1 (without testosterone administration) and 2 (with testosterone administration), within 48 hours before docetaxel administration. A breath sample was obtained at 20 minutes after administration of ¹⁴C-labeled erythromycin, then shipped to Metabolic Solutions (Nashua, NH) for measurement of breath carbon dioxide. The data were reported as the flux of ¹⁴CO₂. The parameter of interest was the percentage of ¹⁴C exhaled per minute at 20 minutes after administration of the radiolabeled erythromycin (C_{20 minutes} [% dose/min]).

Pharmacokinetic Sampling and Analysis
Docetaxel pharmacokinetics were determined in 12 patients at the start of cycles 1 (without testosterone) and 2 (with testosterone administration) at the following time points: immediately before docetaxel treatment, 30 minutes into the infusion, at 59 minutes (just before the end of the docetaxel infusion), and postinfusion at 10 minutes, 30 minutes, 1, 3 and 7 hours, and the morning of days 2 (24 hours), 3 (48 hours), and 8, 15, and 22. Docetaxel concentrations in plasma were quantitated using a validated analytic assay consisting of high-performance liquid chromatography with mass spectrometric detection, as previously described.¹⁵ The lower limit of quantitation for docetaxel was 0.4 ng/mL.

Individual docetaxel pharmacokinetic parameters were estimated using model-dependent methods as implemented in WINNonlin (Scientific Consultant, Apex, NC) version 5.1 (Pharsight Corp, Mountainview, CA). Concentration-time data were fit with a three-compartment model using PK model 19 and the Gauss-Newton (Levenberg and Hartley) method for the fitting of nonlinear regression functions. Calculated secondary pharmacokinetic parameters included systemic clearance, area under the concentration-time curve from time zero to infinity (AUC_inf), half-life during the terminal phase of the disposition curve (t_1/2,), and volume of distribution at steady-state (V_ss). Maximum plasma concentration (C_max) values were the observed values.

Statistical Analysis
The primary end point was the proportion of patients with a treatment-specific undetectable PSA and noncastrate testosterone (> 150 ng/dL) at 18 months from the start of therapy. Treatment-specific undetectable PSA was defined as 0.05 ng/mL after prostatectomy, 0.5 ng/mL after radiation therapy, or 2.0 ng/mL for patients with metastatic disease without prior definitive therapy. We defined this event as a response and planned to declare the treatment active in either study cohort if the probability of a response in the population exceeded 0.15. A single-stage design that differentiated between population response probabilities of 0.15 and 0.35 was used. Progression was defined as three consecutive rises in PSA and/or evidence of disease progression on imaging.

For docetaxel pharmacokinetic studies, the sample size of 12 would detect an effect size of 1.25, assuming no period effects, with of .01 and a power of 95% using a pairwise two-sided analysis. Sample size calculations were performed using NCSS 1001/Pass 2002 (Number Cruncher Statistical Systems, Kaysville, UT). For docetaxel pharmacokinetics and CYP3A activity, a paired t-test was used to compare parameters between cycles 1 and 2.

	RESULTS

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Patients
Between August 3, 2003, and January 6, 2006, 102 patients were enrolled on trial, 63 at MSKCC and 39 at JHU. The demographics, disease status, and prior treatment histories of the patients are detailed in Table 1.

Testosterone levels are detailed in Table 2. The median peak testosterone levels at baseline were in the normal physiologic range ( 150 ng/dL) for all but one patient, and in the non-castrage range for all but one patient postandrogen repletion on both the 21-day and 28-day schedules with 3 and 7 days of androgen repletion, respectively. Trough values before testosterone repletion were all 50 ng/dL.

	DISCUSSION

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The trial builds on our phase I study of rapid androgen cycling which showed that serially declining PSA peaks and troughs to undetectable levels could be achieved.⁴ The design extrapolates from studies in other tumor types showing that a chemotherapy regimen that is not curative in advanced disease can increase cure rates in patients with minimal tumor burdens. We hypothesized that administering chemotherapy to quiescent nonproliferating cells would be of limited value, a concept supported by recent data showing that androgen receptor activation significantly enhanced the response to docetaxel in androgen receptor proficient cells that were actively cycling. The mitogenic effects of androgen were distinct from an effect on PSA secretion, while the proapoptotic effects of docetaxel were reduced significantly by the coadministration of an androgen receptor antagonist.¹⁸ Separately, a microarray analysis of human radical prostatectomy specimens removed after neoadjuvant docetaxel showed a coordinate increase in the enzymes associated with androgen catabolism and a decrease in the levels of those associated with androgen synthesis. The net result was a decrease in androgen bioavailability, and reduced androgen signaling.¹⁹ Repetitive treatments with docetaxel reduced the antiproliferative effects of androgen depletion even when testosterone levels were in the noncastrate range.

To identify strategies likely to succeed in the phase III setting, it is essential to establish a clinical regimen and define a relevant end point that allows the results to be placed in the context of other phase II trials in the same patient group. We have focused our phase II efforts on patients who have a PSA recurrence alone or PSA recurrence with clinical metastases after definitive local treatment, using the unambiguous end point of a treatment-specific undetectable PSA nadir and noncastrate levels of testosterone levels.¹³ This end point allows patients and physicians alike to clearly demarcate those who have had a complete response, a prerequisite for cure, versus those with residual disease evidenced by detectable PSA values. The end point was derived from our work showing that the likelihood of achieving an undetectable PSA varies as a function of disease extent and the presence or absence of detectable disease on scans.¹³ The end point has also been shown to provide prognostic significance in an interim analysis of patients treated with androgen depletion for a rising PSA after primary therapy²⁰ and separately in a Southwest Oncology Group phase III trial of intermittent androgen depletion for patients with noncastrate clinical metastases.²¹ Both analyses showed that patients who did not achieve an undetectable PSA nadir after androgen depletion had an increased risk of prostate cancer–specific mortality.

The results of this study show how the undetectable PSA end point can be utilized in the clinic. In cohort 1, 36% of patients (nine of 25, 95% CI, 20% to 55%) with a rising PSA, and 38% (14 of 37; 95% CI, 24% to 54%) of those with clinical metastases achieved an undetectable PSA at 6 months, but responses were not durable. Consequently, the docetaxel schedule was shortened to every 21 days, (consistent with the approved standard),^22,23 the number of cycles was increased from six to nine, the period of androgen depletion increased from 24 to 36 weeks, and the duration of testosterone administration reduced from 7 days to 3. The rationale for the latter was based on studies in transgenic mouse models showing that after testosterone repletion the proliferation rates of quiescent prostate cancer cells peak at 3 days and decline to baseline after 7 to 20 days.³

In cohort 2, 18 of 28 patients achieved the end point after six docetaxel cycles, and an additional seven patients achieved the end point after nine docetaxel cycles. At 18 months, none of the patients in cohort 1, and 5 (13%) in cohort 2, had undetectable PSA levels. While it is possible that the additional three cycles of docetaxel and 36 weeks versus 24 weeks of GnRH agonist exposure contributed to the durability of outcomes in cohort 2, it is noteworthy that all of the patients with an undetectable PSA at 18 months had achieved it by six cycles of treatment. This suggests that the higher dose intensity of a 21-day versus 28-day cycle, and shorter duration of testosterone repletion, was most contributory to the improved outcomes.

The adverse events were similar to those observed with androgen depletion and chemotherapy administered separately.²¹ Noteworthy, however, was the incidence of febrile neutropenia in this population (14% to 18%) which was higher than that observed in patients with castration-resistant disease (3%) or advanced non–small-cell lung cancer (6%) using comparable docetaxel schedules (75 mg/m² once every 3 weeks).^22-24 This may be explained in part by the approximately 50% reduction in clearance and increase in AUC for docetaxel in the noncastrate population enrolled in this trial, relative to a group with castration-resistant disease.²⁵ The potential significance of these changes was shown in a population pharmacokinetic–pharmacodynamic model for docetaxel in which a 27% reduction of docetaxel clearance was associated with a 1.5-fold increase in the odds of developing febrile neutropenia.²⁶

Two trials have explored docetaxel and androgen depletion for patients with a rising PSA and noncastrate testosterone levels. In one study, after six cycles of docetaxel followed by 12 to 20 months of androgen depletion, five of 39 (12%) patients achieved a serum PSA of 0.1 ng/mL after treatment although testosterone levels were not reported.²¹ This response correlated with our results at 18 months in cohort 2. A similar study administering four cycles of estramustine and docetaxel followed by 15 months of androgen depletion, reported 20 of 56 patients (36%) achieving an undetectable PSA at 1 year after completion of therapy. It is of note that this patient cohort did not include metastatic or untreated primary disease which may have contributed to the relatively high response rate.¹¹

To demonstrate that an intervention in the noncastrate state delays disease progression or prolongs life can be difficult because of patient heterogeneity and an often protracted natural history of disease. This study shows how an objective, unambiguous, and reproducible end point that can be assessed in a reasonable timeframe, can be used to screen different treatment approaches. Given the low durable response rate and increased toxicity, we would not recommend this regimen for further study. Future trials must continue to seek to improve on standard hormone regimens, using end points appropriate to both the disease state under study and individual patient risk. Toward that end, we plan to utilize the undetectable PSA end point in a randomized phase III study of androgen depletion with or without docetaxel for patients with a rapid PSA doubling time and high risk of cancer-specific mortality.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "Urdquo; are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Michael A. Carducci, Sanofi-aventis (C); Michael J. Morris, Sanofi-aventis (C); Mario A. Eisenberger, Sanofi-aventis (C); Howard I. Scher, Sanofi-aventis (U) Stock Ownership: None Honoraria: Michael A. Carducci, Sanofi-aventis; Michael J. Morris, Sanofi-aventis; Mario A. Eisenberger, Sanofi-aventis Research Funding: Mario A. Eisenberger, Sanofi-aventis; Sharyn D. Baker, Sanofi-aventis; Howard I. Scher, Sanofi-aventis Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Michael A. Carducci, Susan F. Slovin, Sharyn D. Baker, Howard I. Scher

Financial support: Michael A. Carducci

Administrative support: Michael A. Carducci, Moshe Kelsen, Howard I. Scher

Provision of study materials or patients: Dana Rathkopf, Michael A. Carducci, Michael J. Morris, Susan F. Slovin, Mario A. Eisenberger, Roberto Pili, Samuel R. Denmeade, Tracy Curley, Melinda Halter, Connie Collins, Martin Fleisher, Howard I. Scher

Collection and assembly of data: Dana Rathkopf, Michael A. Carducci, Samuel R. Denmeade, Moshe Kelsen, Tracy Curley, Melinda Halter, Sharyn D. Baker, Howard I. Scher

Data analysis and interpretation: Dana Rathkopf, Michael A. Carducci, Michael J. Morris, Susan F. Slovin, Mario A. Eisenberger, Moshe Kelsen, Tracy Curley, Connie Collins, Glenn Heller, Sharyn D. Baker, Howard I. Scher

Manuscript writing: Dana Rathkopf, Michael A. Carducci, Michael J. Morris, Sharyn D. Baker, Howard I. Scher

Final approval of manuscript: Michael A. Carducci, Susan F. Slovin, Mario A. Eisenberger, Roberto Pili, Melinda Halter, Connie Collins, Sharyn D. Baker, Howard I. Scher

	NOTES

 
Supported by the Prostate Cancer Foundation, grant No. P50-CA92629 Specialized Program of Research Excellence from the National Cancer Institute, Sanofi-aventis Grant-in-Aid No. 16143 for investigator-sponsored trial 16143, and by the Department of Defense Prostate Cancer Research Program Clinical Consortium Grant No. PC051382 (Johns Hopkins W81XWH-06-1-0241 to D.R.).

Presented in part in abstract format at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007; and at the American Society of Clinical Oncology Prostate Cancer Symposium, Orlando, FL, February 22-24, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted November 2, 2007; accepted January 18, 2008.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rathkopf, D. Articles by Scher, H. I. Search for Related Content PubMed PubMed Citation Articles by Rathkopf, D. Articles by Scher, H. I. Related Articles Related Editorial Social Bookmarking                            What's this?