V O L U M E 2 6 䡠 N U M B E R 2 䡠 J A N U A R Y 1 0 2 0 0 8
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Princess Margaret Hospital
`and University of Toronto, Toronto,
`Ontario, Canada; Erasmus University
`Medical Center, Rotterdam, the Nether-
`lands; and Sydney Kimmel Comprehen-
`sive Cancer Center, Johns Hopkins
`University, Baltimore, MD.
`
`Submitted May 1, 2007; accepted
`October 3, 2007.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: Ian F. Tannock,
`MD, PhD, FRCPC, Princess Margaret
`Hospital, 610 University Ave, Toronto,
`ON, M5G 2M9, Canada; e-mail:
`ian.tannock@uhn.on.ca.
`
`© 2008 by American Society of Clinical
`Oncology
`
`0732-183X/08/2602-242/$20.00
`
`DOI: 10.1200/JCO.2007.12.4008
`
`Docetaxel Plus Prednisone or Mitoxantrone Plus
`Prednisone for Advanced Prostate Cancer: Updated Survival
`in the TAX 327 Study
`Dominik R. Berthold, Gregory R. Pond, Freidele Soban, Ronald de Wit, Mario Eisenberger, and Ian F. Tannock
`
`A
`
`B
`
`S
`
`T
`
`R
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`A
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`C
`
`T
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`Purpose
`The TAX 327 study compared docetaxel administered every 3 weeks (D3), weekly docetaxel (D1),
`and mitoxantrone (M), each with prednisone (P), in 1,006 men with metastatic hormone-resistant
`prostate cancer (HRPC). The original analysis, undertaken in August 2003 when 557 deaths had
`occurred, showed significantly better survival and response rates for pain, prostate-specific
`antigen (PSA), and quality of life for D3P when compared with MP. Here, we report an updated
`analysis of survival.
`Methods
`Investigators were asked to provide the date of death or last follow-up for all participants who
`were alive in August 2003.
`Results
`By March 2007, data on 310 additional deaths were obtained (total ⫽ 867 deaths). The survival
`benefit of D3P compared with MP has persisted with extended follow-up (P ⫽ .004). Median
`survival time was 19.2 months (95% CI, 17.5 to 21.3 months) in the D3P arm, 17.8 months (95%
`CI, 16.2 to 19.2 months) in the D1P arm, and 16.3 months (95% CI, 14.3 to 17.9 months) in the
`MP arm. More patients survived ⱖ 3 years in the D3P and D1P arms (18.6% and 16.6%,
`respectively) compared with the MP arm (13.5%). Similar trends in survival between treatment
`arms were seen for men greater than and less than 65 years of age, for those with and without
`pain at baseline, and for those with baseline PSA greater than and less than the median value of
`115 ng/mL.
`Conclusion
`The present analysis confirms that survival of men with metastatic HRPC is significantly longer
`after treatment with D3P than with MP. Consistent results are observed across subgroups
`of patients.
`
`J Clin Oncol 26:242-245. © 2008 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Men with advanced prostate cancer are usually
`treated with androgen ablation therapies. Most men
`respond initially to hormonal treatment, but their
`disease evolves and becomes resistant to further hor-
`monal therapy. Metastases, particularly to bone and
`lymph nodes, are frequent in men with hormone-
`refractory prostate cancer (HRPC). Men with
`HRPC frequently have pain and other symptoms
`leading to impairment of quality of life (QOL).
`Prostate cancer was considered resistant to
`chemotherapy until the mid-1990s, when mitox-
`antrone with prednisone (MP) was shown in a Ca-
`nadian study to have a role in the palliative
`treatment of metastatic HRPC.1 Men with HRPC
`experienced an improvement in pain and QOL if
`
`treated with MP compared with prednisone alone.
`No survival benefit was detected in trials comparing
`mitoxantrone plus corticosteroids with corticoste-
`roids alone, although the studies were not powered
`to detect small differences in survival.1,2
`In 2004, reports of the TAX 327 and Southwest
`Oncology Group 99-16 studies showed significant
`survival benefit when docetaxel-based treatment
`was compared with mitoxantrone for men with
`metastatic HRPC.3,4 The TAX 327 study randomly
`assigned 1,006 men with metastatic HRPC to receive
`docetaxel 75 mg/m2 administered every 3 weeks
`(D3P), docetaxel 30 mg/m2 administered weekly for
`5 of 6 weeks (D1P), or mitoxantrone 12 mg/m2
`every 3 weeks (MP), each with prednisone 5 mg
`twice daily. The study showed significantly longer
`survival for the D3P arm compared with MP,
`
`242
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`AVENTIS EXHIBIT 2217
`Mylan v. Aventis IPR2016-00712
`
`

`
`TAX 327 Study: Survival Update
`
`Docetaxel 3-weekly
`Docetaxel weekly
`Mitoxantrone
`
`
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Proportion Alive
`
`0
`
`1
`
`2
`
`
`
`
`
`3
`4
`Time (years)
`
`5
`
`6
`
`7
`
`Fig 1. Overall survival data from March 2007, with 867 deaths among 1,006
`randomly assigned patients.
`
`months in the D3P arm, 17.8 months in the D1P arm, and 16.3
`months in the MP arm. When compared with the previous analysis,
`the difference in median survival between the D3P and MP arms has
`increased slightly to 2.9 months, the hazard ratio (HR) has changed
`minimally, and the P value is slightly stronger (P ⫽ .004). The differ-
`ence in survival between the D1P and MP arms remains nonsignifi-
`cant (P ⫽ .09). The percentages of patients who survived for more
`than 3 years in the D3P, D1P, and MP arms were 18.6%, 16.8%, and
`13.5%, respectively (Table 1).
`Subgroup Analyses
`Median survival times and 95% CIs for the defined subgroups as
`a function of treatment arm are shown as a Forrest plot in Figure 2.
`
`Table 1. Survival of Men Treated With D3P, D1P, or MP: Initial and
`Updated Data
`
`Data
`
`D3P (n ⫽ 335) D1P (n ⫽ 334) MP (n ⫽ 337)
`
`Original data, 2003
`Patients who died
`No.
`%
`Survival time, months
`Median
`Range
`Hazard ratio
`95% CI
`
`P
`Updated data, 2006-2007
`Patients who died
`No.
`%
`Survival time, months
`Median
`Range
`Hazard ratio
`95% CI
`
`P
`Survival ⬎ 3 years
`3-year survival rate, %
`
`166
`50
`
`190
`57
`
`18.9
`17.0-21.2
`0.76
`0.62 to 0.94
`.009
`
`17.4
`15.7-19.0
`0.91
`0.75 to 1.11
`.36
`
`285
`85.1
`
`285
`85.3
`
`19.2
`17.5-21.3
`0.79
`0.67 to 0.93
`.004
`
`17.8
`16.2-19.2
`0.87
`0.74 to 1.02
`.086
`
`201
`60
`
`16.5
`14.4-18.6
`
`297
`88.1
`
`16.3
`14.3-17.9
`
`18.6
`
`16.8
`
`13.5
`
`Abbreviations: D3P, docetaxel administered every 3 weeks plus prednisone;
`D1P, weekly docetaxel plus prednisone; MP, mitoxantrone plus prednisone.
`
`although significant differences were not found for the D1P arm. The
`D3P arm also showed better palliation, with a higher probability of
`pain and QOL response (and prostate-specific antigen [PSA] re-
`sponse) compared with MP. At the time of the initial analysis in
`August 2003, 557 of 1,006 participants in the trial had died.3 Here, we
`report an updated survival analysis of the TAX 327 study. We also
`provide results for patient subgroups that were defined according to
`baseline characteristics.
`
`METHODS
`
`Details of eligibility and exclusion criteria are provided in the initial report.3 In
`brief, men with metastatic prostate cancer were eligible if there was clinical or
`radiologic evidence of progressive disease or three increasing values of serum
`PSA, despite primary androgen deprivation. No previous therapy with cyto-
`toxic agents except estramustine was permitted. Patients were required not to
`have other major medical conditions and were stratified by presence or ab-
`sence of significant baseline pain and by Karnofsky performance status (KPS;
`required to be ⱖ 70%).
`Physical examination and radiologic investigations, including computed
`tomography and bone scanning, were performed at baseline, along with blood
`tests, including serum PSA. Pain was self-reported using the Present Pain
`Intensity (PPI) scale from the McGill-Melzack questionnaire.5 Participants
`kept a pain diary, and the daily analgesic intake was summed to give an
`Analgesic Score (AS) by assigning 4 points for a standard dose of narcotic
`analgesics and 1 point for a standard dose of non-narcotic analgesics; patients
`were regarded as having substantial pain if the baseline PPI was ⱖ 2 or ASⱖ 10.
`QOL was assessed with the Functional Assessment of Cancer Therapy–Pros-
`tate (FACT-P) questionnaire.6 The maximum score is 156 points, indicating
`excellent QOL. Minimally symptomatic patients were defined by a near nor-
`mal level of QOL (FACT-P score ⬎ 128), minimal pain (PPI ⬍ 2), and low
`analgesic consumption (AS ⬍ 10). Treatment was planned for up to 10 cycles
`of 3 weeks for the D3P arm and up to five cycles of 6 weeks for the D1P arm.
`Patients were evaluated for pain, QOL, and serum PSA every 3 weeks. They
`were observed until progression of disease, severe adverse event, or withdrawal
`of consent. Investigators were required to observe patients until death.
`The present update of survival has been undertaken by contacting inves-
`tigators and requesting the last date of follow-up or date of death of their
`patients. Ethics board approval was reactivated in centers where the approval
`for the TAX 327 study had expired.
`Overall survival was analyzed using the Kaplan-Meier method, and com-
`parisons between treatment arms were performed using the log-rank test; the
`D1P and D3P arms were compared individually with the MP arm. Exploratory
`subgroup analyses were also performed for patients separated on the basis of
`age, PSA at baseline, presence or absence of visceral disease, KPS, and levels of
`pain and QOL at baseline. For continuous outcomes (eg, age, PSA, and FACT-
`P), patients were grouped by the median value. All randomly assigned patients
`were included in the analysis of survival, and all randomly assigned patients
`with available baseline data were included in the subgroup analyses. All statis-
`tical tests were two-sided.
`
`RESULTS
`
`Overall Survival
`The study included 1,006 patients from 24 countries, and the
`initial survival analysis was performed in August 2003 when 557
`deaths had occurred. By March 2007, 310 additional deaths were
`recorded, resulting in a total of 867 deaths; 111 patients have been lost
`to follow-up, and 28 patients were alive with a last follow-up date
`within the previous year. Updated survival curves are shown in Figure
`1, and details are listed in Table 1. The median survival time was 19.2
`
`www.jco.org
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`243
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Subgroup
`
`All patients
`
`n
`
`Median OS
`
`1,006
`
`17.8
`
`Age ≤ 68
`Age ≥ 69
`
`No pain
`Pain
`
`KPS ≤ 80%
`KPS ≥ 90%
`
`FACT-P < 109
`FACT-P ≥ 109
`
`No visceral Dz
`Visceral Dz
`
`PSA < 115
`PSA ≥ 115
`
`504
`502
`
`550
`456
`
`410
`595
`
`408
`407
`
`777
`229
`
`507
`499
`
`17.6
`18.1
`
`21.3
`14.2
`
`13.5
`21.0
`
`14.8
`19.8
`
`18.9
`13.1
`
`20.4
`14.8
`
`Berthold et al
`
`3-weekly
`Weekly
`
`Fig 2. Survival among various subgroups
`treated on the TAX 327 trial. At left are the
`subgroups defined in this exploratory analysis,
`the number of patients in each subgroup, and
`their median survival time in months, indepen-
`dent of treatment. At right is a Forrest plot
`showing the median hazard ratios and their
`95% CIs for survival on the docetaxel arms
`compared with the mitoxantrone arm. OS,
`overall survival; KPS, Karnofsky performance
`status; FACT-P, Functional Assessment of
`Cancer Therapy–Prostate; Dz, disease; PSA,
`prostate-specific antigen.
`
`0.5
`
`1.3
`1.1
`1.0
`0.9
`0.7
`Hazard Ratio (compared to mitoxantrone)
`
`1.5
`
`Similar trends in survival between treatment arms were seen for pa-
`tients greater than and less than the median age of 68 years. The HRs
`for younger and older patients were 0.81 and 0.77, respectively, for
`D3P compared with MP. Similar results were found when using a
`more extreme age cutoff of 75 years (HR ⫽ 0.80 for older patients).
`In the TAX 327 study, the median serum PSA at baseline was 115
`ng/mL. Among patients with lower and higher PSA levels at baseline, the
`HRs were 0.83 and 0.73, respectively, indicating similar benefits of D3P
`compared with MP for patients with a greater or lesser burden of disease.
`The presence of visceral involvement is a known adverse prog-
`nostic factor for men with metastatic prostate cancer when compared
`with patients with only bone and/or nodal disease. In the present
`study, the 22% of patients with visceral disease died on average 6
`months earlier than those without visceral metastases. The HR was
`0.87 for the subgroup of men with visceral metastases when compar-
`ing D3P with MP.
`Patients with a KPS ⱖ 90% lived approximately 8 months longer
`than patients with a KPS ⱕ 80%; however, the HRs for these groups were
`similar at 0.75 and 0.82, respectively, for D3P compared with MP.
`There were 456 patients with substantial pain at baseline (defined
`by PPI ⱖ 2 and/or AS ⱖ 10), and survival time was shorter for those
`with pain. The HRs for patients without and with pain were 0.73 and
`0.85, respectively, for D3P compared with MP.
`Men with better or worse QOL, as indicated by their FACT-P
`score at baseline, had HRs of 0.92 and 0.66, respectively, when treated
`with D3P compared with MP. For minimally symptomatic patients
`(FACT-P score ⬎ 128, PPI ⬍ 2, and AS ⬍ 10), the trend for survival
`benefit was maintained for D3P compared with MP.
`
`DISCUSSION
`
`This updated survival analysis of the TAX 327 study is consistent with
`the previously reported results. The difference in median survival time
`
`for D3P compared with MP is now 2.9 months (P ⫽ .004, HR ⫽ 0.79).
`Treatment with D1P did not lead to a significant survival benefit
`compared with MP. Although differences in median survival are rel-
`atively small, they are accompanied by improvement in pain control
`and QOL and are clinically meaningful.
`As expected, patients with visceral disease, pain, poorer perfor-
`mance status, and higher values of baseline PSA had shorter survival
`times. In general, the survival benefit for patients randomly assigned to
`the D3P arm compared with the MP arm was consistent across sub-
`groups, adding support to the primary result. Therefore, the earlier
`mentioned factors are indicators of poor prognosis but not predictors
`of response.
`As described previously, men treated with weekly docetaxel were
`more likely to experience early deterioration of QOL.7 This result,
`either because of progression of disease or toxicity as a result of treat-
`ment, and the continuing evidence that this treatment does not lead to
`a significant improvement in survival compared with treatment with
`mitoxantrone indicate that the weekly docetaxel schedule should not
`be adopted, with the possible exception of patients who are at high risk
`of neutropenic fever.
`In contrast to the earlier Canadian study1 that evaluated mitox-
`antrone, the TAX 327 trial has included patients with and without
`symptoms. In general, the chances of prolonging survival with D3P
`seemed similar among patients with higher and lower disease burden
`as indicated by level of serum PSA, the presence or absence of substan-
`tial pain, and the QOL or performance score. This analysis does not
`address whether docetaxel should be used in patients with minimal
`symptoms or whether it is appropriate to defer treatment until more
`symptoms occur. However, considering the similar benefit among
`subgroups and the potential for QOL to deteriorate as a result of
`disease progression, it seems reasonable to offer treatment to patients
`with symptoms and to those who are likely to develop symptoms in
`the near future, based on the burden of disease and the PSA doubling
`
`244
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`
`

`
`TAX 327 Study: Survival Update
`
`time. There is no established second-line therapy for men with HRPC
`who experience progression after docetaxel therapy, but several trials
`are evaluating new agents. The number of patients fit enough for
`second-line therapy is likely to increase if first-line therapy with do-
`cetaxel is initiated earlier in the course of disease, but potential benefits
`of early treatment must be counterbalanced by the potential toxicity of
`treatment. Also, future studies should evaluate the cost effectiveness of
`docetaxel and other new treatments for men with prostate cancer.
`In conclusion, docetaxel administered every 3 weeks with pred-
`nisone remains the preferred treatment option for most patients with
`metastatic HRPC. The consistency of results among subgroups indi-
`cates rigorous data.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`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 “U” 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: Mario Eisenberger, Sanofi-Aventis (C), Saphire (C), Ipsen (C)
`Stock Ownership: None Honoraria: None Research Funding: Mario
`Eisenberger, Sanonfi-Aventis, Celgene, Centocor, Cytogen, Novartis; Ian
`F. Tannock, Sanofi-Aventis Expert Testimony: None Other
`Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Dominik R. Berthold, Ronald de Wit, Mario
`Eisenberger, Ian F. Tannock
`Financial support: Ian F. Tannock
`Provision of study materials or patients: Dominik R. Berthold, Freidele
`Soban, Ronald de Wit, Mario Eisenberger, Ian F. Tannock
`Collection and assembly of data: Freidele Soban, Ronald de Wit, Mario
`Eisenberger, Ian F. Tannock
`Data analysis and interpretation: Dominik R. Berthold, Gregory R.
`Pond, Ian F. Tannock
`Manuscript writing: Dominik R. Berthold, Ian F. Tannock
`Final approval of manuscript: Dominik R. Berthold, Gregory R. Pond,
`Freidele Soban, Ronald de Wit, Mario Eisenberger, Ian F. Tannock
`
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`5. Melzack R: The McGill Pain Questionnaire: Major
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`
`■ ■ ■
`Acknowledgment
`The Acknowledgment is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF
`version (via Adobe® Reader®).
`
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