Articles
`
`Lancet 2010; 376: 1147–54
`This online publication
`has been corrected.
`The corrected version fi rst
`appeared at thelancet.com
`on February 25, 2011
`See Editorial page 1117
`See Comment page 1119
`See Perspectives page 1137
`*Investigators listed in
`webappendix
`Royal Marsden NHS Foundation
`Trust and The Institute of
`Cancer Research, Sutton, UK
`(J S de Bono FRCP); Tulane
`University, New Orleans, LA,
`USA (A O Sartor MD); Hôpital
`Européen Georges Pompidou,
`Paris, France (S Oudard MD);
`Istanbul University, Istanbul,
`Turkey (M Ozguroglu MD);
`Odense University Hospital,
`Odense, Denmark
`(S Hansen MD); Cliniques
`Universitaires Saint-Luc,
`Université Catholique de
`Louvain, Brussels, Belgium
`(J-P Machiels MD); Masarykuv
`Onkologicky Ustav, Brno, Czech
`Republic (I Kocak MD); Institut
`Paoli Calmette Hôpital de Jour,
`Marseille, France (G Gravis MD);
`Orszagos Onkologiai Intezet,
`Kemoterapia C, Budapest,
`Hungary (I Bodrogi MD); London
`Health Sciences Centre, London,
`ON, Canada (M J Mackenzie MD);
`and Sanofi -Aventis, Malvern,
`PA, USA (L Shen PhD, S Gupta
`MD, M Roessner MS)
`Correspondence to:
`Dr Johann Sebastian de Bono,
`Royal Marsden NHS Foundation
`Trust and The Institute of Cancer
`Research, Downs Road, Sutton,
`Surrey SM2 5PT, UK
`johann.de-bono@icr.ac.uk
`
`Prednisone plus cabazitaxel or mitoxantrone for metastatic
`castration-resistant prostate cancer progressing after
`docetaxel treatment: a randomised open-label trial
`
`Johann Sebastian de Bono, Stephane Oudard, Mustafa Ozguroglu, Steinbjørn Hansen, Jean-Pascal Machiels, Ivo Kocak, Gwenaëlle Gravis,
`Istvan Bodrogi, Mary J Mackenzie, Liji Shen, Martin Roessner, Sunil Gupta, A Oliver Sartor, for the TROPIC Investigators*
`Summary
`Background Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant
`cancers. We aimed to compare the effi cacy and safety of cabazitaxel plus prednisone with those of mitoxantrone
`plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after
`docetaxel-based treatment.
`
`Methods We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate
`cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment
`with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were
`randomly assigned to receive either 12 mg/m2 mitoxantrone intravenously over 15–30 min or 25 mg/m2 cabazitaxel
`intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and
`treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis.
`The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety.
`Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079.
`
`Findings 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the
`intention-to-treat analysis. At the cutoff for the fi nal analysis (Sept 25, 2009), median survival was 15·1 months
`(95% CI 14·1–16·3) in the cabazitaxel group and 12·7 months (11·6–13·7) in the mitoxantrone group. The hazard
`ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI
`0·59–0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4–3·0) in the cabazitaxel
`group and 1·4 months (1·4–1·7) in the mitoxantrone group (HR 0·74, 0·64–0·86, p<0·0001). The most common
`clinically signifi cant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs
`mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and fi ve
`(1%) in the mitoxantrone group had febrile neutropenia.
`
`Interpretation Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving
`overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed
`during or after docetaxel-based therapy.
`
`Funding Sanofi -Aventis.
`
`Introduction
`Prostate cancer is the second most common cause of
`cancer death in men in the USA1 and the third most
`common cause of death in developed countries.2 For
`patients with metastatic prostate cancer, androgen
`deprivation therapy improves symptoms, but patients
`invariably develop progressive disease.3 On the basis of
`an improvement in survival compared with mitoxantrone
`plus prednisone in patients with metastatic castration-
`resistant prostate cancer,4–6 docetaxel in combination with
`prednisone is standard fi rst-line chemotherapy in this
`setting. No treatment has been approved by the US Food
`and Drug Administration, however, for patients whose
`disease
`progresses
`after
`docetaxel
`treatment.
`Mitoxantrone is often administered because of its
`favourable eff ects on quality-of-life outcomes.7,8 However,
`no intervention improves survival in this disease setting.
`
`Cabazitaxel (XRP6258; TXD258; RPR116258A) is a
`tubulin-binding taxane drug as potent as docetaxel
`in cell lines.9 Additionally, the drug has antitumour
`activity in models resistant to paclitaxel and docetaxel.10,11
`Phase 1 and 2 clinical studies have shown that
`neutropenia is the primary dose-limiting toxicity,
`and the recommended phase 2 doses were 20 and
`25 mg/m², with antitumour activity in solid tumours
`including docetaxel-refractory metastatic castration-
`resistant prostate
`cancer.12,13 We undertook
`a
`randomised, multicentre, multinational, phase 3 trial
`(EFC6193; TROPIC) with
`the aim of assessing
`whether cabazitaxel plus prednisone improves overall
`survival compared with mitoxantrone plus prednisone
`in men with metastatic castration-resistant prostate
`cancer who had
`progressed
`after
`docetaxel-
`based chemotherapy.
`
`www.thelancet.com Vol 376 October 2, 2010
`
`1147
`
`Sanofi Exh. 2001
`Neptune v. Aventis
`IPR2019-00136
`
`

`

`Articles
`
`920 patients assessed for eligibility
`
`165 excluded (did not meet
`inclusion criteria)
`
`755 randomised
`
`377 assigned mitoxantrone
`
`378 assigned cabazitaxel
`
`6 did not receive intervention
`
`7 did not receive intervention
`
`371 received allocated intervention
`
`371 received allocated intervention
`
`325 patients who had received
`intervention discontinued
`treatment
`267 disease progression
`32 adverse event
`2 lost to follow-up
`17 patient request
`7 other
`
`266 patients who had received
`intervention discontinued
`treatment
`180 disease progression
`67 adverse event
`1 poor compliance to protocol
`8 patient request
`10 other
`
`46 completed study treatment
`
`105 completed study treatment
`
`All 377 randomised patients included in
`intention-to-treat analysis
`
`All 378 randomised patients included in
`intention-to-treat analysis
`
`Figure 1: Trial profi le
`
`Methods
`Patients
`This randomised open-label phase 3 study was
`undertaken at 146 centres in 26 countries. Patients had
`pathologically proven prostate cancer with documented
`disease progression during or after completion of
`docetaxel treatment. Eligible patients were aged at least
`18 years, with an Eastern Cooperative Oncology Group
`(ECOG) performance status of 0–2. Patients who had
`previous mitoxantrone therapy, radiotherapy to 40% or
`more of the bone marrow, or cancer therapy (other than
`luteinising-hormone-releasing
`hormone
`[LHRH]
`analogues) within 4 weeks before enrolment were
`excluded. Patients with measurable disease were
`required to have documented disease progression by
`Response Evaluation Criteria in Solid Tumors (RECIST)14
`with at least one visceral or soft-tissue metastatic lesion.
`Patients with non-measurable disease were required to
`have rising serum prostate-specifi c antigen (PSA) con-
`cen trations (at least two con secutive increases relative to
`a reference value measured at least a week apart) or the
`appearance of at
`least one new demonstrable
`radiographic lesion.
`Additional
`inclusion criteria were: previous and
`ongoing castration by orchiectomy or LHRH agonists, or
`both; antiandrogen withdrawal followed by progression
`had to have taken place at least 4 weeks (6 weeks for
`bicalutamide) before enrolment; adequate haematological,
`
`Data are number of patients (%) or median (IQR). *Serum PSA concentrations
`were available for 370 mitoxantrone and 371 cabazitaxel patients. †Pain was
`assessed with the McGill-Melzack present pain intensity scale15 and analgesic score
`was derived from analgesic consumption (morphine equivalents). ‡Two patients
`in the cabazitaxel group did not receive previous orchiectomy or hormone therapy.
`ECOG=Eastern Cooperative Oncology Group. PSA=prostate-specifi c antigen.
`
`Table 1: Baseline characteristics and treatment history of patients in the
`intention-to-treat population
`
`hepatic, renal, and cardiac function; and a left-ventricular
`ejection fraction of more than 50% assessed by multi-
`gated radionuclide angiography or echocardiogram.
`
`1148
`
`www.thelancet.com Vol 376 October 2, 2010
`
`Mitoxantrone
`(n=377)
`
`Cabazitaxel
`(n=378)
`
`67 (61−72)
`70 (19%)
`
`314 (83%)
`32 (8%)
`20 (5%)
`11 (3%)
`344 (91%)
`
`Age
`Median (years)
`≥75 years
`Ethnic origin
`White
`Asian
`Black
`Other
`ECOG performance status 0 or 1
`Extent of disease
`Metastatic
`Bone metastases
`Visceral metastases
`Locoregional recurrence
`Unknown
`Median serum PSA concentration
`(μg/L)*
`Serum PSA concentration ≥20 μg/L
`Measurable disease
`Pain at baseline†
`Previous therapy
`Hormonal‡
`Number of chemotherapy regimens
`1
`2
`>2
`Radiation
`Surgery
`Biological agent
`Number of previous docetaxel regimens
`1
`327 (87%)
`2
`43 (11%)
`>2
`7 (2%)
`529·2
`Total previous docetaxel dose
`(mg/m2)
`(380·9−787·2)
`Disease progression relative to docetaxel administration
`During treatment
`104 (28%)
`<3 months from last dose
`181 (48%)
`≥3 months from last dose
`90 (24%)
`Unknown
`2 (1%)
`Median time from last docetaxel dose
`0·7 (0·0−2·9)
`to disease progression (months)
`
`356 (94%)
`328 (87%)
`94 (25%)
`20 (5%)
`1 (<1%)
`127·5
`(44·0−419·0)
`325 (86%)
`204 (54%)
`168 (45%)
`
`375 (99%)
`
`268 (71%)
`79 (21%)
`30 (8%)
`222 (59%)
`205 (54%)
`36 (10%)
`
`68 (62−73)
`69 (18%)
`
`317 (84%)
`26 (7%)
`20 (5%)
`15 (4%)
`350 (93%)
`
`364 (96%)
`303 (80%)
`94 (25%)
`14 (4%)
`0
`143·9
`(51·1−416·0)
`329 (87%)
`201 (53%)
`174 (46%)
`
`375 (99%)
`
`260 (69%)
`94 (25%)
`24 (6%)
`232 (61%)
`198 (52%)
`26 (7%)
`
`316 (84%)
`53 (14%)
`9 (2%)
`576·6
`(408·4−761·2)
`
`115 (30%)
`158 (42%)
`102 (27%)
`3 (1%)
`0·8 (0·0−3·1)
`
`

`

`Articles
`
`Mitoxantrone
`Cabazitaxel
`
`HR 0·70 (95% CI 0·59–0·83)
`Log-rank p<0·0001
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Probability of overall survival (%)
`
`30
`
`14
`
`6
`
`300
`321
`
`12
`
`188
`231
`
`Months
`
`18
`
`67
`90
`
`24
`
`11
`28
`
`0
`
`0
`
`377
`378
`
`Number at risk
`Mitoxantrone
`Cabazitaxel
`
`B
`
`All randomised patients
`ECOG status: 0, 1
`ECOG status: 2
`Measurable disease: no
`Measurable disease: yes
`Number of previous chemotherapies: 1
`Number of previous chemotherapies: ≥2
`Age: <65 years
`Age: ≥65 years
`Pain at baseline: no
`Pain at baseline: yes
`Rising PSA at baseline: no
`Rising PSA at baseline: yes
`Total docetaxel dose: <225 mg/m2
`Total docetaxel dose: ≥225–450 mg/m2
`Total docetaxel dose: ≥450–675 mg/m2
`Total docetaxel dose: ≥675–900 mg/m2
`Total docetaxel dose: ≥900 mg/m2
`Progression during docetaxel treatment
`Progression <3 months after docetaxel
`Progression ≥3 months after docetaxel
`
`Patient
`number
`755
`694
`61
`350
`405
`528
`227
`295
`460
`374
`342
`159
`583
`59
`206
`217
`131
`134
`219
`339
`192
`
`HR (95% CI)
`
`0·70 (0·59–0·83)
`0·68 (0·57–0·82)
`0·81 (0·48–1·38)
`0·72 (0·55–0·93)
`0·68 (0·54–0·85)
`0·67 (0·55–0·83)
`0·75 (0·55–1·02)
`0·81 (0·61–1·08)
`0·62 (0·50–0·78)
`0·55 (0·42–0·72)
`0·77(0·61–0·98)
`0·88 (0·61–1·26)
`0·65 (0·53–0·80)
`0·96 (0·49–1·86)
`0·60 (0·43–0·84)
`0·83 (0·60–1·16)
`0·73 (0·48–1·10)
`0·51 (0·33–0·79)
`0·65 (0·47–0·90)
`0·70 (0·55–0·91)
`0·75 (0·51–1·11)
`
`0·25
`
`0·50
`
`1
`
`2
`
`Favours
`cabazitaxel
`
`Favours
`mitoxantrone
`
`Figure 2: Overall survival
`(A) Kaplan-Meier estimates of the probability of survival in patients in all patients randomly assigned to treatment
`with cabazitaxel plus prednisone or mitoxantrone plus prednisone. The points on the curves show censored
`observations. (B) Intention-to-treat analysis of overall survival in subgroups of patients defi ned by baseline
`characteristics. Hazard ratios (HRs) lower than 1 favour the cabazitaxel group and greater than 1 favour the
`mitoxantrone group.
`
`patients using an interactive voice response system and
`for the computer-generated random allocation schedule,
`but had no other involvement in the trial. A dynamic
`allocation method was used
`to avoid
`treatment
`assignment imbalances within a centre. Patients and
`
`Mitoxantrone
`(n=377)
`
`Cabazitaxel
`(n=378)
`
`A
`
`371 (98%)
`46 (12%)
`
`Patients receiving study treatment
`Patients completing planned ten
`cycles of study treatment
`325 (86%)
`Discontinuation of study treatment
`Reasons for discontinuation of study treatment
`Disease progression
`267 (71%)
`Adverse event
`32 (8%)
`Non-compliance with protocol
`0
`Lost to follow-up
`2 (1%)
`Patient request
`17 (5%)
`Other
`7 (2%)
`Median number of treatment cycles*
`4 (2−7)
`Median relative dose intensity (%)*
`97·3%
`(92·0–99·3)
`
`Treatment delays, number of cycles†
`≤9 days
`>9 days
`Dose reductions, number of cycles†
`
`110 (6%)
`28 (2%)
`88 (5%)
`
`371 (98%)
`105 (28%)
`
`266 (70%)
`
`180 (48%)
`67 (18%)
`1 (<1%)
`0
`8 (2%)
`10 (3%)
`6 (3−10)
`96·1%
`(90·1–98·9)
`
`157 (7%)
`51 (2%)
`221 (10%)
`
`Data are number of patients or cycles (%) or median (IQR). *Assessed in patients
`who received study treatment. †Percentages are of total number of treatment
`cycles (1736 for mitoxantrone and 2251 for cabazitaxel).
`
`Table 2: Treatment received and reasons for discontinuation in the
`intention-to-treat population*
`
`Concomitant use of bisphosphonates was allowed if the
`dose had been stable for 12 weeks before enrolment.
`Patients receiving LHRH agonists were mandated to
`continue this treatment during the study. Additional
`exclusion criteria were active grade 2 or higher peripheral
`neuro pathy or stomatitis, other serious illness (including
`secondary cancer), or a history of hypersensitivity to
`polysorbate 80-containing drugs or prednisone.
`On the basis of emerging guidelines recommending
`the delivery of 12 weeks of treatment before adjustment
`of therapy for metastatic castration-resistant prostate
`cancer, an amendment was made to the trial protocol
`after 59 patients had been enrolled to exclude patients
`previously receiving a cumulative docetaxel dose lower
`than 225 mg/m². The study was undertaken in accordance
`with principles of the Declaration of Helsinki and Good
`Clinical Practice guidelines, and with
`local ethics
`committee approval. Written informed consent was
`obtained from all participants.
`
`Procedures
`All patients received oral prednisone 10 mg daily (or
`similar doses of prednisolone where prednisone was
`unavailable). Patients were centrally randomly assigned
`to receive cabazitaxel 25 mg/m² intravenously over 1 h or
`mitoxantrone 12 mg/m² intravenously over 15–30 min
`on day 1 of each 21-day cycle, and were stratifi ed for
`disease measurability (measurable vs non-measurable)
`and ECOG performance status (0–1 vs 2). A contract
`research organisation was responsible for randomising
`
`www.thelancet.com Vol 376 October 2, 2010
`
`1149
`
`

`

`Physical examinations and blood tests were repeated
`before each infusion of study drug and at the end of
`treatment. Complete blood counts were taken on days 1,
`8, and 15 of each treatment cycle and repeated when
`clinically indicated. Patients who progressed or started
`another anticancer therapy were followed up every
`3 months; patients who withdrew before documented
`disease progression were followed up every 6 weeks for
`the fi rst 6 months and thereafter every 3 months.
`The primary endpoint of overall survival was calculated
`from date of randomisation to death. Secondary endpoints
`included a composite endpoint of progression-free
`survival, defi ned as the time between randomisation and
`the fi rst date of progression as measured by PSA
`progression, tumour progression, pain progression, or
`death. Other secondary endpoints were PSA response
`(reduction in serum PSA concentration of ≥50% in
`patients with a baseline value of ≥20 μg/L); PSA
`progression
`(increase of ≥25% over nadir PSA
`concentration provided that the increase in the absolute
`PSA value was ≥5 μg/L for men with no PSA response,
`or ≥50% over nadir for PSA responders); objective
`tumour response for patients with measurable disease
`based on RECIST; pain response (for patients with
`median PPI score of ≥2 or mean analgesic score of
`≥10 points at baseline, or both), which was defi ned as a
`reduction of 2 points or more from baseline median PPI
`score without increasing analgesic score, or decreases of
`more than 50% in analgesic use without an increase in
`pain, maintained for 3 or more weeks;15 pain progression
`(increase in median PPI score of ≥1 point from the
`reference value or an increase of ≥25% in the mean
`analgesic
`score
`or
`requirement
`for palliative
`radiotherapy);15 and time to tumour progression, defi ned
`as the number of months from randomisation until
`evidence of progressive disease (RECIST).
`Adverse events, biochemistry, haematology, vital signs,
`and electrocardiograms were monitored throughout the
`study. Left-ventricular ejection fraction was monitored
`throughout the study in mitoxantrone-treated patients,
`but only if clinically indicated in those who received
`cabazitaxel. All adverse events were graded according to
`National Cancer Institute Common Terminology Criteria
`for adverse events (version 3.0).16
`
`Statistical analysis
`SAS (version 9.1.3) was used for all analyses. The study
`required an estimated sample size of 720 patients (360 per
`group) to detect a 25% reduct ion in the hazard ratio (HR)
`for death in the cabazitaxel group relative to the
`mitoxantrone group with 90% power, with a two-sided
`log-rank test at a signifi cance level of 0·05 and on the
`assumption of 8 months median overall survival in the
`mitoxantrone group. We planned for the fi nal analysis to
`take place when 511 deaths had occurred. Analysis of the
`primary endpoint was for the intention-to-treat population
`(all patients randomly assigned to treatment groups).
`
`Mitoxantrone
`Cabazitaxel
`
`HR 0·74 (95% CI 0·64–0·86)
`Log-rank p<0·0001
`
`Articles
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Probability of progression-free survival (%)
`
`21
`
`20
`
`18
`
`40
`
`15
`
`64
`
`9
`
`27
`52
`
`Months
`
`12
`
`9
`15
`
`3
`
`115
`168
`
`6
`
`52
`90
`
`0
`
`0
`
`377
`378
`
`Number at risk
`Mitoxantrone
`Cabazitaxel
`
`Figure 3: Progression-free survival
`Kaplan-Meier estimates of the probability of progression-free survival in all patients randomly assigned to treatment
`with cabazitaxel plus prednisone or mitoxantrone plus prednisone. The points on the curves show censored obser-
`vations. Progression-free survival was established from the date of randomisation to whichever event occurred fi rst—
`prostate-specifi c antigen progression, radiological progression, symptomatic progression, or death. HR=hazard ratio.
`
`treating physicians were not masked to treatment
`allocation, but the study team was masked to the data
`analysis. Premedication, consisting of single intravenous
`doses of an antihistamine, corticosteroid (dexamethasone
`8 mg or equivalent), and histamine H2-antagonist (except
`cimetidine), was administered 30 min or more before
`cabazitaxel. Antiemetic prophylaxis was given at
`physicians’ discretion.
`Treatment was continued for a maximum of ten cycles
`to minimise risk of mitoxantrone-induced cardiac toxicity,
`while allowing for comparable exposure to the study
`treatment and a similar schedule of evaluation. Patients
`were followed up until the cutoff date for analysis or until
`death (whichever occurred fi rst). Treatment delays of up
`to 2 weeks were allowed, with one dose reduction
`(cabazitaxel 20 mg/m² or mitoxantrone 10 mg/m²) per
`patient. Prophylactic granulocyte colony-stimulating
`factor was not allowed during the fi rst cycle, but was
`allowed (at physicians’ discretion) after fi rst occurrence
`of either neutropenia
`lasting 7 days or more or
`neutropenia complicated by fever or infection.
`Pretreatment evaluations included a medical history,
`ECOG performance status, physical examination,
`laboratory screening, serum PSA concentration, CT,
`bone scan, electrocardiography, and assessment of left-
`ventricular ejection
`fraction. Pain and analgesic
`consumption were assessed at baseline. Pain was
`assessed with the McGill-Melzack present pain intensity
`(PPI) scale15 and analgesic use was derived from
`consumption normalised to morphine equivalents.8
`
`1150
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`
`

`

`Articles
`
`Mitoxantrone
`
`Cabazitaxel
`
`Hazard ratio (95% CI)
`
`p value for comparison
`
`Tumour response rate*
`Number of evaluable patients
`Response rate (%)
`PSA response rate†
`Number of evaluable patients
`Response rate (%)
`Pain response rate‡
`Number of evaluable patients
`Response rate (%)
`Progression
`Number of patients in intention-to-treat analysis
`Median time to tumour progression (months)
`Median time to PSA progression (months)
`Median time to pain progression (months)§
`
`204
`4·4% (1·6–7·2)
`
`201
`14·4% (9·6–19·3)
`
`325
`17·8% (13·7–22·0)
`
`329
`39·2% (33·9–44·5)
`
`168
`7·7% (3·7–11·8)
`
`174
`9·2% (4·9–13·5)
`
`··
`··
`
`··
`··
`
`··
`··
`
`377
`5·4 (2·3–10·0)
`3·1 (0·9–9·1)
`Not reached
`
`378
`8·8 (3·9–12·0)
`6·4 (2·2–10·1)
`11·1 (2·9–not reached)
`
`··
`0·61 (0·49−0·76)
`0·75 (0·63–0·90)
`0·91 (0·69–1·19)
`
`··
`0·0005
`
`··
`0·0002
`
`··
`0·63
`
`··
`<0·0001
`0·001
`0·52
`
`*Tumour response was evaluated only for patients with measurable disease according to Response Evaluation Criteria in Solid Tumors.14 †Prostate-specifi c antigen (PSA)
`response was defi ned as a 50% or more reduction in serum PSA concentration, established only for patients with a serum PSA concentration of 20 μg/L or more at baseline,
`confi rmed by a repeat PSA measurement after at least 3 weeks. ‡Pain response was established only for patients with median present pain intensity (PPI) score of 2 or more
`or mean analgesic score (AS) of 10 points or more at baseline, or both, and was defi ned as a two-point or greater reduction from baseline median PPI score without an
`increased AS or a decrease of 50% or more in the AS without an increase in the PPI score, maintained for at least 3 weeks. §Data for 265 patients in the cabazitaxel group and
`279 patients in the mitoxantrone group were censored as a result of more than two PPI or AS assessments, or both, being missed during the same week (unless a complete
`evaluation of ≥5 values showed pain progression).
`
`Table 3: Response to treatment and disease progression
`
`Safety analyses included patients who received at least
`part of one dose of study drug.
`We analysed overall survival using the Kaplan-Meier
`method, with log-rank comparisons stratifi ed according
`to disease measurability
`(measurable versus non-
`measure able)
`and
`ECOG
`performance
`status
`(0–1 versus 2). HRs and 95% CIs were calculated with a
`Cox proportional hazards model (for both primary and
`secondary analyses). Overall survival data were censored
`at the last date the patient was known to be alive or at the
`analysis cutoff date, whichever was earliest. Progression-
`free survival and progression of tumour, PSA, and pain
`were compared between treatments by log-rank testing.
`A planned futility analysis of progression-free survival
`was done after 225 patients had a progression event.
`Additionally, an interim analysis of the primary effi cacy
`endpoint of overall survival was planned after 307 events,
`but was actually done after 365 events with an adjusted
`signifi cance
`level of 0·016, on the basis of the
`O’Brien-Fleming type 1 error spending function. A two-
`sided signifi cance level of 0·0452 was used for the fi nal
`analysis. Although the study team was masked to
`treatment allocation and patient outcomes throughout
`the trial, an independent contract statistician provided
`unmasked results to an independent data monitoring
`committee with the appropriate analyses for assessment.
`This
`study
`is
`registered
`at ClinicalTrials.gov,
`NCT00417079.
`
`Role of the funding source
`The chief investigators (JSB and AOS) designed the trial
`protocol and analysed the data, with input from the
`
`sponsor, who funded the trial. The decision to submit the
`report for publication was made by the chief investigators,
`who drafted and then fi nalised the report with the help of
`a medical writer. The sponsor funded editorial assistance
`and reviewed the fi nal draft before submission.
`
`Results
`Between Jan 2, 2007, and Oct 23, 2008, 755 patients were
`randomly assigned to treatment groups (378 cabazitaxel
`and 377 mitoxantrone; fi gure 1). The treatment groups
`were well balanced at baseline with respect to demographic
`and disease characteristics and previous treatments
`(table 1). Roughly 50% of patients had measurable soft-
`tissue disease and 25% had visceral (poor prognosis)
`disease. The median dose of docetaxel received before the
`study was 576·6 mg/m² (IQR 408·4–761·2) in the
`cabazitaxel group and 529·2 mg/m² (380·9–787·2) in the
`mitoxantrone group. Overall, 59 (8%) patients had
`received
`a
`cumulative dose of docetaxel
`less
`than 225 mg/m² and 482 (65%) received a cumulative
`dose of 450 mg/m² or more. About 70% of patients had
`progressive disease either during or within 3 months of
`completing docetaxel treatment, including about 30% of
`patients who had disease progression during docetaxel
`treatment (table 1). The median time from last docetaxel
`dose to disease progression, before trial participation,
`was 0·8 months (IQR 0·0–3·1) for the cabazitaxel group
`and 0·7 months (0·0–2·9) for the mitoxantrone group.
`Patients in the cabazitaxel group were on study
`treatment longer—a median of six treatment cycles
`compared with four cycles—and were more likely to
`complete study treatment than were those in the
`
`www.thelancet.com Vol 376 October 2, 2010
`
`1151
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`

`Articles
`
`Haematological†
`Neutropenia
`Febrile neutropenia
`Leukopenia
`Anaemia
`Thrombocytopenia
`Non-haematological
`Diarrhoea
`Fatigue
`Asthenia
`Back pain
`Nausea
`Vomiting
`Haematuria
`Abdominal pain
`Pain in extremity
`Dyspnoea
`Constipation
`Pyrexia
`Arthralgia
`Urinary-tract infection
`Pain
`Bone pain
`
`Mitoxantrone (n=371)
`
`Cabazitaxel (n=371)
`
`All grades
`
`Grade ≥3
`
`All grades
`
`Grade ≥3
`
`325 (88%)
`··
`343 (92%)
`302 (81%)
`160 (43%)
`
`39 (11%)
`102 (27%)
`46 (12%)
`45 (12%)
`85 (23%)
`38 (10%)
`14 (4%)
`13 (4%)
`27 (7%)
`17 (5%)
`57 (15%)
`23 (6%)
`31 (8%)
`11 (3%)
`18 (5%)
`19 (5%)
`
`215 (58%)
`5 (1%)
`157 (42%)
`18 (5%)
`6 (2%)
`
`1 (<1%)
`11 (3%)
`9 (2%)
`11 (3%)
`1 (<1%)
`0
`2 (1%)
`0
`4 (1%)
`3 (1%)
`2 (1%)
`1 (<1%)
`4 (1%)
`3 (1%)
`7 (2%)
`9 (2%)
`
`347 (94%)
`··
`355 (96%)
`361 (97%)
`176 (47%)
`
`173 (47%)
`136 (37%)
`76 (20%)
`60 (16%)
`127 (34%)
`84 (23%)
`62 (17%)
`43 (12%)
`30 (8%)
`44 (12%)
`76 (20%)
`45 (12%)
`39 (11%)
`27 (7%)
`20 (5%)
`19 (5%)
`
`303 (82%)
`28 (8%)
`253 (68%)
`39 (11%)
`15 (4%)
`
`23 (6%)
`18 (5%)
`17 (5%)
`14 (4%)
`7 (2%)
`7 (2%)
`7 (2%)
`7 (2%)
`6 (2%)
`5 (1%)
`4 (1%)
`4 (1%)
`4 (1%)
`4 (1%)
`4 (1%)
`3 (1%)
`
`Data are number of patients (%). *Toxic eff ects were graded according to the National Cancer Institute Common
`Terminology Criteria for Adverse Events (version 3.0)16 and summarised with the Medical Dictionary for Regulatory
`Activities terminology (version 12.0).17 Events listed are those occurring at grade 3 or higher severity in ≥1% of patients
`in either treatment group. Grade 3 or higher events include those reported as leading to death (grade 5). †Data for
`haematogical adverse events were based on laboratory assessments.
`
`Table 4: Adverse events reported in patients who received at least one dose of study treatment*
`
`See Online for webappendix
`
`mitoxantrone group (table 2). In the cabazitaxel group,
`282 (76%) patients received more than 90% of the
`planned dose intensity, compared with 301 (81%) in the
`mitoxantrone group. The primary reason for treatment
`discontinuation in both groups was disease progression
`(table 2). Dose reductions were reported for 45 (12%)
`patients
`in
`the cabazitaxel group and 15
`(4%)
`mitoxantrone-treated patients, and treatment delays
`occurred in 104 (28%) and 56 (15%) patients, respectively.
`Overall, 5% of mitoxantrone treatment courses were
`dose reduced compared with 10% of cabazitaxel
`treatment courses; delays to treatment were similar in
`both groups (table 2). Per protocol, crossover to
`cabazitaxel was not allowed for the mitoxantrone group,
`although 44 (12%) patients in this group received
`treatment with tubulin-binding drugs at progression.
`The median follow-up for both treatment groups
`combined was 12·8 months (IQR 7·8–16·9). At the cutoff
`date for the fi nal analysis (Sept 25, 2009), 234 deaths had
`occurred in the cabazitaxel group and 279 in the
`mitoxantrone group. The Kaplan-Meier analysis showed
`an overall survival benefi t in favour of cabazitaxel
`(fi gure 2). Median overall survival was 15·1 months
`
`(95% CI 14·1–16·3) versus 12·7 months (11·6–13·7). This
`result corresponds to a 30% reduction in relative risk of
`death (HR 0·70, 95% CI 0·59–0·83, p<0·0001). Subgroup
`analyses of survival consistently favoured cabazitaxel
`(fi gure 2), with no signifi cant interactions between
`prognostic factors and treatment response.
`Median progression-free survival (a composite endpoint)
`was 2·8 months (95% CI 2·4–3·0) in the cabazitaxel
`group and 1·4 months (1·4–1·7) in the mitoxantrone
`group (fi gure 3; HR 0·74, 95% CI 0·64–0·86, p<0·0001).
`Patients treated with cabazitaxel had signifi cantly higher
`rates of tumour response and PSA response than did
`those who received mitoxantrone (table 3). Signifi cant
`improvements in time to tumour progression and time to
`PSA progression were also noted in the cabazitaxel group
`(table 3). Pain response rates were similar in the two
`groups; there was no signifi cant diff erence between the
`treatment groups in time to pain progression. Similar
`proportions of patients in each group had either reductions
`or increases in pain (data not shown).
`The most common toxic eff ects of cabazitaxel were
`haematological; the most frequent haematological grade
`3 or higher adverse events were neutropenia, leukopenia,
`and anaemia (table 4). The most common non-
`haematological grade 3 or higher adverse event was
`diarrhoea, which was managed expectantly. Grade 3
`peripheral neuropathy was uncommon (reported in three
`[1%] patients
`in each group). Overall, peripheral
`neuropathy (all grades) was reported during the study in
`52 (14%) patients in the cabazitaxel group and 12 (3%) in
`the mitoxantrone group. Peripheral oedema (all grades)
`occurred in 34 (9%) patients in each group.
`18 (5%) patients treated with cabazitaxel and nine (2%)
`treated with mitoxantrone died within 30 days of the last
`infusion. Table 5 summarises causes of death in patients
`who received at least one dose of study drug (the safety
`population). The most frequent cause of death in the
`cabazitaxel group was neutropenia and its clinical
`consequences. Analysis of the incidence of neutropenia
`and diarrhoea by subgroups suggested diff erences in
`rates of adverse events by age, previous radiotherapy, and
`geographical region (webappendix p 1).
`
`Discussion
`Cabazitaxel is the fi rst drug to improve survival in patients
`with metastatic castration-resistant prostate cancer with
`progressive disease after docetaxel-based
`treatment,
`resulting in a 30% reduction in the risk of death and an
`improved median overall survival compared with
`mitoxantrone (panel). Currently, these patients have few
`therapeutic options, with no treatment able to prolong
`survival in this setting. The analysis of survival in
`subgroups defi ned by prognostic factors supports the
`robustness of the primary endpoint, favouring cabazitaxel
`over mitoxantrone, even
`in patients with disease
`progression during docetaxel treatment and in those who
`received high cumulative doses of docetaxel. Cabazitaxel
`
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`
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`

`Articles
`
`Mitoxantrone (n=371)
`
`Cabazitaxel (n=371)
`
`Total deaths during the study
`Deaths ≤30 days after last dose of study drug
`Causes of death ≤30 days after last dose of study drug
`Disease progression
`Adverse events
`Neutropenia and clinical consequences/sepsis
`Cardiac
`Dyspnoea†
`Dehydration/electrolyte imbalance
`Renal failure
`Cerebral haemorrhage
`Unknown cause
`Motor vehicle accident
`Deaths >30 days after last dose of study drug
`
`275 (74%)
`9 (2%)
`
`6 (2%)*
`
`1 (<1%)
`0
`1 (<1%)
`0
`0
`0
`0
`1 (<1%)
`266 (72%)
`
`227 (61%)
`18 (5%)
`
`0
`
`7 (2%)
`5 (1%)
`0
`1 (<1%)
`3 (1%)
`1 (<1%)
`1 (<1%)
`0
`209 (56%)
`
`Data are number of patients (%). *Includes three patients whose death was