T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Abiraterone in Metastatic Prostate Cancer
`without Previous Chemotherapy
`Charles J. Ryan, M.D., Matthew R. Smith, M.D., Ph.D.,
`Johann S. de Bono, M.B., Ch.B., Ph.D., Arturo Molina, M.D.,
`Christopher J. Logothetis, M.D., Paul de Souza, M.B., Ph.D.,
`Karim Fizazi, M.D., Ph.D., Paul Mainwaring, M.D., Josep M. Piulats, M.D., Ph.D.,
`Siobhan Ng, M.D., Joan Carles, M.D., Peter F.A. Mulders, M.D., Ph.D.,
`Ethan Basch, M.D., Eric J. Small, M.D., Fred Saad, M.D., Dirk Schrijvers, M.D., Ph.D.,
`Hendrik Van Poppel, M.D., Ph.D., Som D. Mukherjee, M.D., Henrik Suttmann, M.D.,
`Winald R. Gerritsen, M.D., Ph.D., Thomas W. Flaig, M.D., Daniel J. George, M.D.,
`Evan Y. Yu, M.D., Eleni Efstathiou, M.D., Ph.D., Allan Pantuck, M.D.,
`Eric Winquist, M.D., Celestia S. Higano, M.D., Mary-Ellen Taplin, M.D.,
`Youn Park, Ph.D., Thian Kheoh, Ph.D., Thomas Griffin, M.D., Howard I. Scher, M.D.,
`and Dana E. Rathkopf, M.D., for the COU-AA-302 Investigators*
`
`Abs tr act
`
`Background
`Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival
`in patients with metastatic castration-resistant prostate cancer after chemotherapy.
`We evaluated this agent in patients who had not received previous chemotherapy.
`Methods
`In this double-blind study, we randomly assigned 1088 patients to receive abiraterone
`acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The
`coprimary end points were radiographic progression-free survival and overall survival.
`Results
`The study was unblinded after a planned interim analysis that was performed after
`43% of the expected deaths had occurred. The median radiographic progression-
`free survival was 16.5 months with abiraterone–prednisone and 8.3 months with
`prednisone alone (hazard ratio for abiraterone–prednisone vs. prednisone alone,
`0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up
`period of 22.2 months, overall survival was improved with abiraterone–prednisone
`(median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI,
`0.61 to 0.93; P = 0.01) but did not cross the efficacy boundary. Abiraterone–predni-
`sone showed superiority over prednisone alone with respect to time to initiation of
`cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific anti-
`gen progression, and decline in performance status. Grade 3 or 4 mineralocorti-
`coid-related adverse events and abnormalities on liver-function testing were more
`common with abiraterone–prednisone.
`Conclusions
`Abiraterone improved radiographic progression-free survival, showed a trend toward
`improved overall survival, and significantly delayed clinical decline and initiation
`of chemotherapy in patients with metastatic castration-resistant prostate cancer.
`(Funded by Janssen Research and Development, formerly Cougar Biotechnology;
`ClinicalTrials.gov number, NCT00887198.)
`
`The authors’ affiliations are listed in the
`Appendix. Address reprint requests to
`Dr. Ryan at the Genitourinary Medical
`Oncology Program, UCSF Helen Diller
`Family Comprehensive Cancer Center,
`1600 Divisadero St., San Francisco, CA
`94115, or at ryanc@medicine.ucsf.edu.
`
`* Additional investigators in the COU-AA-
`302 study are listed in the Supplemen-
`tary Appendix, available at NEJM.org.
`
`This article was published on December 10,
`2012, and updated on January 17, 2013, at
`NEJM.org.
`
`N Engl J Med 2013;368:138-48.
`DOI: 10.1056/NEJMoa1209096
`Copyright © 2012 Massachusetts Medical Society.
`
`138
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 1
`
`

`
`Abiraterone in Prostate Cancer
`
`Metastatic castration-resistant
`
`prostate cancer, defined by tumor
`growth despite a testosterone level of
`less than 50 ng per deciliter (1.7 nmol per liter),
`causes approximately 258,400 deaths annually
`worldwide.1,2 Death of patients with this condition,
`which typically occurs within 24 to 48 months
`after the onset of castration resistance, is common-
`ly preceded by a sequence of landmark events as-
`sociated with deterioration of overall health and
`worsening symptoms (Fig. S1 in the Supplemen-
`tary Appendix, available with the full text of this
`article at NEJM.org).3-7
`Among the treatment options for patients with
`metastatic castration-resistant prostate cancer who
`have not undergone chemotherapy are a variety
`of second-line hormonal manipulations8 that pro-
`duce responses in many patients; however, none
`of these options have been shown to delay progres-
`sion or prolong life. Subsequent to such second-
`line therapy, a standard approach is docetaxel
`chemotherapy, which has a survival benefit,4 al-
`though many patients with metastatic castration-
`resistant prostate cancer never receive it.9,10 Ow-
`ing to the limited use of chemotherapy in the
`management of metastatic castration-resistant
`prostate cancer, there is an unmet need for effec-
`tive therapy that delays or prevents the landmark
`events that characterize the morbidity associated
`with this cancer.2 One treatment, sipuleucel-T, an
`immunotherapy, is associated with a modest sur-
`vival benefit but without tumor regression, symp-
`tom relief, or delay in disease progression.11
`Abiraterone acetate is a first-in-class inhibitor
`of cytochrome P-450c17, a critical enzyme in ex-
`tragonadal and testicular androgen synthesis.12-18
`Abiraterone plus low-dose prednisone improves
`survival in patients with metastatic castration-
`resistant prostate cancer who have already re-
`ceived docetaxel,19 and the combination therapy
`has received regulatory approval for this indica-
`tion. Phase 1 and 2 studies in patients who have
`not received chemotherapy, however, have shown
`a high proportion of durable responses, suggesting
`that the benefits of abiraterone may be optimal in
`this patient group.20-22 In our randomized, phase
`3 study, we evaluated the effects of abiraterone
`plus prednisone on radiographic progression-
`free survival, overall survival, increase in pain,
`and clinically relevant measures of disease pro-
`gression in patients with progressive metastatic
`castration-resistant prostate cancer who had not
`
`received chemotherapy and in whom clinically
`significant cancer-related symptoms had not
`developed.
`
`Methods
`
`Study Oversight and Conduct
`This study was designed by academic and sponsor-
`employed investigators. The lead academic author
`initially drafted the manuscript with sponsor in-
`put, and all coauthors subsequently provided input
`and approval. The sponsor provided funding for
`editorial assistance with an early draft of the man-
`uscript. All authors made the decision to submit
`the manuscript for publication. The database was
`held at a third-party contract clinical research or-
`ganization (CRO), and queries were issued by
`both the sponsor and the CRO staff. The indepen-
`dent CRO statistician provided the results of anal-
`ysis to an independent data and safety monitoring
`committee, whose members were invited by the
`sponsor. The committee monitored safety at reg-
`ular intervals and evaluated efficacy and safety at
`prespecified interim analyses. At the time of un-
`blinding, analyses were performed by statisti-
`cians who were employees of the sponsor. The
`authors assume responsibility for the complete-
`ness and integrity of the data and the fidelity of
`the study to the protocol and statistical analysis
`plan (available at NEJM.org).
`The review boards at all participating institu-
`tions approved the study, which was conducted
`according to the principles of the Declaration of
`Helsinki, the International Conference on Harmo-
`nisation, and the Guidelines for Good Clinical
`Practice. All patients provided written informed
`consent.
`
`Patients
`Eligibility criteria were an age of 18 years or old-
`er; metastatic, histologically or cytologically con-
`firmed adenocarcinoma of the prostate; prostate-
`specific antigen (PSA) progression according to
`Prostate Cancer Clinical Trials Working Group 2
`(PCWG2) criteria2 or radiographic progression in
`soft tissue or bone with or without PSA progres-
`sion; ongoing androgen deprivation with a serum
`testosterone level of less than 50 ng per deciliter
`(1.7 nmol per liter); an Eastern Cooperative On-
`cology Group (ECOG) performance status grade
`of 0 or 1 (asymptomatic or restricted in strenuous
`activity but ambulatory, respectively); no symp-
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`139
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 2
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`toms or mild symptoms, as defined according to
`the Brief Pain Inventory–Short Form (BPI-SF)
`(scores of 0 to 1 [asymptomatic] or 2 to 3 [mildly
`symptomatic], respectively); and hematologic and
`chemical laboratory values that met predefined cri-
`teria. Previous therapy with an antiandrogen was
`required. Patients with visceral metastases or pa-
`tients who had received previous therapy with keto-
`conazole lasting more than 7 days were excluded.
`
`Study Design and Treatment
`In this multinational, double-blind, placebo-con-
`trolled study, patients were randomly assigned in
`a 1:1 ratio to receive abiraterone acetate plus pred-
`nisone or placebo plus prednisone. Patients were
`stratified according to the baseline ECOG per-
`formance status grade (0 vs. 1). Patients in the
`abir a ter one–prednisone group received abir a ter-
`one at a dose of 1 g (administered as four 250-mg
`tablets), and patients in the prednisone-alone group
`received four placebo tablets once daily at least
`1 hour before and 2 hours after a meal. All pa-
`tients received prednisone at a dose of 5 mg oral-
`ly twice daily. Safety and dosing compliance were
`evaluated during each study visit, at treatment
`discontinuation if applicable, and at the end-of-
`study visit.
`
`End Points
`The coprimary efficacy end points were radio-
`graphic progression-free survival and overall sur-
`vival, defined as the time from randomization to
`death from any cause. Radiographic progression-
`free survival was determined by an independent
`radiologist who was unaware of study-group as-
`signments, and dates of death were confirmed.
`Radiographic progression-free survival was defined
`as freedom from death from any cause; freedom
`from progression in soft-tissue lesions as mea-
`sured with the use of computed tomography (CT)
`or magnetic resonance imaging (MRI), defined
`as “progressive disease” according to modified
`Response Evaluation Criteria in Solid Tumors
`(RECIST) criteria; or progression on bone scanning
`according to criteria adapted from the PCWG2
`(Table S1 in the Supplementary Appendix).2
`Changes in PSA level were not included in the
`definition of radiographic progression-free sur-
`vival.
`The prespecified secondary end points were
`times to opiate use for cancer-related pain, to
`
`initiation of cytotoxic chemotherapy, to a decline
`in ECOG performance status, and to PSA pro-
`gression (on the basis of PCWG2 criteria).2
`Other end points included radiographic progres-
`sion-free survival as measured by investigators
`(rather than a blinded review), PSA response rate
`(≥50% decline in PSA level from baseline), rate
`of objective response according to RECIST crite-
`ria, and health-related quality of life, as measured
`by means of patients’ reports of pain and func-
`tional status. An increase in pain was defined as
`an increase in the baseline pain score at two
`consecutive visits by 30% or more, as measured by
`the average of the pain scores on the BPI-SF
`(range, 0 to 10, with higher scores indicating
`worse average pain), without a decrease in anal-
`gesic use. A decline in functional status was
`defined as a decline of 10 or more points in the
`Functional Assessment of Cancer Therapy–Pros-
`tate (FACT-P) total score at any visit (range, 0 to
`156, with higher scores indicating better overall
`quality of life).
`
`Assessments
`Efficacy assessments included sequential radio-
`graphic imaging to assess radiographic progres-
`sion-free survival (CT or MRI and bone scanning)
`and measurement of PSA levels.2 CT or MRI and
`bone scanning were performed every 8 weeks
`during the first 24 weeks and every 12 weeks
`thereafter. All patients underwent serial moni-
`toring of blood chemical levels, hematologic val-
`ues, coagulation studies, serum lipids, and kid-
`ney function. Cardiac safety was monitored by
`means of serial electrocardiography. The left ven-
`tricular ejection fraction was measured at base-
`line. Patient-reported outcomes were assessed at
`baseline and at every visit with the use of the BPI-
`SF. FACT-P questionnaires were completed every
`third visit.
`
`Statistical Analysis
`The overall level of significance for the study was
`0.05, allocated between the coprimary end points
`of radiographic progression-free survival (0.01)
`and overall survival (0.04). A single analysis was
`planned for the coprimary end point of radio-
`graphic progression-free survival on the basis of
`a blinded review by the central radiologist after
`378 progression-free events, which would pro-
`vide a statistical power of 91% to detect a hazard
`
`140
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 3
`
`

`
`Abiraterone in Prostate Cancer
`
`ratio of 0.67 at a two-tailed level of significance
`of 0.01. The results of subsequent analyses of
`this end point based on investigator assessment
`are also reported. For the coprimary end point of
`overall survival, 773 events were required to de-
`tect a hazard ratio of 0.80 at a two-tailed signifi-
`cance level of 0.04 with a statistical power of 85%.
`Three interim analyses were planned for over-
`all survival, with the first analysis planned after
`the observation of approximately 116 of the re-
`quired 773 events (15%) (in conjunction with the
`independent review of radiographic progression-
`free survival), the second analysis planned after
`311 events (40%), and the third analysis planned
`after 425 events (55%); a final analysis was planned
`for after 773 events had occurred (Table S2 in the
`Supplementary Appendix). The group-sequential
`design was used for the overall survival end point
`with the use of the O’Brien–Fleming boundaries
`as implemented by the Lan–DeMets alpha spend-
`ing method (Table S3 in the Supplementary Ap-
`pendix).
`We planned to enroll approximately 1000 pa-
`tients in the study. The primary statistical method
`of comparison for the time-to-event end points
`was the stratified log-rank test with stratification
`according to the baseline ECOG score. The Cox
`proportional-hazards model was used to estimate
`the hazard ratio and its associated confidence
`interval. The Hochberg procedure was used to
`adjust for multiplicity testing of the secondary
`efficacy end points.23 The strength of associa-
`tion between radiographic progression-free sur-
`vival and overall survival was evaluated by means
`of Spearman’s correlation coefficient estimated
`with the use of the Clayton copula.24
`
`R esults
`
`Patients and Treatment
`From April 2009 through June 2010, we randomly
`assigned 1088 patients to receive study treatment:
`abiraterone plus prednisone in 546 patients and
`placebo plus prednisone in 542 patients (Fig. S2
`in the Supplementary Appendix). The clinical cut-
`off date for the blinded central radiologic review
`of radiographic progression-free survival and the
`first overall survival interim analysis was Decem-
`ber 20, 2010 (at which time 13% of deaths had
`occurred), and the clinical cutoff date for the sec-
`ond interim analysis of overall survival was De-
`
`cember 20, 2011 (at which time 43% of deaths
`had occurred). The median follow-up duration
`for all patients was 22.2 months. Baseline demo-
`graphic characteristics were well balanced be-
`tween the two study groups (Table S4 in the
`Supplementary Appendix).
`
`Primary End Points
`Radiographic Progression-free Survival
`On the basis of the blinded central radiologic re-
`view, at the time of the first interim analysis,
`treatment with abiraterone plus prednisone, as
`compared with placebo plus prednisone, resulted
`in a 57% reduction in the risk of radiographic
`progression or death (median not reached vs.
`median of 8.3 months; hazard ratio for abira-
`terone–prednisone vs. prednisone alone, 0.43;
`95% confidence interval [CI], 0.35 to 0.52; P<0.001).
`At the time of the second interim analysis, the me-
`dian time to radiographic progression-free sur-
`vival on the basis of investigator assessment was
`16.5 months in the abiraterone–prednisone group
`and 8.3 months in the prednisone-alone group
`(hazard ratio, 0.53; 95% CI, 0.45 to 0.62; P<0.001)
`(Fig. 1A). The treatment effect of abiraterone on
`radiographic progression-free survival was con-
`sistently favorable (all hazard ratios, <1.0) across
`all prespecified subgroups (Fig. 1C).
`
`Overall Survival
`The planned interim analysis of overall survival
`was performed after 333 deaths (43% of 773
`events) were observed. More deaths were ob-
`served in the prednisone-alone group than in the
`abiraterone–prednisone group (186 of 542 pa-
`tients [34%] vs. 147 of 546 patients [27%]). Me-
`dian overall survival was not reached for the abir-
`a ter one–prednisone group and was 27.2 months
`(95% CI, 26.0 to not reached) in the prednisone-
`alone group. There was a 25% decrease in the
`risk of death in the abiraterone–prednisone group
`(hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P = 0.01)
`(Fig. 1B), indicating a strong trend toward im-
`proved survival with abiraterone–prednisone; how-
`ever, the prespecified boundary for significance
`(P≤0.001) was not reached at the observed num-
`ber of events. The treatment effect of abir a ter one
`on overall survival was consistently favorable (all
`hazard ratios, <1.0) across all prespecified sub-
`groups (Fig. 1D). Radiographic progression-free
`survival was positively correlated with overall
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`141
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 4
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`PrednisoneAloneBetter
`
`Abiraterone–PrednisoneBetter
`
`1.50
`
`0.751.00
`
`0.20
`
`0.89 (0.65–1.22)
`0.66 (0.49–0.88)
`
`0.66 (0.46–0.94)
`0.79 (0.60–1.04)
`
`0.79 (0.55–1.12)
`0.69 (0.53–0.91)
`
`0.77 (0.38–1.09)
`0.72 (0.43–0.94)
`
`0.71 (0.51–1.00)
`0.73 (0.57–0.94)
`0.80 (0.51–1.24)
`
`0.81 (0.61–1.06)
`0.68 (0.48–0.96)
`
`0.87 (0.59–1.29)
`0.71 (0.54–0.94)
`
`0.86 (0.58–1.28)
`0.71 (0.55–0.92)
`
`0.75 (0.61–0.93)
`
`NR
`27.2
`
`27.5
`23.6
`
`27.5
`23.6
`
`NR
`23.8
`
`23.8
`26.4
`NR
`
`27.5
`27.2
`
`NR
`27.2
`
`26.4
`27.2
`
`27.2
`
`NR
`NR
`
`NR
`NR
`
`NR
`NR
`
`NR
`26.9
`
`NR
`NR
`NR
`
`NR
`NR
`
`25.5
`NR
`
`NR
`NR
`
`NR
`
`HazardRatio(95%CI)
`
`median (mo)
`
`Alone
`
`Prednisone
`
`Prednisone
`Abiraterone–
`
`Other
`North America
`
`Region
`
`No
`Yes
`
`Baseline ALK-P above median
`
`No
`Yes
`
`Baseline LDH above median
`
`No
`Yes
`
`Baseline PSA above median
`
`≥75 yr
`≥65 yr
`<65 yr
`
`Age
`
`No
`Yes
`
`Bone metastases only at entry
`
`2–3
`0–1
`
`Baseline BPI-SF
`
`01
`
`Baseline ECOG
`All patients
`
`Subgroup
`
`00
`
`02
`
`25
`27
`
`106
`120
`
`237
`258
`
`387
`412
`
`437
`452
`
`465
`482
`
`493
`503
`
`509
`524
`
`534
`538
`
`542
`546
`
`Prednisone alone
`Abiraterone–prednisone
`No.atRisk
`
`33
`
`30
`
`27
`
`24
`
`21
`
`18
`
`15
`
`12
`
`9
`
`6
`
`3
`
`Months
`
`Prednisone alone: 186
`Abiraterone–prednisone: 147
`No.ofEvents
`
`Prednisone alone, 27.2 mo
`
`not reached
`
`Abiraterone–prednisone,
`
`P=0.01
`Hazard ratio, 0.75 (95% CI, 0.61–0.93)
`
`0
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`OverallSurvival(%)
`
`BOverallSurvival
`
`PrednisoneAloneBetter
`
`Abiraterone–PrednisoneBetter
`
`1.50
`
`0.751.00
`
`0.20
`
`0.56 (0.45–0.71)
`0.51 (0.40–0.63)
`
`0.48 (0.38–0.61)
`0.54 (0.43–0.68)
`
`0.57 (0.45–0.71)
`0.47 (0.38–0.60)
`
`0.48 (0.38–0.61)
`0.54 (0.43–0.68)
`
`0.64 (0.48–0.84)
`0.55 (0.46–0.67)
`0.48 (0.35–0.66)
`
`0.51 (0.41–0.62)
`0.55 (0.42–0.71)
`
`0.61 (0.44–0.83)
`0.53 (0.43–0.65)
`
`0.43 (0.30–0.61)
`0.56 (0.47–0.67)
`
`0.53 (0.45–0.62)
`
`8.3
`8.2
`
`9.7
`5.6
`
`10.8
`5.6
`
`10.2
`5.8
`
`8.2
`8.3
`8.1
`
`5.7
`11.1
`
`7.4
`8.3
`
`7.4
`8.3
`
`8.3
`
`16.3
`16.6
`
`19.4
`13.6
`
`16.6
`14.1
`
`19.4
`12.8
`
`14.9
`16.5
`16.6
`
`11.2
`20.7
`
`10.7
`16.7
`
`18.0
`16.4
`
`16.5
`
`Other
`North America
`
`Region
`
`No
`Yes
`
`Baseline ALK-P above median
`
`No
`Yes
`
`Baseline LDH above median
`
`No
`Yes
`
`Baseline PSA above median
`
`≥75 yr
`≥65 yr
`<65 yr
`
`Age
`
`No
`Yes
`
`Bone metastases only at entry
`
`2–3
`0–1
`
`Baseline BPI-SF
`
`01
`
`Baseline ECOG
`All patients
`
`DOverallSurvival
`
`HazardRatio(95%CI)
`
`median (mo)
`
`Alone
`
`Prednisone
`
`Prednisone
`Abiraterone–
`CRadiographicProgression-freeSurvival
`
`Subgroup
`
`00
`
`91
`
`14
`38
`
`37
`85
`
`80
`155
`
`100
`195
`
`133
`240
`
`177
`311
`
`244
`389
`
`406
`485
`
`542
`546
`
`Prednisone alone
`Abiraterone–prednisone
`No.atRisk
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`30
`
`27
`
`24
`
`21
`
`18
`
`15
`
`12
`
`9
`
`6
`
`3
`
`Months
`
`Prednisone alone: 336
`Abiraterone–prednisone: 271
`No.ofEvents
`
`0
`
`0
`
`Prednisone alone, 8.3 mo
`
`Abiraterone–prednisone, 16.5 mo
`
`P<0.001
`Hazard ratio, 0.53 (95% CI, 0.45–0.62)
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Progression-freeSurvival(%)
`
`ARadiographicProgression-freeSurvival
`
`142
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 5
`
`

`
`Abiraterone in Prostate Cancer
`
`Figure 1 (facing page). Kaplan–Meier Estimates of Radio-
`graphic Progression-free Survival, Overall Survival, and
`Subgroup Analyses at the Second Interim Analysis.
`Panels A and C show data for radiographic progression-
`free survival on the basis of investigator review, and
`Panels B and D show data for overall survival. The
`dashed line in Panels A and B indicates the median.
`In Panels C and D, the size of the circle reflects the num-
`ber of patients affected. All analyses were performed
`with the use of a stratified log-rank test according to
`the baseline score on the Eastern Cooperative Oncology
`Group (ECOG) scale (a performance status grade of
`0 indicates asymptomatic, and 1 restricted in strenuous
`activity but ambulatory). Scores on the Brief Pain Inven-
`tory–Short Form (BPI-SF) range from 0 to 10, with
`higher scores indicating worse average pain. ALK-P
` denotes alkaline phosphatase, LDH lactate dehydro-
`genase, and PSA prostate-specific antigen.
`
`survival, with an estimated correlation coeffi-
`cient of 0.72.
`
`Secondary End Points
`Prespecified secondary and exploratory efficacy
`end points are summarized in Table 1. Abir aterone–
`prednisone decreased the risk of decline (by ≥1
`point) in ECOG performance-status score by
`18%, as compared with prednisone alone (time
`to decline, 12.3 vs. 10.9 months; hazard ratio for
`decline, 0.82; 95% CI, 0.71 to 0.94; P = 0.005)
`(Fig. 2A). The median time to the initiation of
`cytotoxic chemotherapy was 25.2 months in the
`abiraterone–prednisone group and 16.8 months
`in the prednisone-alone group (hazard ratio,
`0.58; 95% CI, 0.49 to 0.69; P<0.001) (Fig. 2B). A
`significant delay in the time to opiate use for
`
`Table 1. Prespecified Secondary and Exploratory Efficacy End Points.*
`
`Abiraterone–
`Prednisone
`(N = 546)
`
`Prednisone
`Alone
`(N = 542)
`
`Value
`(95% CI)†
`
`End Point
`Secondary end points
`
`Median time to opiate use for cancer-related pain — mo
`
`Median time to initiation of cytotoxic chemo therapy — mo
`
`Median time to decline in ECOG performance score by
`≥1 point — mo
`
`Median time to PSA progression — mo‡
`
`Exploratory end points§
`
`Median time to increase in pain — mo¶
`
`Median time to functional-status decline measured
`as FACT-P total score — mo‖
`
`Patients with decline of ≥50% in PSA level — %**
`
`Patients with a RECIST response — %‡‡
`
`Defined objective response
`
`Stable disease
`
`Progressive disease
`
`NR
`
`25.2
`
`12.3
`
`11.1
`
`26.7
`
`12.7
`
`62
`
`36
`
`61
`
`2
`
`P Value
`
`<0.001
`
`<0.001
`
`0.005
`
`23.7
`
`16.8
`
`10.9
`
`0.69 (0.57–0.83)
`
`0.58 (0.49–0.69)
`
`0.82 (0.71–0.94)
`
`5.6
`
`0.49 (0.42–0.57)
`
`<0.001
`
`18.4
`
`8.3
`
`0.82 (0.67–1.00)
`
`0.78 (0.66–0.92)
`
`0.049
`
`0.003
`
`2.59 (2.19–3.05)†† <0.001
`
`2.27 (1.59–3.25)†† <0.001
`
`24
`
`16
`
`69
`
`15
`
`* Percentages may not sum to 100 because of rounding. CI denotes confidence interval, NR not reached, and PSA
`prostate-specific antigen.
`† Values are hazard ratios unless otherwise specified.
` PSA progression was based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria.2
`‡
`§ The exploratory analyses are reported with no adjustment for multiplicity.
`¶
`Increase in pain is defined as an increase in the baseline pain level by 30% or more, as measured by the average of
`the pain scores on the Brief Pain Inventory–Short Form (range, 0 to 10, with higher scores indicating worse average
`pain) at two consecutive visits, without a decrease in analgesic use.
` The time to a decline in functional status is defined as the months from randomization to the first date a patient has
`a decrease of 10 points or more on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) instrument
`(range, 0 to 156, with higher scores indicating better overall quality of life).
`** A decline of 50% or more in the PSA level was based on modified PCWG2 criteria.
`†† Values are relative risks.
`‡‡ Response Evaluation Criteria in Solid Tumors (RECIST) criteria were ascertained in patients with measurable disease
`at baseline: 220 in the abiraterone–prednisone group and 218 in the prednisone-alone group.
`
`‖
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`143
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 6
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`A ECOGPerformanceScore
`100
`
`B InitiationofCytotoxicChemotherapy
`100
`
`Abiraterone–
`prednisone,
`25.2 mo
`
`Prednisone alone, 16.8 mo
`
`Hazard ratio, 0.58 (95% CI, 0.49–0.69)
`P<0.001
`
`3
`
`6
`
`9
`
`12
`
`15
`Months
`
`18
`
`21
`
`24
`
`27
`
`30
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Chemotherapy(%)
`
`PatientswithoutCytotoxic
`
`Abiraterone–prednisone, 12.3 mo
`
`Prednisone alone, 10.9 mo
`
`80
`
`60
`
`40
`
`20
`
`inECOGScore(%)
`
`PatientswithoutDecline
`
`0
`
`0
`
`Hazard ratio, 0.82 (95% CI, 0.71–0.94)
`P=0.005
`
`3
`
`6
`
`9
`
`12
`
`18
`15
`Months
`
`21
`
`24
`
`27
`
`30
`
`33
`
`0 0
`
`75
`
`48
`
`16
`
`5
`
`546
`
`529
`
`493
`
`453
`
`393
`
`341
`
`289
`
`176
`
`542
`
`507
`
`436
`
`368
`
`309
`
`251
`
`208
`
`122
`
`No.atRisk
`Abiraterone–
`prednisone
`Prednisone
`alone
`
`0 0
`
`0 2
`
`41
`
`27
`
`13
`
`6
`
`546
`
`455
`
`390
`
`326
`
`263
`
`217
`
`183
`
`99
`
`542
`
`431
`
`344
`
`290
`
`227
`
`191
`
`127
`
`73
`
`No.atRisk
`Abiraterone–
`prednisone
`Prednisone
`alone
`
`C OpiateUse
`100
`
`D PSAProgression
`100
`
`Hazard ratio, 0.49 (95% CI, 0.42–0.57)
`P<0.001
`
`Abiraterone–prednisone, 11.1 mo
`
`Prednisone
`alone,
`5.6 mo
`
`3
`
`6
`
`9
`
`12
`
`15
`Months
`
`18
`
`21
`
`24
`
`27
`
`30
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Progression(%)
`
`PatientswithoutPSA
`
`Abiraterone–
`prednisone,
`not reached
`
`Prednisone alone, 23.7 mo
`
`Hazard ratio, 0.69 (95% CI, 0.57–0.83)
`P<0.001
`
`3
`
`6
`
`9
`
`12
`
`18
`15
`Months
`
`21
`
`24
`
`27
`
`30
`
`33
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Use(%)
`
`PatientswithoutOpiate
`
`0 0
`
`6 1
`
`21
`
`11
`
`63
`
`15
`
`546
`
`472
`
`337
`
`241
`
`189
`
`145
`
`116
`
`542
`
`335
`
`169
`
`106
`
`71
`
`57
`
`39
`
`No.atRisk
`Abiraterone–
`prednisone
`Prednisone
`alone
`
`0 0
`
`0 2
`
`15
`
`13
`
`546
`
`518
`
`492
`
`451
`
`403
`
`360
`
`310
`
`190
`
`81
`
`542
`
`500
`
`442
`
`406
`
`366
`
`314
`
`254
`
`150
`
`62
`
`No.atRisk
`Abiraterone–
`prednisone
`Prednisone
`alone
`
`Figure 2. Secondary Efficacy End Points.
`Shown are the time until a decline in the Eastern Cooperative Oncology Group (ECOG) score by one point or more (Panel A), the time
`until the initiation of cytotoxic chemotherapy (Panel B), the time until the use of opiates for pain from prostate cancer (Panel C), and the
`time until prostate-specific antigen (PSA) progression according to Prostate Cancer Clinical Trials Working Group 2 criteria2 (Panel D).
`The dashed line indicates the median. All analyses were performed with the use of a stratified log-rank test according to the baseline
`ECOG score.
`
`cancer-related pain was observed with abir aterone
`(not reached vs. 23.7 months; hazard ratio, 0.69;
`95% CI, 0.57 to 0.83; P<0.001) (Fig. 2C). The me-
`dian time to PSA progression was 11.1 months in
`the abiraterone–prednisone group and 5.6 months
`in the prednisone-alone group, a 51% reduction
`in risk (hazard ratio, 0.49; 95% CI, 0.42 to 0.57;
`P<0.001) (Fig. 2D). On the basis of aggregate ef-
`ficacy and safety data from the second interim
`analysis, the data and safety monitoring commit-
`tee unanimously recommended unblinding the
`study in February 2012.
`
`Other End Points
`The median time to increase in pain was 26.7
`months among patients receiving abir a ter one–
`prednisone and 18.4 months among those receiv-
`ing prednisone alone (hazard ratio, 0.82; 95% CI,
`0.67 to 1.00; P = 0.049) (Table 1). The median time
`to a decline in the FACT-P total score was 12.7
`months in the abiraterone–prednisone group and
`8.3 months in the prednisone-alone group (haz-
`ard ratio, 0.78; 95% CI, 0.66 to 0.92; P = 0.003).
`The rates of PSA response and objective response
`to therapy were significantly higher in the abir-
`
`144
`
`n engl j med 368;2 nejm.org
`
`january 10, 2013
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 10, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 7
`
`

`
`Abiraterone in Prostate Cancer
`
`aterone–prednisone group than in the predni-
`sone-alone group (Table 1).
`
`Table 2. Adverse Events.*
`
`Adverse Event
`
`Any adverse event
`
`Grade 3 or 4 adverse event
`
`Any serious adverse event
`
`Adverse event leading to treat-
`ment discontinuation
`
`Abiraterone–Prednisone
`(N = 542)
`
`Prednisone Alone
`(N = 540)
`
`no. of patients (%)
`
`537 (99)
`
`258 (48)
`
`178 (33)
`
`55 (10)
`
`Adverse event leading to death*
`
`20 (4)
`
`Adverse event of grade 1–4 in
`≥15% of patients in either
`group
`
`Fatigue
`
`Back pain
`
`Arthralgia
`
`Nausea
`
`Constipation
`
`Hot flush
`
`Diarrhea
`
`Bone pain
`
`Muscle spasm
`
`Pain in extremity
`
`212 (39)
`
`173 (32)
`
`154 (28)
`
`120 (22)
`
`125 (23)
`
`121 (22)
`
`117 (22)
`
`106 (20)
`
`75 (14)
`
`90 (17)
`
`524 (97)
`
`225 (42)
`
`142 (26)
`
`49 (9)
`
`12 (2)
`
`185 (34)
`
`173 (32)
`
`129 (24)
`
`118 (22)
`
`103 (19)
`
`98 (18)
`
`96 (18)
`
`103 (19)
`
`110 (20)
`
`85 (16)
`
`73 (14)
`
`Safety
`Adverse events are summarized in Tables 2 and
`3. Grade 3 or 4 adverse events were reported in
`48% of patients in the abiraterone–prednisone
`group and 42% of patients in the prednisone-
`alone group; serious adverse events were reported
`in 33% and 26% of patients, and adverse events
`resulting in death were reported in 4% and 2% of
`patients, respectively. Fatigue, arthralgia, and pe-
`ripheral edema were among the adverse events
`reported more frequently in the abir a ter one–
`prednisone group than in the prednisone-alone
`group. Grade 3 or 4 adverse events classified as
`hepatotoxicity, consisting primarily of a revers-
`ible elevation in aminotransferase levels, were
`reported in 8% of patients in the abiraterone–
`prednisone group and 3% of patients in the pred-
`nisone-alone group. No patient in either study
`group died from hepatotoxicity-related adverse
`events.
`The frequency of adverse events resulting in
`treatment discontinuation was similar in the
`two study groups. A total of 19% of patients in
`the abiraterone–prednisone group and 12% of
`patients in the prednisone-alone group had ad-
`verse events leading to dose modification or in-
`terruption of study treatment. In the two study
`groups, the most frequently occurring adverse
`events resulting in death were those related to
`disease progression (0.6% of patients in each
`group). The proportions of patients with grade 3
`or 4 serious adverse events were similar in the
`two groups. Adverse events that were classified
`as cardiac disorders were reported in 19% of
`patients in the abiraterone–prednisone group
`and 16% of those in the prednisone-alone group.
`Mineralocorticoid-related toxic effects were more
`common in the abiraterone–prednisone group
`than in the prednisone-alone group, including
`hypertension