AVENTIS EXHIBIT 2126
`Mylan v. Aventis, IPR2016-00712
`
`
`

`
`VOLUME 31
`
`- NUMBER 31 - NOVEMBER 1 2013
`
`JOURNAL OF CLINICAL ONCOLOGY
`
` ©i§.?ii@:itiir,ix:-.\i.t
`f.itE—‘i$'(a)e‘i“i‘r"
`
`Susan Halabi, Andrew J. Armstrong,
`Ellen Kaplan, Chen-Yen Lin, and Nicole
`C. Solomon, Duke University, Durham,
`NC; Oliver Sartor, Tulane University,
`New Orleans, LA; Johann de Bono,
`Royal Marsden Hospital, Sutton, United
`Kingdom; and Eric J. Small, University
`of California at San Francisco, San
`Francisco, CA.
`
`Published online ahead of print at
`www.jco.org on October 7, 2013.
`
`Supported in part by National lnstitutes
`of Health Grant No. CA 155296-1A1
`and by sanofi-aventis.
`
`Terms in Lilu-2 are defined in the glos-
`sary, found at the end of this article
`and online at www.jco.org.
`Presented orally at the 48th Annual
`Meeting of the American Society of
`Clinical Oncology, Chicago,
`IL, June
`1-5, 2012.
`
`The study sponsor did not have a role in
`the analysis, interpretation of data, writing
`of the manuscript, or decision to submit
`the manuscript for publication.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: Susan Halabi,
`PhD, Duke University Medical Center,
`2424 Erwin Rd, Suite 11088, Durham,
`NC 27710; e-mail: susan.halabi@
`dukeedu.
`
`© 2013 by American Society of Clinical
`Oncology
`
`0732-l83X/13/3131-3944/$20.00
`DOl: 10,1200/JCO.20l3.50.3201
`
`Prostate—Specific Antigen Changes As Surrogate for Overall
`Survival in Men With Metastatic Castration-Resistant
`
`Prostate Cancer Treated With Second—Line Chemotherapy
`Susan Halabi, Andrew I. Armstrong, Oliver Sartor, Iolzann de Bono, Ellen Kaplan, Clicii~Yeiz Lin,
`Nicole C. Solomon, and Eric I. Small
`
`Purpose
`Prostate-specific antigen (PSA) kinetics, and more specifically a 2 30% decline in PSA within 3
`months after initiation of first—|ine chemotherapy with docetaxel, are associated with improvement
`in overall survival (OS) in men with metastatic castration—resistant prostate cancer (mCRPC). The
`objective of this analysis was to evaluate post—treatment PSA kinetics as surrogates for OS in
`patients receiving second—|ine chemotherapy.
`
`,
`g
`_
`Patients and Methods
`trial of patients with mCRPC randomly assigned to cabazitaxel plus
`Data from a phase lll
`prednisone (C + P) or mitoxantrone plus prednisone were used. PSA decline (2 30% and 2 50%),
`velocity, and rise within the first 3 months of treatment were evaluated as surrogates for OS. The
`Prentice criteria, proportion of treatment explained (PTE), and meta-analytic approaches were used
`as measures of surrogacy.
`Resuhs
`The observed hazard ratio (HR) for death for patients treated with C + P was 0.66 (95% Cl, 0.55
`to 0.79; P < .001). Furthermore, a 2 30% decline in PSA was a statistically significant predictor
`of OS (HR for death, 0.52; 95% Cl, 0.43 to 0.64; P< .001). Adjusting for treatment effect, the HR
`for a 2 30% PSA decline was 0.50 (95% Cl, 0.40 to 0.62; P < .001). but ‘treatment remained
`statistically significant, thus failing the third Prentice criterion. The PTE for a 2 30% decline in PSA
`was 0.34 (95% Cl, 0.11 to 0.56), indicating a lack of surrogacy for OS. The values of R2 were < 1,
`suggesting that PSA decline was not surrogate for OS.
`
`A
`_
`A
`Conclusion
`Surrogacy for any PSA—based end point could not be demonstrated in this analysis. Thus, the
`benefits of cabazitaxel in mediating a survival benefit are not fully captured by early PSA changes.
`
`J C//n Oncol 31:3944-3950. (0 2073 by American Society of Clinical Onco/ogy
`
`t
`L,-_s._. _.-_
`
`211‘ i‘l':i Ti I i llii Ti ii 1 1*
`
`Investigators have long been challenged by the lack
`of Stll’l'(>g2llC end points for clinical trials in men
`with metastatic castration—resistant prostate cancer
`(mCRPC)."5 True surrogacy requires meeting sev-
`eral rigorous statistical criteria defined by l’i't-iiiice
`( Prciitice cri lCl'ld).6 The degree ofsurrogacy can also
`be measured by the proportion of treatment effect
`explained (PTE).7 Reductions in serum pi'ost;iii.~-
`specific ziiitigeri
`(l—’Si\) with systemic therapy may
`reflect reductions in tumor burden, which may be
`linked to improved long-term outcomes; this has
`been a natural intermediate end point to assess sur-
`rogacy. Kelly et al' first proposed the use of post-
`therapy changes in PSA from baseline as an
`intermediate marker of response in patients with
`
`mCRPC. Numerous subsequent reports confirmed
`that patients with mCRPC who had experienced
`2 50% decline in PSA from baseline had improved
`survival, compared with those patients who did not
`achieve 2 50% reduction in PSA.“ In retrospective
`studies, several investigators have reported that PSA
`decline 2 50% correlated with improved survival.
`Not all investigators have correlated PSA decline
`from baseline with improved survival.8‘° However,
`Petrylak ct al”"” demonstrated that both 2 30%
`and 2 50% decline in PSA satisfied the Prentice
`
`criteria in patients with mCRPC treated with first-
`line chemotherapy, whereas Z 50% decline in PSA
`
`failed to meet the surrogacy criteria as measured by
`PTE. By contrast, Armstrong et al” found that al-
`though 2 30% decline in PSA after docetaxel treat-
`ment in the phase III TAX327 trial fulfilled the
`
`3944
`
`© 2013 by American Society of Clinical Oncology
`
`This material was-to-piecl
`at: the NLM and may be
`
`

`
`PSA Changes As Surrogate for OS
`
`Prentice criteria, the degree of surrogacy as measured by PTE in this
`decline was modest.” Evidence to support PSA decline as a surro-
`gate for overall sur\'iyal (OS) across multiple agent classes and
`mechanisms ofactioii is lacking.
`The primary objective of this analysis was to evaluate whether
`2 30% decline in PSA within 3 months of treatment initiation was a
`
`surrogate end point of OS in patients with niCRPC receiving second-
`line chemotherapy (cabazitaxel or mitoxaiitrone) after progression
`with docetaxel. A secondary objective was to assess whether 2 50%
`decline in PSA was a surrogate end point for OS. In addition, we
`performed exploratory analysis of other PSA kinetics as surrogate end
`points for OS.
`. ~V,I'x">vVt Vac,» Bony “M/‘lV'V‘i’4(l"1 ,1-,,....w«-s»«.~.~.,.,‘
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`».— -.7
`v
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`Eta llili 3? 1............-.s..._.s.4_...H........-.._._......_a~.._ .-.........-.,.-.. _._a........ .
`,. ..___._.............__._ M...
`
`Patients
`
`This analysis used data from the TROPIC trial, a phase 111 trial of 755
`men with niCPRC previously treated with a docetaxel~containing regimen.”
`Participants were randomly assigned to receive either 12 mg/m2 iiiitoxaiitroiie
`intravenously over 15 to 30 mimites plus oral prednisone 10 mg daily (M + P)
`or cabazitaxel 25 my1112 administered over 1 hour every 3 weeks in combina-
`tion with prednisone (C + P). Eligible patients had progressive mCRPC after
`treatment with a d0cetaxel—based regimen, Eastern Cooperative Oncology
`Group performance status of 0 to 2, and adequate hematologic, hepatic, renal,
`and cardiac function. Those who received iiiitoxaiitrone, radiotherapy, or
`other cancer therapies within 4 weeks before enrollment were excluded. De-
`tails ofeligibility have been previously reported.”
`End Points
`
`The primary end point of the clinical trial was OS, which was defined as
`the time from random assignment to date of death resulting from any cause.
`Secondaiy end points were 2 50% decline in PSA using the Prostate Cancer
`Working Group 2 criteria.” Serum PSA was measured at baseline and then
`every 3 weeks until progression, with a PSA response per protocol defined as
`2 50% decline from baseline PSA, if baseline PSA was > 0.2 ng/nil. and was
`maintained for at least 3 weeks.
`
`For the purposes oftliis analysis, the surrogate end point to be examined
`was 2 30% decline in PSA. The rationale for using this end point as a binary
`was to confirm the findings reported in patients with mCRPC after docetaxel
`treatment.‘ "'2 Similar to previous studies, 2 30% was defined as a decline
`2 30% from the baseline PSA measurement at any time within the first 90 days
`of treatment.‘ 1'1 *7 In a case in which confirniation was required, there had to be
`a second consecutive decline at least 21 days after the first decline. Ranges of
`P5/\ tlecliiie/i'ise and velocity were explored as markers ofOS. PSA velocity was
`calculated as the slope of log PSA ( log 2 scale) by time based on the least squares
`method using at least two postbaseline PSA measurements. PSA rise was
`computed as percent increase from the baseline PSA ineasurenient. An indi-
`cator variable was created if the percent value was 2 the percent specified in
`the analysis.
`
`Data Analysis
`As part ofa research federal grant, this analysis was approved by the Duke
`University Institutional Review Board. We used the logistic regression model
`to test whether treatment arm predicted 2 30% and 2 50% decline in PSA and
`employed three different approaches to evaluate wlietlicr PSA decline or PSA
`rise was a surrogate end point for OS. These approaches were: one, Prentice
`criteria; two, 1"l‘F,; and three, meta-analysis. The Prentice criteria define a
`surrogate as a “response variable for which a test of the null hypothesis of no
`relationship to the treatment groups under comparison is also a valid test ofthe
`corresponding null hypothesis based on the true end poiiit.""l""”) To test the
`Prentice criteria, we fit a series oftliree proportional lialards models ofOS with
`the following covariates: model one, included treatment arm; model two,
`included PSA decline (or rise) as a surrogate marker; and model three, in-
`cluded both treatment arm and PSA decline (or rise). To fulfill the Prentice
`
`criteria, a marker is considered a surrogate end point if it is statistically signif-
`icantly associated (P < .05) with OS in both univariate models. However, in
`the multivariable model, the ma1'ker but not treatment arm needs to be
`statistically significant. The Schoenfeld test was used to check for the propoiu
`tional hazards assumption, and there was no evidence that this was violated in
`these three models.“’
`PTE is obtained from two proportional hazards models and is computed
`as 1 minus the ratio of the estimated regression coefficient for treatment effect
`in model three (adjusted) over estimated regression coefficient for treatment
`arm in model one (unadjusted).7 A value of 1 for the PTI3 indicates a perfect
`surrogate end point, whereas a value of0 represents no surrogacy. The 95% C1
`foi' PTE was computed using a nonparametric bootstrapped procedure to
`estimate the variaiice—covariance matrix of the estimated regression coeffi-
`cients for unadjusted and adjusted treatment effects (models one and three).7
`Following Burzykowski ct all7 and Busye et all,” we considered a iii«;t.i
`aiialytic approacli to assess the Surrogacy of PSA decline for OS. The meta-
`analysis procedure allows one to evaluate the Surrogacy from individual and
`trial levels. The trial level assessed the overall prediction power of the surrogate
`end point on the true end point, whereas the individual level evaluated the
`strength of the dependency between surrogate end point and true end point
`after adjusting for the treatment effect. A surrogate end point is considered
`valid if it presents a high degree (closer to one) of association at both the trial
`and individual levels.
`
`The data in this report were from a single trial, and to implement the
`meta-analysis framework, we randomly partitioned the TROPIC data into five
`clusters and assumed that each cluster was obtained from an independent trial.
`The number five was chosen to ensure the number of patients in each treat-
`ment group was Z 50 within each fold. Because the partitioning was per-
`formed randomly, the procedure was repeated 500 times. The global odds ratio
`(OR) and R2 were averaged over 500 replicates.
`The Kaplan—Meier estimator was used to estimate the OS distributions
`by patients who experienced and did not experience 2 30% and 2 50%
`decline in PSA. R software (R Foundation for Statistical Computing, Vienna,
`Austria) was used for the data analyses, and all statistical tests were two sided.
`
`i‘;iE5:iai<rr:,
`
`Baseline Characteristics
`
`Of the 755 patients enrolled onto the TROPIC trial, 17 patients
`did not have PSA data at baseline, and 85 patients had PSA < 0.20
`ng/mL and were excluded from the analysis. The current analysis
`was based on 653 patients (86%) who had sufficient PSA data
`post-treatnieiit. Participants in this analysis had similar baseline
`characteristics compared with patients who did not have PSA
`decline data. Moreover, the survival distributions were not differ-
`
`ent between patieiits who were and were not included in the
`analysis (log-rank P = .852).
`Baseline clinical and laboratory characteristics of the 653 patients
`are summarized in Table 1. A majority were white, with a median age
`of 67 years; 91% had Eastern Cooperative Oncology Group perfor-
`mance status of 0 to 1; 54% had measurable disease. Median PSA was
`
`170 ng/mL (interquartile range [IQR], 68 to 465). There were no
`differences between the two arms with respect to baseline variables
`(Table 1).
`
`PSA Decline
`
`Median PSA decline in each arm was 31.1% (IQR, 0 to 61.4) and
`0% (IQR, 0 to 31.2) for C + P and M + P, respectively. Two hundred
`fifty men (38%) experienced 2 30% decline in PSA from baseline
`(51% with C + P; 26% with M + P), whereas 25% of patients had
`2 50% decline in PSA (33% with C+ P; 26% with M + P). Treatment
`
`wivw.jt'o.m'g
`
`This material wasicsn-pied
`at the N Liv/1a rid may be
`Subject U355-pyright Laws
`
`© 2013 by American SOCIBIY of Clinical Oncology
`
`3945
`
`

`
`Halabi et al
`
`
`
`Table 1. Baseline Characteristics of Patients With PSA Decline Data by
`
`Treatment Arm
`M + P
`C + P
`Total
`Characteristic
`(n = 325)
`(n = 328)
`(N = 653)
`
`
`
`
`
`
`57
`62-73
`
`58
`62.75-73
`
`57
`62-73
`
`81
`9
`5
`3
`
`32
`59
`10
`
`95
`89
`25
`4
`
`86
`6
`5
`3
`
`39
`54
`7
`
`97
`83
`23
`3
`
`84
`8
`5
`3
`
`35
`56
`8
`
`96
`86
`24
`4
`
`Age, years
`Median
`25th and 75th percentile
`Race, %
`White
`Asian
`Black
`Other
`ECOG PS, %
`O
`1
`2
`Disease extent, %
`Metastatic
`Bone
`Visceral
`Locoregional
`PSA, ng/mL
`Median
`25th and 75th percentile
`Alkaline phosphatase, U/L
`Median
`25th and 75th percentile
`Hemoglobin, g/L
`Median
`25th and 75th percentile
`Measurable disease, %
`Baseline pain, %
`Prior hormonal therapy, %
`Hormonal
`Irradiation
`Surgery
`Biologic
`No. of chemotherapy lines, %
`1
`2
`2 2
`No. of docetaxel regimens, %
`85
`84
`86
`1
`13
`14
`12
`2
`2
`2
`2
`2 2
` __j
`
`169.5
`68.441792
`
`169.5
`686-4495
`
`1695
`684-4650
`
`1535
`942-3120
`
`149.5
`822-2885
`
`1505
`890-3000
`
`120 ,
`109.0-130.0
`56
`46
`
`119
`109.4-129.2
`53
`49
`
`120
`109.0-130.0
`54
`43
`
`99
`62
`54
`10
`
`70
`22
`8
`
`99
`65
`52
`8
`
`67
`26
`7
`
`99
`64
`53
`9
`
`69
`24
`8
`
`Abbreviation: C + P, cabazitaxel plus prednisone; ECOG PS, Eastern Coop-
`erative Oncology Group performance status; M + P, mitoxantrone plus
`prednisone; PSA, prostate-specific antigen.
`
`
`arm significantly predicted Z 30% decline in PSA for patients receiv-
`ing C + P (OR, 3.02; 95% CI, 2.17 to 4.21; P < .001) compared with
`patients receiving M + P.
`There were 449 deaths observed among 653 patients, and median
`follow-up time among 204 surviving patients was 16.4 months (95%
`CI, 14.8 to 18.5). Median OS by PSA decline by arm is listed in Table 2.
`
`Test for Surrogacy
`The Prentice criteria. Prentice operational criteria were appliec .6
`First, treatment arm was a statistically significant predictor of OS (Fig
`1A). The observed hazard ratio (HR) for death for patients treated
`with C + P was 0.66 (95% CI, 0.55 to 0.79; P < .001) compared with
`
`
`Table 2. OS by Treatment Arm and Percent Decline in PSA Within 3 Months
`of Treatment
`
`
`M + P
`
`C + P
`
`Total
`
`Median
`H/ledian
`Median
`O8
`O8
`No. of
`OS
`No. of
`Decline in
`(months)
`(months)
`Patients
`(months)
`Patients
`PSA (%)
`15.6
`16.3
`242
`15.1
`154
`2 O
`15.5
`16.3
`237
`14.8
`143
`2 5
`15.5
`16.5
`221
`14.8
`129
`.>_ 10
`15.9
`16.7
`192
`15.2
`108
`2 20
`16.1
`17.2
`178
`15.2
`94
`2 25
`16.2
`17.2
`167
`15.4
`83
`2 30
`16.6
`18.0
`143
`15.2
`67
`2 40
`16.9
`19.7
`108
`15.2
`55
`2 50
`17.8
`20.5
`84
`15.1
`43
`2 60
`17.2
`22.6
`59
`14.5
`25
`2 70
`2 80
`14
`15.1
`44
`NA
`22.6
`2 90
`7
`10.6
`21
`22.6
`22.6
`
`
`Abbreviations: C + P, cabazitaxel plus prednisone; M + P, mitoxantrone plus
`prednisone; OS, overall survival; PSA, prostate—specific antigen.
`
`patients treated with M -1- P. The observed median survival times were
`15.0 (95% CI, 14.0 to 16.3) and 12.7 months (95% CI, 11.2 to 13.6) for
`C + P and M + P, respectively. Second, 2 30% decline in PSA was a
`statistically significant predictor of OS, with an HR for death of 0.52
`(95% CI, 0.43 to 0.64; P < .001) among patients who experienced
`2 30% PSA decline compared with those who did not (Fig 1 B). Third,
`in a multivariable model with _>. 30% PSA decline and treatment arm,
`
`both PSA decline and treatment arm remained statistically significant.
`The adjusted HR for treatment arm was 0.76 (95% CI, 0.62 to 0.92;
`P < .005). Because of this, the third Prentice criterion was not met.
`In addition, 2 50% decline in PSA was also tested for surrogacy
`of OS. Following the same steps described in the previous paragraph,
`treatment arm significantly predicted 2 50% decline in PSA with
`patients treated with C + P having an OR of2.41 (95% CI, 1.66 to 3.49;
`P < .001) compared with patients treated with M + P. PSA decline
`2 50% from baseline was also a statistically significant predictor of OS
`(HR for death, 0.56; 95% CI, 0.44 to 0.71; P < .001) among patients
`who experienced 2 50% PSA decline compared with those who did
`not (Fig 2). The observed median survival times were 15.0 (95% CI,
`14.0 to 16.3) and 12.7 months (95% CI, 11.3 to 13.6) for C + P and
`M + P, respectively. Similar to the analysis for 2 30% PSA decline in
`PSA, after adjusting for Z 50% PSA decline, treatment arm remained
`a statistically significant predictor of survival. The adjusted HR for
`death for patients treated with C + P was 0.71 (95% CI, 0.59 to 0.86;
`P = .005) compared with patients treated with M + P. Thus, 2 50%
`decline in PSA also failed to meet the third Prentice criterion.
`
`PSA decline as a continuous surrogate end point was also ex-
`plored as a potential surrogate of OS. In multivariable analysis, the
`adjusted HR for death decline for patients treated with C + P was 0.78
`(95% CI, 0.64 to 0.95; P = .01) compared with patients treated with
`M + P. Thus, PSA decline as a continuous outcome did not meet the
`third criterion of Prentice.
`
`PTE. As a measure of degree of surrogacy within this trial, the
`PTE analysis of the 0% to 90% decline in PSA within 3 months after
`treatment was undertaken. PTE for 2 30% decline in PSA was 0.34
`(95% Cl, 0.11 to 0.56), whereas PTE for _>. 50% decline in PSA was
`
`3946
`
`© 2013 by American Society of Clinical Oncology
`
`Jounmr. or-' CL1N1(‘.\L ONL‘()1.()(:\'
`
`This material was tau-pied
`at: the NLlv1an.~:l may be
`
`

`
`PSA Changes As Surrogate for OS
`
` B
`
`
`
`OverallSurvival
`
`0'4
`
`0.2
`
`0
`
`.0-b
`
`
`
`OverallSurvival
`
`(probability)
`
`.0 cu
`
`.0 N
`
`0
`
`
`was
`++""
`- Mitoxantrone + prednisone
`-H-l-—+
`— Cabazitaxel + prednisone, P< .001
`
`
`6
`12
`18
`24
`30
`
`
`
`(probability)
`
`6
`
`12
`
`18
`
`*%.;rh~M‘"‘l“"iIki.
`M WM
`
`W» 4,
`
`*fiiiq}+
`1*-+-+
`
`— < 30% decline
`— 2 30% decline, P< .001
`
`No. at risk
`Mitoxantrone
`+ prednisone
`Cabazitaxel
`+ prednisone
`
`325
`
`328
`
`Time (months)
`
`262
`
`286
`
`161
`
`205
`
`56
`
`79
`
`8
`
`26
`
`1
`
`3
`
`No. at risk
`< 30% decline
`2 30% decline
`
`403
`250
`
`Time (months)
`
`317
`231
`
`193
`‘I73
`
`68
`67
`
`Fig 1. (A) Treatment arm predicting for overall survival. (B) Greater than or equal to 30% decline in prostate-specific antigen predicting overall survival.
`
`24
`
`8
`26
`
`30
`
`0
`4
`
`0.20 (95% CI, 0.05 to 0.35). The lower bound ofthe 95% Cl did not
`exceed 0.50, suggesting a lack ofsurrogacy (Appendix Fig A1A, online
`only). A similar analysis using a confirmatory PSA value after a decline
`of either 2 30% or 2 50% failed to provide evidence of surrogacy
`for survival.
`
`PSA rise. Exploratory analyses ofa 0% to 90% rise in PSA within
`3 months after treatment were performed (Appendix Fig AIB, online
`only). The lower bounds ofthe 95% CI were < 0.50, implying a lack of
`surrogacy for PSA rise. The results were similar when confirmation of
`PSA rise was required, with the lower bound not meeting the PTE
`requirement for surrogacy (data not shown).
`1)/Iela-ariab/tic approach. Associations between 2 30% and
`2 50% decline in PSA and OS are presented in Figure 3. At the
`individual level, global ORs for 2 30% (Fig 3A) and 2 50% decline
`in PSA were 2.46 (95% Cl, 2.45 to 2.47) and 2.08 (95% Cl, 2.07 to
`2.09), respectively (Fig 3C). At the trial level, Rzs for 2 30% and
`
`1.0 —
`
`0.8
`
`7'; A
`'5 E*— 3-; 0.6
`3 .0
`U3 to: _C:
`‘.3 E 0.4
`co
`:2.
`> ._.
`C)
`
`0.2
`
`0
`
`
`
`
`TI
`
`V
`-— < 50% decline
`— 2 50% decline, P< .001
`
`6
`
`12
`
`18
`
`24
`
`30
`
`Time (months)
`
`490
`163
`
`399
`149
`
`256
`110
`
`88
`47
`
`15
`19
`
`0
`4
`
`Fig 2. Greater than or equal
`predicting overall survival.
`
`to 50% decline in prostate—specific antigen
`
`No, at risk
`< 50% decline
`a 50% decline
`
`2 50% decline in PSA were 0.30 (95% Cl, 0.27 to 0.32; Fig 3B) and
`0.27 (95% CI, 0.25 to 0.3; Fig 3D), respectively. The association
`between PSA decline as a continuous surrogate and OS is shown in
`Appendix Figure A2 (online only). Rzs were 0.62 (95% CI, 0.61 to
`0.62) and 0.50 (95% CI, 0.47 to 0.52) at the individual and trial
`levels, respectively. The values of R3 were < 1, suggesting that PSA
`decline is not a surrogate for OS.
`
`
`
`In this analysis, surrogacy for any PSA—based end point could not be
`demonstrated using either the Prentice criteria or PTE. In addition, an
`analysis based on split sample in random subgroups did not demon-
`strate liial-level t;iii'i‘t>gacy. Although surrogacy for some PSA-based
`end points has been met in patients with mCRPC receiving primary
`docetaxel-based chemotherapy, surrogacy does not seem to be main-
`tained for second-line chemotherapy used in the postdocetaxel set-
`ting. To our knowledge, this is the first analysis of these surrogate end
`points in patients receiving second-line chemotherapy.
`OS remains the gold-standard end point in phase III trials of
`mCRPC, and although retrospective analyses have demonstrated
`some modest degree of surrogacy for PSA decline, these intermediate
`end points have not been prospectively validated.”‘”‘19 The need for
`surrogate markers of OS will only increase as more agents are ap-
`proved for the treatment of patients with mCRPC.Z°‘33 Fortunately,
`these agents lead to prolonged survival for patients; however, their
`open-label use will push survival farther out. Moreover, their use
`subsequent to clinical-trial treatment may reduce the hypothesized
`effect size of the therapies being evaluated.2°‘23 The dilution will re-
`quire larger trial sizes, longer follow-up periods, or larger effect sizes if
`OS is to be used as the primary end point, all ofwhich make the OS end
`point less desirable.
`It has become increasingly common to use 2 30% decline in PSA
`as an end point for all patients with mCRPC based on the original
`first-line data. It is with these concerns in mind that we evaluated the
`
`WW|V,jl'0. org
`
`This material W‘aS-°EsEl~plEtd
`at the N LM a rid may be
`Subject US {in-pyright Laws
`
`© 2013 by American Society of Clinical Oncology
`
`3947
`
`

`
`Halabi et al
`
`200
`
`150
`
`100
`
`200
`
`150
`
`100
`
`Frequency
`
`Frequency
`
`O
`
`0.2
`
`0.4
`
`0.6
`
`0.8
`
`1.0
`
`50
`50
`
`
`
`Frequency
`
`2.5
`
`Odds Ratio
`
`
` Frequency
`
`
`
`Odds Ratio
`
`2.1
`
`
`
`Fig 3. (A, C) individual and (B, D) trial-level effects for (A, B) 2 30% and (C, D) 2 50% decline in prostate—speeifie antigen. Dashed line indicates empirical mean.
`
`utility ofPSA kinetics as surrogates for OS in patients with mCRPC in
`atrial involving second-line chemotherapy. Our analysis impugns the
`utility of PSA or PSA kinetics as surrogates for OS in patients with
`mCRPC receiving second-line chemotherapy. Furthermore, the data
`demonstrate that there are different disease states with in the group of
`patients with mCRPC. There are a number of potential explanations
`for why PSA kinetics may have some utility as a surrogate in patients
`treated with first-line chemotherapy, but not those treated with
`second-line therapy. First, the benefit of cabazitaxel in improving OS
`may not be mediated through PSA-dependent mechanisms.2“ PSA
`may decline for reasons unassociated, or not linearly associated, with
`cell killing by second chemotherapy treatment.” Stated alternatively,
`patients with mCRPC previously treated with first-line docetaxel may
`have selected prostate cancer cells with a greater degree ofdissociation
`between PSA decline and cancer-cell killing. Although there are no
`data to support this possibility, it is also possible that cabazitaxel, as
`opposed to docetaxel, has a narrower spectrum of activity while still
`resulting in PSA declines.
`Although the results of these data suggest that measures of PSA
`are not appropriate as surrogate markers of clinical benefit in this
`setting, it should be recognized that the only reason it was even possi-
`ble to evaluate PSA kinetics using the Prentice criteria for surrogacy in
`this setting was because cabazitaxel prolonged OS in men with
`mCRPC.6 However, the Prentice criteria do not determine trial-level
`surrogacy. Several authors have used different approaches to the vali-
`
`3948
`
`© 2013 by American Society of Clinical Oncology
`
`dation of surrogate end points, such as indivitlnal—lcvel Stll‘l‘()g,tlC}'
`based on individual patient <latzt.2(’*"’ Thus, an intermediate end point
`of OS may be of great clinical trial utility, even ifit does not meet the
`Prentice criteria. The successful identification of a surrogate, such as
`progression-free survival, for OS would have wide-ranging implica-
`tions for the design, conduct, and analysis of trials in this population.
`There are many strengths to the analysis reported in this article.
`First, post-therapy changes in PSA have been considered as both
`binary and continuous outcomes. Second, different analytic ap-
`proaches were undertaken where both individual-level and lrinl—le\‘cl
`
`surrogacy associations were assessed. Although the Prentice criteria
`establish only individual-level surrogacy after adjusting for treatment,
`the meta-analytic approaches consider association at both individual
`and trial levels. Finally, because the data are from a trial in which
`patients were treated with cabazitaxel, an innovative approach was
`implemented where the data were randomly divided into five clusters,
`and each cluster was assumed to come front an independent trial.
`Although data splitting is a useful tool, it cannot substitute for a true
`meta-analysis. As new drugs and new paradigms are introduced, ad-
`ditional validation will be warranted.
`
`In summary, based on this extensive analysis, there is no evidence
`that PSA kinetics are appropriate markers of clinical benefit, and as
`such,
`they cannot be used as surrogates for OS in patients with
`mCRPC receiving second-line chemotherapy after progression with
`
`JounN,\1, or CLlNl(‘.\l. ON(,'0L()G\‘
`
`This material was-can-pied
`at: the N LM a net may be
`Subject LIE {in-wright Laws
`
`

`
`PSA Changes As Surrogate for OS
`
`docetaxel. Decisions to stop treatment should not be guided by short-
`term, isolated changes in PSA measurements, and the identification
`and validation of surrogate end points for OS for tlte approximately
`29,720 men“ who will die as a result of this disease in 2013 remain
`unmet needs in mCRPC trials.
`
`
`
`Although all authors coinpleterl the tllS(‘l0SlIl'C declaration, thefollowing
`anthor(s) and/or an attthor’s innnetliatefamily inemher(5) indicated a
`financial or other interest tlzat is relevant to the subject matter under
`consideration in this article. Certain relationships marked with a “U” are
`tlzasefor which no compensation was received; those relationships marked
`with a “C” were C0lllpL’Il$!Jl(’(l. Fora detailed description ofthe disclosure
`categories, orfor more information about ASCO’s conflict ofinterest policy,
`please refer to the Author Disclosure Declaration and the Disclosures of
`Potential Conflicts oflnterest section in Informationfor Contributors.
`Employment or Leadership Position: None Consultant or Advisory
`ts
`Role: Andrew J. Armstron r, sanofi-aventis C , Medivation C ; ohann
`
`de Bono, sanofi-aventis (C), AstraZeneca (C), Johnson 8t Johnson (C)
`Stock Ownership: None Honoraria: Andrew J. Armstrong,
`sanofi-aventis; Johann de Bono, Astellas Pharma, Johnson & Johnson,
`Medivation Research Funding: Susan Halabi, sanofi-aventis; Andrew 1.
`Armstrong, Medivation, Janssen Pharmaceuticals, sanofi-aventis; Johann
`de Bono, AstraZeneca, sanofi-aventis, Genentcch; Ellen Kaplan,
`sanofi-avcntis; Nicole C. Solomon, sanofi-aventis Expert Testimony:
`None Patents: None Other Remuneration: None
`
`F.
`
`....................._...._.c.....__._._............... .._____.....,..._. _...._..-...... .... _
`t
`Hgitfifli lili
`ii:-l'1l.l3l7ll1ill:lr!3'ii‘lilit?
`
`Conception and design: Susan Halabi, Andrew J. Armstrong, liric Small
`Provision of study materials or patients: Oliver Sartor, Johann de Bono
`Collection and assembly of data: Johann de Bono
`Data analysis and interpretation: Susan Halabi, Andrew J. Armstrong,
`Oliver Sartor, Ellen Kaplan, Chen-Yen Lin, Nicole C. Solomon,
`Eric J. Small
`Manuscript writing: All authors
`Final approval of manuscript: All authors
`
`
`
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