Published Ahead of Print on December 9, 2013 as 10.1200/JCO.2012.48.5268
`
`The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.48.5268
`
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Author affiliations appear at the end of
`this article.
`
`Published online ahead of print at
`www.jco.org on December 9, 2013.
`
`Supported by Pfizer Inc.
`
`Presented at the American Society of
`Clinical Oncology Annual Meeting,
`Chicago, IL, June 3-7, 2011.
`
`Terms in blue are defined in the glos-
`sary, found at the end of this article
`and online at www.jco.org.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical trial information: NCT00676650.
`
`Corresponding author: M. Dror Michael-
`son, MD, PhD, Massachusetts General
`Hospital Cancer Center, The Claire and
`John Bertucci Center for Genitourinary
`Cancers, 55 Fruit St, Yawkey 7E,
`Boston, MA 02114; e-mail:
`dmichaelson1@partners.org.
`
`© 2013 by American Society of Clinical
`Oncology
`
`0732-183X/13/3199-1/$20.00
`
`DOI: 10.1200/JCO.2012.48.5268
`
`Randomized, Placebo-Controlled, Phase III Trial of
`Sunitinib Plus Prednisone Versus Prednisone Alone in
`Progressive, Metastatic, Castration-Resistant
`Prostate Cancer
`M. Dror Michaelson, Stephane Oudard, Yen-Chuan Ou, Lisa Sengeløv, Fred Saad, Nadine Houede,
`Peter Ostler, Arnulf Stenzl, Gedske Daugaard, Robert Jones, Fredrik Laestadius, Anders Ulle`n, Amit Bahl,
`Daniel Castellano, Juergen Gschwend, Tristan Maurina, Edna Chow Maneval, Shaw-Ling Wang,
`Maria Jose Lechuga, Jolanda Paolini, and Isan Chen
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of
`metastatic castration-resistant prostate cancer (mCRPC).
`Patients and Methods
`Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1
`to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg
`twice daily. The primary end point was overall survival (OS); secondary end points included
`progression-free survival (PFS). Two interim analyses were planned.
`Results
`Overall, 873 patients were randomly assigned to receive sunitinib (n ⫽ 584) or placebo (n ⫽ 289).
`The independent data monitoring committee stopped the study for futility after the second interim
`analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8
`months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097;
`stratified log-rank test, P ⫽ .168). PFS was significantly improved in the sunitinib arm (median 5.6
`v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P ⬍ .001). Toxicity and
`rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib
`than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%),
`asthenia (8% v 2%), and hand–foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4
`hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia
`(6% v ⬍ 1%).
`Conclusion
`The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-
`refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.
`
`J Clin Oncol 31. © 2013 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Docetaxel-based chemotherapy is standard front-
`line treatment for metastatic castration-resistant
`prostate cancer (mCRPC), with demonstrated sur-
`vival benefits compared with mitoxantrone plus
`prednisone.1-3 Treatment options for men with
`mCRPCafterprogressionondocetaxel-basedchem-
`otherapy are historically limited, although recent
`advances have led to the approvals of cabazitaxel,
`abiraterone acetate, and enzalutamide.4-6 The role of
`antiangiogenic therapies in mCRPC has also been
`investigated, based on cumulative evidence suggest-
`ing that prostate cancer growth is dependent on
`
`angiogenesis. The proangiogenic factor vascular en-
`dothelial growth factor (VEGF) and its receptors
`(VEGFRs) are expressed in prostate tumors,7-9
`and increasing VEGF plasma levels correlate with
`progressive disease.10-12 Additionally, VEGF
`plasma and urine levels are independent predic-
`survival (OS) in CRPC.13,14
`tors of overall
`Platelet-derived growth factor (PDGF) and its re-
`ceptors (PDGFRs) have also been implicated in
`prostate cancer progression.15-17
`Sunitinib malate (SUTENT; Pfizer Inc, New
`York, NY), a multitargeted inhibitor of VEGFRs,
`PDGFRs, and other receptor tyrosine kinases,18-23
`is approved for treatment of advanced renal
`
`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`Copyright 2013 by American Society of Clinical Oncology
`
`
`
`1
`
`JANSSEN EXHIBIT 2076
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`Michaelson et al
`
`cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and
`pancreatic neuroendocrine tumors (NETs). Three phase II trials of
`single-agent sunitinib in progressive mCRPC suggested antitumor
`activity, as assessed by both ⱖ 50% decline in prostate-specific
`antigen (PSA) levels and tumor shrinkage, with an acceptable
`safety profile.24-26 In two of the studies, sunitinib was given at a
`starting dose of 50 mg/d on a 4-week-on-2-week-off schedule,24,25
`and, in the third, sunitinib was given at 37.5 mg/d on a continuous
`dosing schedule.26 Based on these promising results and an unmet
`therapy need in this patient population, we conducted a phase III
`trial of sunitinib plus prednisone in men with progressive mCRPC
`after docetaxel-based chemotherapy.
`
`PATIENTS AND METHODS
`
`Patients
`The study population comprised patients with histologically or cytolog-
`ically confirmed adenocarcinoma of the prostate that was metastatic and
`castration-resistant (refractory to androgen ablation), with surgical or ongoing
`chemical castration and baseline testosterone level ⱕ 50 ng/dL. Other eligibil-
`ity criteria included the following: failure of one previous docetaxel-based
`regimen, because of either disease progression (docetaxel resistant) or intoler-
`ance; documented evidence of progressive disease, defined by either PSA
`progression (minimum of two rising values obtained ⱖ 1 week apart, with the
`last result being ⱖ 2.0 ng/mL), new or increasing nonbone disease on the basis
`of RECIST,27 or positive bone scan with ⱖ two new lesions28; Eastern Coop-
`erative Oncology Group (ECOG) performance status 0 or 1; and adequate
`organ function. Patients were excluded if they had received more than one
`prior chemotherapy regimen in the metastatic disease setting; impending
`complication from bone metastases; urinary obstruction requiring medical
`intervention; known brain metastases; clinically significant cardiovascular
`events or disease during the preceding 6 months, including ongoing cardiac
`dysrhythmias of National Cancer Institute Common Terminology Criteria for
`Adverse Events grade ⱖ 2; uncontrolled hypertension; grade ⱖ 3 hemorrhage
`within 4 weeks; or ongoing treatment with therapeutic doses of coumadin or
`heparin. All patients provided written, informed consent.
`
`Study Design and Treatment
`This was an international, double-blind, placebo-controlled, random-
`ized phase III study. Stratification criteria were ECOG performance status (0 v
`1); docetaxel-resistant v docetaxel-intolerant; nature of disease progression at
`entry (PSA progression only v radiographic progression); and previous ther-
`apy with a VEGF pathway inhibitor (yes v no v unknown). Patients were
`randomly assigned 2:1 to either oral sunitinib at a starting dose of 37.5 mg/d or
`matched placebo on a continuous dosing schedule, in 28-day cycles. In both
`arms, patients also received oral prednisone (or prednisolone, where predni-
`sone was not commercially available) 5 mg twice daily. If toxicity occurred, the
`sunitinib or placebo dose could be either interrupted or reduced to 25 mg/d
`and then to 12.5 mg/d. In the absence of grade ⬎ 1 nonhematologic or grade
`⬎ 2 hematologic toxicity, the sunitinib or placebo dose could be escalated to 50
`mg/d at the third cycle start. Patients remained on study as long as they derived
`clinical benefit and were followed until death. The study was run in accordance
`with the Declaration of Helsinki, in compliance with the International Con-
`ference on Harmonization Good Clinical Practice Guidelines and applicable
`local regulatory requirements and laws, and was approved by the institutional
`review board or independent ethics committee of each participating center.
`
`Study End Points and Assessments
`The primary end point was OS, defined as the time from random assign-
`ment to death. Secondary end points included progression-free survival (PFS),
`defined as the time from random assignment to first documentation of objec-
`tive progressive disease (as determined by investigators using radiographic, but
`not PSA, progression) or death on study from any cause (whichever occurred
`first), objective response rate (ORR), and safety.
`
`Disease was assessed by tumor imaging and bone scan at baseline and
`every 8 weeks thereafter, and to confirm a response or if progression was
`suspected. Bone scan progression was defined by the presence of two new
`lesions in order to account for bone scan flare. Tumor response was
`evaluated by using RECIST (version 1.0). Disease assessments were initially
`reviewed by a central independent third-party core imaging laboratory to
`determine disease response and progression. However, independent re-
`view was stopped after the second interim analysis when a decision was
`made to halt the study, and PFS and ORR analyses reported here used
`investigator-derived assessments.
`Safety and tolerability were monitored throughout the study by physical
`examination, hematology and biochemistry tests, ECOG performance status,
`vital signs and cardiac function (12-lead ECG), and by recording all adverse
`events (AEs), graded according to the National Cancer Institute Common
`Terminology Criteria for Adverse Events version 3.0.
`
`Statistical Analysis
`A 35% improvement in median OS from 12 months (placebo) to 16.2
`months (sunitinib) was considered clinically relevant. A total of 501 OS events
`would be required to detect this improvement by using a stratified log-rank
`test with an overall one-sided significance level of 0.025 and approximately
`85% power. With 2:1 randomization, a planned accrual period of 18.8 months,
`and a minimum follow-up period of 13.3 months, it was estimated that 819
`patients would need to be enrolled. Two interim analyses were planned, the
`first (after 120 PFS events) for safety and futility on the basis of PFS, and the
`second (after approximately 225 OS events; 45% of the total needed) for safety,
`efficacy, and futility on the basis of OS. A Pocock-like stopping boundary was
`used for futility.29 The nominal significance level for the interim and final
`efficacy analyses was determined by using the Lan-DeMets procedure30 with
`an O’Brien-Fleming stopping rule.31 The O’Brien-Fleming stopping bound-
`ary was used for efficacy stopping criteria, and the futility stopping criteria were
`constructed by using rho stopping boundary. Interim analyses were reviewed
`by an independent third-party data monitoring committee (DMC).
`All efficacy analyses used an intent-to-treat approach, whereas safety
`analyses included all patients who received ⱖ one dose of study medica-
`tion. OS and PFS were summarized by using Kaplan-Meier methods, and
`for each the median event time with corresponding two-sided 95% CI was
`provided, with the hazard ratio (HR) and its 95% CI. A log-rank test
`(one-sided, ⱕ 0.025) was used to compare OS and PFS between arms,
`stratifying for ECOG performance status (0 v 1) and type of disease pro-
`gression (PSA progression only v radiographic progression). ORR was
`summarized for each arm with the corresponding two-sided 95% CI by
`using an exact method based on binomial distribution. A point estimate of
`the ORR difference between arms and its corresponding 95% CI were
`calculated by using the normal approximation.
`
`RESULTS
`
`Patients
`Between July 2008 and August 2010, 873 patients were ran-
`domly assigned from 152 sites in 22 countries, with 584 patients
`allocated to sunitinib and 289 to placebo (Fig 1). Baseline charac-
`teristics were well balanced between arms (Table 1). Median age
`was 68 years (range, 39 to 90 years) and approximately 49% had
`tumors with Gleason score ⱖ 8.
`The study was stopped early on the recommendation of the
`DMC after a second interim analysis determined that an OS difference
`between arms was statistically improbable.
`
`Treatment Exposure
`Median treatment duration with sunitinib and placebo was 98
`days (range, 1 to 783 days) and 97 days (range, 6 to 661 days), respec-
`tively. Median duration of study follow-up was 8.7 months. Median
`
`2
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Sunitinib Plus Prednisone Versus Prednisone Alone in mCRPC
`
`Randomly assigned
`(N = 873)
`
`Allocated to sunitinib plus prednisone
` Received allocated intervention
` Did not receive intervention
`
`(n = 584)
`(n = 581)
`(n = 3)
`
`Allocated to placebo plus prednisone
` Received allocated intervention
` Did not receive allocated intervention
`
`(n = 289)
`(n = 285)
`(n = 4)
`
`Discontinued study
` Progressive disease/relapse
` htaeD
` tneve esrevdA
` Consent withdrawn
` Study terminated by sponsor
` pu-wollof ot tsoL
` rehtO
`
`Analyzed for efficacy
`Analyzed for safety
` stneve esrevdA
` atad yrotarobaL
`
`(n = 581)
`(n = 255)
`)54 = n(
`)951 = n(
`(n = 48)
`(n = 57)
`)0 = n(
`)71 = n(
`
`(n = 584)
`
`)185 = n(
`)575 = n(
`
`Discontinued study
` Progressive disease/relapse
` htaeD
` tneve esrevdA
` Consent withdrawn
` Study terminated by sponsor
` pu-wollof ot tsoL
` rehtO
`
`Analyzed for efficacy
`Analyzed for safety
` stneve esrevdA
` atad yrotarobaL
`
`(n = 285)
`(n = 171)
`)41 = n(
`)12 = n(
`(n = 24)
`(n = 43)
`)1 = n(
`)11 = n(
`
`(n = 289)
`
`)582 = n(
`)972 = n(
`
`Fig 1. CONSORT diagram.
`
`relative dose intensity for sunitinib was 82% overall, and ⬎ 95% for
`the first four cycles and ⬎ 65% for most other cycles. Relative dose
`intensity was not determined for placebo. A total of 32% of patients in
`the sunitinib arm required ⱖ one sunitinib dose reduction, to 25 mg
`and 12.5 mg in approximately 29% and 4% of patients, respectively.
`Of 581 patients who received the allocated intervention in the
`sunitinib arm (Fig 1), 44 (8%) had their dose increased to 50 mg/d,
`with no apparent effect on clinical outcome. The most common
`treatment-emergent AEs leading to sunitinib dose reduction or delay
`were hand-foot syndrome (11%) and diarrhea, fatigue, and asthenia
`(each 9%). The placebo dose was reduced to a nominal 25 mg in only
`12 patients (4%) and to 12.5 mg in one patient (⬍ 1%). At analysis,
`581 patients (99%) and 285 patients (99%) in the sunitinib and
`placebo arms, respectively, had discontinued the study (including
`one patient lost to follow-up in the placebo arm; Fig 1). Fewer
`withdrawals occurred due to progressive disease in the sunitinib
`than the placebo arm (44% v 60%). Overall, 27% discontinued
`primarily because of an AE (most commonly fatigue or asthenia),
`compared with 7% on placebo.
`
`Efficacy
`OS, the primary end point, did not differ significantly between
`treatment arms (Fig 2), with a median of 13.1 months (95% CI, 12.0 to
`14.1 months) and 11.8 months (95% CI, 10.8 to 14.2 months) with
`sunitinib and placebo, respectively, and HR of 0.914 (95% CI, 0.762 to
`1.097; P ⫽ .168; stratified log-rank test). A high proportion of patients
`in each arm (42% and 38% in the sunitinib and placebo arms, respec-
`tively) was censored in the OS analysis. The most frequent reason for
`censoring was that the patient was alive at the time of data analysis.
`Based on investigator-derived assessment of disease response and
`progression, PFS was significantly longer with sunitinib compared
`with placebo (median PFS, 5.6 months [95% CI, 5.4 to 6.5 months] v
`4.1 months [95% CI, 3.6 to 5.6 months]; HR ⫽ 0.725 [95% CI, 0.591
`to 0.890]; P ⬍ .001; stratified log-rank test; Fig 3). In this analysis, 56%
`and 48% of patients were censored in the sunitinib and placebo arms,
`
`respectively. The most common reason for censoring was study ter-
`mination before disease progression.
`A total of 327 and 167 patients in the sunitinib and placebo arms,
`respectively, had measurable disease with baseline target assessments.
`ORR was marginally higher with sunitinib (6%; 95% CI, 4% to 9%)
`than with placebo (2%; 95% CI, ⬍ 1% to 5%). The odds ratio for
`sunitinib v placebo was 3.56 (95% CI, 1.0 to 19.0; P ⫽ .040). No
`complete responses were observed. The proportion of patients with a
`best response of stable disease ⱖ 3 months was similar in each arm
`(26% and 30% for sunitinib and placebo, respectively).
`
`Safety
`A higher proportion of patients on sunitinib than on placebo
`reported treatment-related AEs (94% v 62%). The most frequent
`sunitinib- or placebo-related, nonhematologic any-grade toxicities
`were diarrhea (41% v 9%), decreased appetite (35% v 12%), nausea
`(35% v 12%), fatigue (30% v 15%), hand-foot syndrome (29% v 3%),
`dysgeusia (28% v 8%), and vomiting (25% v 7%), in the sunitinib
`versus placebo arms, respectively. The most commonly reported
`grade 3 or 4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and
`hand-foot syndrome (7% v 0%; Table 2). Bone and back pain of any
`cause were reported less frequently in the sunitinib than in the placebo
`arm (bone pain: 12% v 16%; back pain: 15% v 21%). With the
`exception of anemia, the incidence of treatment-emergent hemato-
`logic abnormalities (mostly grade 1 or 2) was substantially higher in
`patients receiving sunitinib. In particular, grade 3 lymphopenia was
`more common with sunitinib than placebo (Table 2). However, op-
`portunistic infections were not observed. The incidence of grade 4
`hematologic toxicity was low in both arms (ⱕ 2%; Table 2).
`A total of 57 patients (10%) in the sunitinib arm and 30 patients
`(11%) in the placebo arm died during the study. The large majority of
`deaths were due to prostate cancer (72% in the sunitinib arm and 80%
`in the placebo arm). Other causes of death reported in ⱖ two patients
`overall included pneumonia (n ⫽ 1 in each arm), sepsis (n ⫽ 2, both in
`the sunitinib arm), and cardiopulmonary arrest (n ⫽ 1 in each arm).
`
`www.jco.org
`
`© 2013 by American Society of Clinical Oncology
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`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`3
`
`

`

`Michaelson et al
`
`Sunitinib + prednisone (n = 584)
`Median, 13.1 months (95% CI, 12.0 to 14.1)
`Placebo + prednisone (n = 289)
`Median, 11.8 months (95% CI, 10.8 to 14.2)
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Overall Survival
`
`(probability)
`
`HR, 0.914 (95% CI, 0.762 to 1.097)
`P = .168 (one-sided stratified log-rank test)
`
`0
`
`6
`
`24
`18
`12
`Time (months)
`
`30
`
`36
`
`No. at risk
`Sunitinib + prednisone 584
`Placebo + prednisone
`289
`
`437
`211
`
`243
`111
`
`106
`44
`
`24
`12
`
`1
`2
`
`0
`0
`
`Fig 2. Kaplan-Meier estimates of overall survival by treatment arm. HR,
`hazard ratio.
`
`compared docetaxel and prednisone with and without bevacizumab
`in mCRPC32 and also failed to reveal an OS advantage despite signif-
`icantly improved PFS and other efficacy end points.
`The reason that improved PFS does not appear to translate to OS
`benefit with antiangiogenic agents is not clear. The magnitude of PFS
`may be too small to affect OS, or other factors may be involved. A
`phase III trial in mCRPC with lenalidomide was also discontinued
`early because of futility33 and, in the first-line mCRPC setting, the
`VENICE (VEGF Trap Administered With Docetaxel in Metastatic
`Androgen-Independent Prostate Cancer) phase III aflibercept study
`failed to meet its primary end point of extending OS compared with
`placebo.34 The multikinase inhibitor sorafenib has revealed some an-
`titumor activity in phase II studies in mCRPC.35-37 However, no
`sorafenib phase III studies have been pursued in this indication. In a
`
`Sunitinib + prednisone (n = 584)
`Median, 5.6 months (95% CI, 5.4 to 6.5)
`Placebo + prednisone (n = 289)
`Median, 4.1 months (95% CI, 3.6 to 5.6)
`
`HR, 0.725 (95% CI, 0.591 to 0.890)
`P < .001 (one-sided stratified log-rank test)
`
`6
`
`12
`18
`Time (months)
`
`24
`
`30
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`Progression-Free Survival
`
`(probability)
`
`No. at risk
`Sunitinib + prednisone 584
`Placebo + prednisone
`289
`
`110
`44
`
`25
`12
`
`6
`4
`
`3
`0
`
`0
`0
`
`Fig 3. Kaplan-Meier estimates of progression-free survival by treatment arm.
`HR, hazard ratio.
`
`Table 1. Baseline Patient Characteristics by Treatment Arm
`
`Characteristic
`
`Age, years
`Median
`Range
`ECOG performance status
`0
`1
`Gleason score
`ⱕ 6
`7
`8-10
`Not done/missing
`Disease progression at entry
`PSA progression only
`Radiographic progression
`Prior therapy with VEGF inhibitor
`Number of prior systemic
`treatment regimensⴱ
`
`1
`2
`⬎ 2
`Not reported
`Prior cycles of docetaxel†
`Median
`Range
`Reasons for stopping docetaxel
`Disease progression
`Intolerance
`
`Sunitinib ⫹
`Prednisone
`(n ⫽ 584)
`
`Placebo ⫹
`Prednisone
`(n ⫽ 289)
`
`No.
`
`%
`
`No.
`
`%
`
`69
`39-90
`
`68
`47-86
`
`292
`292
`
`76
`177
`296
`35
`
`316
`267
`14
`
`503
`59
`21
`1
`
`50
`50
`
`13
`30
`51
`6
`
`54
`46
`2
`
`86
`10
`4
`⬍ 1
`
`145
`144
`
`43
`88
`129
`29
`
`144
`145
`6
`
`249
`31
`9
`0
`
`8
`⬍ 1-160
`
`8
`⬍ 1-70
`
`534
`50
`
`91
`9
`
`265
`24
`
`50
`50
`
`15
`30
`45
`10
`
`50
`50
`2
`
`86
`11
`3
`0
`
`92
`8
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; PSA, prostate-
`specific antigen; VEGF, vascular endothelial growth factor.
`ⴱIncludes hormone therapy and chemotherapy (ie, docetaxel), and excludes
`ketoconazole, estrogens, and antiandrogens.
`†One docetaxel cycle is 3 weeks.
`
`The percentage of deaths due to unknown causes was higher in the
`sunitinib arm (11% v 0%).
`
`DISCUSSION
`
`Compared with placebo, the addition of sunitinib to prednisone did
`not significantly prolong OS in men with mCRPC after failure of a
`docetaxel-based regimen. PFS was significantly improved with
`sunitinib compared with placebo (median PFS 5.6 months v 4.1
`months; P ⬍ .001) and ORR was also higher with sunitinib than
`placebo (6% v 2%; P ⫽ .040). Based on these results, use of antiangio-
`genic therapy in unselected patients with advanced prostate cancer
`remains investigational.
`In addition to improvement in PFS and response rate, there was
`less back and bone pain reported among patients randomly assigned
`to receive sunitinib compared with placebo. Taken together, these
`results suggest that there may be a role for sunitinib or other antian-
`giogenic therapy in prostate cancer, but that further investigation is
`required to identify the most appropriate patient population. Al-
`though in a different setting, our results are similar to a recently
`reported Cancer and Leukemia Group B (CALGB) 90401 study that
`
`4
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
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`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Sunitinib Plus Prednisone Versus Prednisone Alone in mCRPC
`
`Table 2. Grade ⱖ 3 Treatment-Related Adverse Events and Treatment-
`Emergent Hematologic Abnormalities
`
`Sunitinib ⫹
`Prednisone
`(n ⫽ 581)
`
`Placebo ⫹
`Prednisone
`(n ⫽ 285)
`
`Grade 3
`
`Grade 4
`
`Grade 3
`
`Grade 4
`
`OS benefit),32 this study did not allow maintenance of VEGF
`inhibition beyond disease progression, despite OS benefit observed
`with postprogression continuation of bevacizumab in other tumor
`types (eg, colon cancer).43 It is conceivable that prolonged VEGF
`inhibition may be required to achieve clinical benefit.
`The safety profile of sunitinib did not point to any new or unex-
`pected AEs compared with those previously reported in mCRPC24,25
`or other tumor types, including GIST, RCC, and pancreatic NET.44-46
`The 37.5 mg/d dose was chosen for its perceived flexibility in manag-
`ing potential AEs, via dose titration or brief interruption. Nevertheless,
`tolerance to sunitinib was worse in the present trial. This poor tolera-
`bility may have been because of the older median age in this trial
`compared with trials in other cancer types (68 years v 56 to 62
`years),44-46 to previous chemotherapy with docetaxel, and/or to com-
`bination treatment with prednisone. In the present study, 27% of
`patients halted sunitinib treatment before disease progression because
`of toxicity compared with 9%, 8%, and 17% of patients in the phase III
`GIST, RCC, and pancreatic NET trials, respectively.44-46 The relatively
`poor tolerance to sunitinib may have limited treatment and affected
`OS, and is a plausible explanation for the discrepancy between PFS
`and OS. To that point, the short treatment duration (median, 98 days)
`may have been sufficient to improve PFS but not OS.
`Since this trial was launched in 2008, a number of positive phase
`III mCRPC studies have been reported. Abiraterone acetate, in com-
`bination with prednisone, improved PFS and OS in docetaxel-
`pretreated patients and was recently reported to extend PFS in
`chemotherapy-naive patients as well.5,47 Three other compounds, en-
`zalutamide, cabazitaxel, and radium-223 dichloride, have also dem-
`onstrated survival benefit in mCRPC patients,4,6,48 and together these
`agents constitute a new and improved armamentarium for advanced
`prostate cancer treatment. However, since each therapy improves OS
`by only a few months compared with placebo, it is clear that further
`advances are needed. Antiangiogenic agents may yet have a role to play
`in treating patients with mCRPC, but their future development in this
`area will require enhanced patient selection by using predictive bio-
`markers of response to guide therapy in a rational manner.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) and/or an author’s immediate family member(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: Fredrik Laestadius, Roche (C);
`Shaw-Ling Wang, Pfizer (C); Maria Jose Lechuga, Pfizer (C); Jolanda
`Paolini, Pfizer (C); Isan Chen, Pfizer (C); Edna Chow Maneval, Pfizer
`(C), Consultant or Advisory Role: M. Dror Michaelson, Pfizer (U); Lisa
`Sengeløv, Amgen (C), Janssen Pharmaceutica (C), sanofi-aventis (C);
`Robert Jones, Pfizer (C), Astellas Pharma (C), Janssen Pharmaceutica
`(C), sanofi-aventis (C); Juergen Gschwend, Astellas Pharma (C), Bayer
`HealthCare Pharmaceuticals (C), GlaxoSmithKline (C), Novartis (C),
`Pfizer (C), Roche (C), Janssen Pharmaceutica (C); Fred Saad, Astellas
`Pharma (C), Janssen Pharmaceutica (C), Pfizer (C), sanofi-aventis (C)
`Stock Ownership: Shaw-Ling Wang, Pfizer; Maria Jose Lechuga, Pfizer;
`
`No. % No. % No. % No. %
`2 ⬍ 1
`3 ⬍ 1
`0
`0
`0
`0
`1 ⬍ 1
`0
`0
`0
`0
`1 ⬍ 1
`12
`2
`0
`0
`0
`0
`
`1
`4
`2
`6
`0
`0
`0
`0
`2 ⬍ 1
`1 ⬍ 1
`1 ⬍ 1
`0
`0
`0
`0
`2 ⬍ 1
`0
`0
`
`0
`0
`1 ⬍ 1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`3
`1
`0
`0
`0
`0
`
`8
`49
`8
`44
`7
`38
`5
`28
`4
`25
`4
`24
`3
`20
`3
`17
`1 ⬍ 1
`10
`2
`9
`2
`
`Adverse Event
`
`Fatigue
`Asthenia
`Hand-foot syndrome
`Diarrhea
`Decreased appetite
`Hypertension
`Nausea
`Mucosal inflammation
`Pulmonary embolism
`Vomiting
`Stomatitis
`Hematologic abnormalitiesⴱ
`Anemia
`Leukopenia
`Neutropenia
`Lymphopenia
`Thrombocytopenia
`
`39
`19
`31
`110
`19
`
`7
`3
`5
`19
`3
`
`2
`11
`0
`0
`1 ⬍ 1
`7
`1
`8
`1
`
`6
`17
`1 ⬍ 1
`0
`0
`29
`10
`3
`1
`
`2
`5
`1 ⬍ 1
`2 ⬍ 1
`3
`1
`0
`0
`
`NOTE. Occurring in ⱖ 1% of patients in at least one treatment arm. All
`adverse events and laboratory abnormalities graded according to the National
`Cancer Institute Common Terminology Criteria for Adverse Events, version
`3.0. Grade 5 treatment-related adverse events were reported in 12 (2%) of
`patients in the sunitinib arm and one patient (⬍ 1%) in the placebo arm.
`ⴱFor hematologic abnormalities, n ⫽ 574 in the sunitinib arm (apart from
`platelets, for which n ⫽ 573) and n ⫽ 279 in the placebo arm.
`
`randomized phase II study, tasquinimod (an oral quinoline-3 carbox-
`amide derivative targeting S100A9) improved PFS and OS compared
`with placebo in chemotherapy-naive men with mCRPC and minimal
`symptoms.38,39 The results of a phase III trial investigating the role of
`tasquinimod are awaited.40
`A number of other VEGF tyrosine kinase inhibitors in develop-
`ment, such as axitinib, tivozanib, or the dual VEGFR-2/c-Met inhibi-
`tor cabozantinib, may still be of substantial interest in this indication.
`In particular, cabozantinib has demonstrated intriguing activity in
`advanced prostate cancer, particularly with regard to bone scan re-
`sponse,41 and will be studied in phase III trials. Whether c-Met inhi-
`bition contributes to this activity remains unknown. Interestingly,
`sunitinib may also produce bone scan responses in men who do not
`appear to be responding based on other outcome measures42; the
`potential discrepancy between bone scan results and true clinical out-
`comes is an area of active investigation.
`An important limitation to the overall interpretation of this
`study was the fact that the DMC recommended early termination
`after the second interim analysis. This confounded the analysis of
`PFS as well as response rates, and precluded central review of all
`imaging studies. In addition, the high censoring rate, which to a
`great extent reflected patient discontinuation from therapy before
`disease progression, could limit interpretation of PFS results. Fur-
`thermore, although progression was not defined in terms of PSA
`levels in this study, changes in PSA levels may potentially have
`influenced treatment decisions. Finally, like the CALGB 90401
`study, which had similar results (ie, improvement in PFS, minus
`
`www.jco.org
`
`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`5
`
`

`

`Michaelson et al
`
`Jolanda Paolini, Pfizer; Edna Chow Maneval, Pfizer Honoraria: Stephane
`Oudard, Amgen, Bayer HealthCare Pharmaceuticals, Novartis, Pfizer, Roche,
`Keocyt; Robert Jones, Pfizer, Astellas Pharma, Janssen Pharmaceutica,
`sanofi-aventis; Anders Ulle`n, Pfizer, Novartis, Roche, sanofi-aventis,
`Laboratoires Pierre Fabre; Amit Bahl, Amgen, Janssen Pharmaceutica, Novartis,
`Pfizer, sanofi-aventis, Roche; Research Funding: M. Dror Michaelson, Pfizer;
`Lisa Sengeløv, Pfizer, Bristol-Myers Squibb, Celgene, sanofi-aventis; Robert
`Jones, Pfizer; Amit Bahl, Ipsen, sanofi-aventis Expert Testimony: None Patents:
`None Other Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: M. Dror Michaelson, Yen-Chuan Ou, Edna
`Chow Maneval, Shaw-Ling Wang, Isan Chen
`
`Provision of study materials or patients: M. Dror Michaelson,
`Yen-Chuan Ou, Lisa Sengeløv, Peter Ostler, Gedske Daugaard, Robert
`Jones, Anders Ulle`n, Tristan Maurina
`Collection and assembly of data: M. Dror Michaelson, Stephane
`Oudard, Yen-Chuan Ou, Lisa Sengeløv, Fred Saad, Nadine Houede,
`Peter Ostler, Arnulf Stenzl, Gedske Daugaard, Robert Jones, Fredrik
`Laestadius, Anders Ulle`n, Amit Bahl, Tristan Maurina, Edna Chow
`Maneval, Maria Jose Lechuga, Jolanda Paolini
`Data analysis and interpretation: M. Dror Michaelson, Stephane
`Oudard, Yen-Chuan Ou, Lisa Sengeløv, Fred Saad, Peter Ostler, Gedske
`Daugaard, Robert Jones, Fredrik Laestadius, Anders Ulle`n, Amit Bahl,
`Daniel Castellano, Juergen Gschwend, Edna Chow Maneval, Shaw-Ling
`Wang, Maria Jose Lechuga, Jolanda Paolini, Isan Chen
`Manuscript writing: All authors
`Final approval of manuscript: All authors
`
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`4. de Bono JS, Oudard