A Phase 3 Randomized Controlled Trial of the Efficacy
`and Safety of Atrasentan in Men With Metastatic
`Hormone-refractory Prostate Cancer
`
`3
`
`1
`Michael A. Carducci, MD
`2
`Fred Saad, MD
`Per-Anders Abrahamsson, MD
`4
`David P. Dearnaley, MD
`Claude C. Schulman, MD
`6
`Scott A. North, MD
`7
`Darryl J. Sleep, MD
`Jeffrey D. Isaacson, PhD
`8
`Joel B. Nelson, MD
`for the Atrasentan Phase III Study
`Group Institutions.
`
`5
`
`7
`
`BACKGROUND. The objective of this study was to evaluate the efficacy and safety
`of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients
`
`with metastatic hormone-refractory prostate cancer (HRPC).
`METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809
`men with metastatic HRPC. Patients were randomized 1:1 to receive either atra-
`
`sentan 10 mg per day or placebo. The primary endpoint was time to disease pro-
`
`gression (TTP), which was determined according to radiographic and clinical
`
`measures. Analyses of overall survival and changes in biomarkers also were per-
`
`formed.
`RESULTS. Atrasentan did not reduce the risk of disease progression relative to
`placebo (hazards ratio, 0.89; 95% confidence interval, 0.76–1.04; P 5 .136). Most
`patients progressed radiographically at the first 12-week bone scan without con-
`
`comitant clinical progression. In exploratory analyses, increases from baseline to
`
`final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels
`were significantly lower with atrasentan treatment (P < .05 for each). The median
`time to BAP progression (50% increase from nadir) was twice as long with atra-
`sentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA pro-
`gression did not reach statistical significance. Atrasentan generally was tolerated
`
`well, and the most common adverse events associated with treatment were head-
`
`ache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-reten-
`
`tion properties of endothelin-A receptor antagonism.
`CONCLUSIONS. Atrasentan did not delay disease progression in men with meta-
`static HRPC despite evidence of biologic effects on PSA and BAP as markers of
`disease burden. Cancer 2007;110:1959–66. Ó 2007 American Cancer Society.
`
`KEYWORDS: atrasentan, endothelin-A receptor antagonist, hormone-refractory
`prostate cancer, time to disease progression, bone metastasis.
`
`Dr. Sleep is an employee of Abbott Laboratories
`and owns stock in the company.
`
`Dr. Isaacson was an employee of Abbott Labora-
`tories during the time the current study was
`being conducted.
`
`Dr. Nelson has acted as a consultant for Abbott
`Laboratories.
`
`We thank Sarah Duban, ELS, and Claire Gilmore
`for their expert editorial assistance in preparing
`this article.
`
`Address for reprints: Michael A. Carducci, MD,
`Johns Hopkins Kimmel Cancer Center, 1M59
`Bunting-Blaustein, 1650 Orleans Street, Balti-
`more, MD 21231-1000; Fax:
`(410) 614-8160;
`E-mail: carducci@jhmi.edu
`
`1 Prostate Cancer
`Program, Sidney Kimmel
`Comprehensive Cancer Center at Johns Hopkins,
`Baltimore, Maryland.
`
`2 Urology/Oncology, Notre Dame Hospital, Mon-
`treal, Quebec, Canada.
`
`3 Department of Urology, Malmo University Hos-
`pital, Malmo, Sweden.
`
`4 Academic Unit of Radiotherapy, the Institute of
`Cancer Research, Surrey, United Kingdom.
`
`5 Department of Urology, Erasme Hospital Univer-
`sity Clinics, Brussels, Belgium.
`
`6 Department of Medicine, Cross Cancer Institute,
`Edmonton, Alberta, Canada.
`
`7 Abbott Laboratories, Abbott Park, Illinois.
`
`8 Department of Urology, University of Pittsburgh
`School of Medicine, Pittsburgh, Pennsylvania.
`See editorial on pages 18779, this issue.
`
`Supported by a grant from Abbott Laboratories,
`Abbott Park, Ill.
`
`Dr. Carducci received honoraria from Abbott Lab-
`oratories for acting as a consultant and member
`of the Speakers’ Bureau.
`
`Dr. Saad has acted as an investigator and con-
`sultant for Abbott Laboratories.
`
`Dr. Dearnaley has acted as a consultant and pro-
`vided expert testimony to the US. Food and Drug
`Administration for Abbott Laboratories.
`
`the
`the 40th Annual Meeting of
`Presented at
`American Society of Clinical Oncology, New Orle-
`ans, Louisiana, June 58, 2004.
`
`Received March 29, 2007; revision received May
`11, 2007; accepted May 15, 2007.
`
`ª 2007 American Cancer Society
`DOI 10.1002/cncr.22996
`Published online 20 September 2007 in Wiley InterScience (www.
`
`
`
`JANSSEN EXHIBIT 2079
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`1960
`
`CANCER November 1, 2007 / Volume 110 / Number 9
`
`A dvanced hormone-refractory prostate
`
`cancer
`(HRPC), which is characterized by the develop-
`ment of painful osteoblastic metastases, remains an
`incurable disease. Despite recent improvements in
`survival reported with docetaxel-based chemother-
`apy,1,2 independent data collected from OncoTrack, a
`comprehensive patient records database that tracks
`drug use and patient characteristics, indicates that
`only approximately 50% of patients with metastatic
`HRPC ever receive chemotherapy.3 Effective, well-tol-
`erated agents that delay disease progression, particu-
`larly the onset of the often severe and debilitating
`consequences of bone metastases associated with
`HRPC, still are needed.
`Atrasentan (Xinlay) is a highly potent, selective
`endothelin-A (ETA) receptor antagonist that blocks or
`reverses the biologic effects of endothelin-1 (ET-1).4
`ET-1 is a weak mitogen for prostate cancer cell
`lines but a significant inhibitor of chemotherapy-
`induced apoptosis in vitro and in vivo.5 It is highly
`secreted by normal prostate epithelial cells and is ex-
`pressed in all stages of prostate cancer, both within
`the gland and in all metastatic lesions tested.6 More-
`over, the predominant receptor subtype shifts from ETB
`in normal prostate tissue to ETA in prostate tumors.7
`Mounting evidence indicates that ET-1 is in-
`volved in the osteoblastic bone remodeling response
`the disease.8,9 Osteoblasts express ETA
`typical of
`receptors at high density (from 105 to 106 receptors
`per cell), and tumor-derived ET-1 drives osteoblast
`proliferation and new bone formation through this
`receptor.10–13 Proliferating osteoblasts generate other
`growth factors that appear to stimulate local meta-
`static tumor production reciprocally, creating a
`positive feedback loop.14–16 Preclinical studies dem-
`onstrate that the effects of ET-1 on prostate cancer
`cells and osteoblasts can be blocked by selective
`endothelin receptor antagonists.5–14,17 Therefore, the
`ETA receptor and the endothelin axis are attractive
`targets for the management of HRPC.
`Phase 1 pharmacokinetic studies demonstrated
`that atrasentan can be administered on a once-daily
`oral dosing schedule.18,19 In a randomized, double-
`blind, placebo-controlled, dose-ranging Phase 2 trial,
`atrasentan at a dose of 10 mg per day demonstrated
`a significant effect on prostate-specific antigen (PSA),
`bone alkaline phosphatase (BAP), and other markers
`of bone remodeling in men with metastatic HRPC. In
`an intent-to-treat
`(ITT) analysis, a nonsignificant
`trend in delaying clinical disease progression was
`noted in favor of atrasentan.20,21 In the current
`report, we present findings from a larger randomized
`Phase 3 trial of atrasentan 10 mg per day that was
`
`conducted in a similar group of men with metastatic
`HRPC.
`
`MATERIALS AND METHODS
`Eligibility Criteria
`This Phase 3 randomized, double-blind, placebo-
`controlled study was conducted at 180 sites in 21
`countries. Patients were recruited between June 25,
`2001 and November 25, 2002 and were eligible to
`participate if they had metastatic prostatic adenocar-
`cinoma that was refractory to androgen-ablation
`therapy, as defined by standard criteria (rising PSA or
`PSA >20 ng/mL).22 A centralized, independent radi-
`ologic reviewer confirmed the presence of distant
`metastases at baseline by computed tomography
`(CT) scans, magnetic resonance images (MRI), and/
`or bone scans. Surgical or pharmacologic castration
`3 months before randomization and a screening
`testosterone level <50 ng/dL were required. Patients
`with pharmacologic castration were to continue
`androgen-suppression therapy during the study.
`Patients had to be free of disease-related pain that
`required opioids, and they had to have a Karnofsky
`performance score between 70 and 100 with a life ex-
`pectancy >6 months. Patients were ineligible if they
`had ever received radionuclides or chemotherapy, if
`they had inadequate withdrawal from antiandrogen
`therapy (4 weeks for flutamide and 6 weeks for
`nilutamide and bicalutamide), or if they had received
`bisphosphonates within 4 weeks of randomization.
`Patients with central nervous system metastases or
`with New York Heart Association grade 2 heart fail-
`ure were excluded. Only patients who had signed an
`informed consent form were enrolled, and the study
`was conducted according to the Declaration of Hel-
`sinki under the supervision of institutional review
`boards.
`
`Study Design
`The study consisted of a screening period no longer
`than 35 days followed by a double-blind treatment
`period. Enrolled patients were assigned randomly 1:1
`to receive once-daily oral atrasentan 10 mg or pla-
`cebo. Treatment continued until the patient experi-
`enced disease progression or discontinued study
`drug or until the study was stopped. Patients who
`experienced confirmed disease progression and those
`who were active at the time the study was stopped
`were eligible to receive open-label atrasentan in an
`extension study.
`Patients visited the study site on Days 1 and 14;
`Weeks 4, 8, and 12; and every 12 weeks thereafter
`until the final visit. Follow-up survival assessments
`
`

`

`TABLE 1
`Criteria for Disease Progression
`
`Measure
`
`Criteria
`
`Radiographic measures
`New measurable bone
`lesions
`New measurable
`soft-tissue lesions
`
`Clinical measures
`Metastatic pain
`
`Skeletal-related event
`
`New intervention
`
`At least 2 new lesions determined by bone scan
`scheduled every 12 wk
`One new lesion or changes to existing lesion(s)
`determined by CT scan or MRI using modified
`RECIST criteria
`
`Prostate cancer-related pain as demonstrated by
`evidence of disease at the site and requiring
`opiates (oral or transdermal opioids administered
`for 10 of 14 d or a single dose of intravenous,
`intramuscular, or subcutaneous opioids),
`chemotherapy, radiotherapy, radionuclide therapy,
`or glucocorticoids (5 mg oral prednisone for 10
`of 14 d or a doubling of the current dose for 10 of
`14 d for patients on chronic steroid therapy)
`A clinically manifested skeletal-related event with
`evidence of disease at the site (a pathologic or
`vertebral compression facture not related to
`trauma, prophylactic radiation, or surgery for an
`impending fracture, or spinal cord compression)
`Progression requiring other intervention, eg, urinary
`tract obstruction, malignant pleural effusion, brain
`metastases, or other similar events, and not
`including an increase in PSA
`
`CT indicates computed tomography; MRI, magnetic resonance imaging; RECIST, Response Evalua-
`tion Criteria in Solid Tumors; PSA, prostate-specific antigen.
`
`were performed every 12 weeks after discontinuation
`and during the open-label extension. Serum BAP and
`PSA values were measured at baseline; at Weeks 4, 8,
`and 12; and every 12 weeks thereafter. Bone and CT/
`MRI scans were obtained at screening. All patients
`underwent follow-up bone scans at 12-week inter-
`vals; patients who had evidence of extraskeletal
`metastases at baseline and, at the investigator’s dis-
`cretion, had CT or MRI scans every 12 weeks.
`Patients who experienced disease progression by any
`measure were not followed for subsequent progres-
`sion events.
`
`Outcome Measures
`The primary endpoint was time to disease progres-
`sion in the ITT population. Disease progression was
`defined as the first occurrence of any one of the
`events summarized in Table 1, which included a rig-
`orous composite of clinical and radiographic criteria.
`An independent radiologist reviewed all scans, and
`an independent oncologist confirmed all endpoints.
`Secondary endpoints included change in BAP
`values, time to PSA progression, mean rate of change
`
`Phase 3 Trial of Atrasentan in HRPC/Carducci et al.
`
`1961
`
`in Bone Scan Index (BSI),23 and overall survival (OS).
`The time to PSA progression was defined as the days
`from randomization to the first of 2 consecutive
`postbaseline measurements (at least 14 days apart)
`that demonstrated a rise 50% from nadir. Patients
`with both a baseline measurement and at least 2
`postbaseline measurements were included in the
`analysis. Tertiary analyses included time to BAP pro-
`gression (defined the same as the time to PSA pro-
`gression) and longitudinal analyses of PSA.
`Safety
`assessments were performed on all
`patients who received study drug and included eva-
`luation of adverse events, vital sign measurements,
`and laboratory analyses. An independent data moni-
`toring committee (IDMC) regularly reviewed safety
`and efficacy data.
`
`Statistical Analysis
`We estimated that 650 events would be needed to
`achieve 90% power at the 2-sided .05 level of signifi-
`cance to detect a treatment difference of a magni-
`tude similar to that demonstrated in the Phase 2 trial
`for the ITT population (hazards ratio [HR], 0.77; 95%
`confidence interval [95% CI], 0.55–1.09).20
`Demographic and baseline variables were com-
`pared between groups. The Fisher exact test was
`used to compare equality of proportions, and F tests
`were used for equality of means for continuous vari-
`ables. The primary endpoint was analyzed using the
`weighted log-rank statistic, G1,1.24 All time-to-event
`analyses were performed using Kaplan-Meier meth-
`odology and the log-rank and G1,1 test statistics. Cox
`proportional hazards modeling also was applied,
`with HRs <1.00 favoring atrasentan. Ad hoc analyses
`were conducted on the radiographic and clinical
`components of the primary endpoint. In these analy-
`ses, patients were censored at the time of disease
`progression for any reason and were not followed for
`subsequent progression events. Mean changes from
`baseline in biomarkers were analyzed using analysis
`of covariance with treatment group and baseline
`value as covariates. The Fisher exact test was used to
`compare frequencies of adverse events between
`treatment arms.
`
`RESULTS
`Disposition of Patients
`Eight hundred nine patients were randomized to
`receive either atrasentan (n 5 408) or placebo (n 5
`401) and are included in the ITT cohort. Patients
`ranged in age from 45 years to 93 years (mean age,
`72 years), and 95% of patients were Caucasian. There
`were no clinically meaningful differences between
`
`

`

`1962
`
`CANCER November 1, 2007 / Volume 110 / Number 9
`
`TABLE 2
`Baseline Characteristics
`
`Variable
`
`Median
`
`Range
`
`Median
`
`Range
`
`Placebo group (n 5 401)
`
`Atrasentan group (n 5 408)
`
`Age, y
`Hemoglobin, g/dL
`LDH, IU/L
`Bone alkaline phosphatase, ng/mL
`PSA, ng/mL
`Total Gleason score
`Time since diagnosis, y
`Karnofsky PS: no. of patients (%)
`70
`80
`90
`100
`
`72.0
`13.2
`188
`24.8
`79.6
`7.0
`4.8
`
`12 (3)
`41 (10)
`125 (31)
`223 (56)
`
`45.0–92.0
`9.1–18.1
`108–2365
`2.0–1599.0
`2.2–5424.8
`2.0–10.0
`0.1–23.2
`
`73.0
`13.4
`186
`25.5
`69.8
`7.0
`5.0
`
`10 (2)
`40 (10)
`151 (37)
`207 (51)
`
`LDH indicates lactate dehydrogenase; PSA, prostate-specific antigen; PS, performance status.
`
`45.0–93.0
`9.3–17.4
`97–1318
`2.0–1903.8
`1.7–5784.0
`3.0–10.0
`0.3–23.7
`
`TABLE 3
`Results of Primary and Secondary Endpoint Analyses in the
`Intent-to-treat Population (N 5 809)
`
`Endpoint
`
`TTP
`OS
`TTPSA
`
`HR (95% CI)*
`
`0.89 (0.76–1.04)
`0.97 (0.81–1.17)
`0.84 (0.70–1.01)
`
`Mean change from baseline:
`BAP, ng/mL
`BSI
`
`220.66
`20.003
`
`between-group comparison
`
`P
`
`y
`.136
`y
`.775
`y
`.366
`
`{
`.001
`{
`.723
`
`HR indicates hazards ratio; 95% CI, 95% confidence interval; TTP, time to disease progression; OS,
`overall survival; TTPSA, time to prostate-specific antigen progression; BAP, bone alkaline phospha-
`tase; BSI, Bone Scan Index.
`* An HR <1.00 favors atrasentan; an HR >1.00 favors placebo (Cox proportional hazards model).
`y
`Determined by the weighted log-rank statistic (G1,1).
`Determined by analysis of covariance.
`
`{
`
`FIGURE 1. This graph illustrates the time to disease progression caused
`by either a radiographic or a clinical event. G1,1 indicates the weighted log-
`rank statistic.
`
`treatment arms in baseline characteristics, including
`factors with established prognostic importance in
`prostate cancer (Table 2).25
`Enrollment ceased at the recommendation of the
`IDMC in September 2002 because, with 137 events
`already accrued,
`they estimated that a sufficient
`number of patients had been enrolled to achieve the
`prespecified number of endpoint events. The com-
`mittee subsequently recommended in February 2003
`that the study be stopped, because it was unlikely to
`achieve statistical significance in the primary analy-
`sis. The IDMC based their decision on 343 confirmed
`events plus additional events not yet adjudicated.
`Once all patients had completed final study visits
`and undergone final imaging procedures, 610 disease
`progression events had occurred.
`
`Primary Endpoint
`Protocol-defined disease progression was unexpect-
`edly rapid in both treatment arms, with >50% of
`patients demonstrating progression within 100 days
`(Fig. 1). Estimates of progression were based on the
`dose-ranging study, in which clinical investigators
`determined progression without mandated radio-
`graphic scans every 12 weeks. In this study, the ma-
`jority of progression events
`resulted from the
`acquisition of new lesions on scheduled bone
`scans, and most were identified on the first scan at
`Week 12. Atrasentan did not affect the time to dis-
`ease progression relative to placebo in the ITT
`population (G1,1; P 5 .136) (Table 3). It is note-
`worthy that the vast majority of radiographic pro-
`gression events (433 of 498 events; 87%) occurred
`
`

`

`in the absence of any protocol-defined clinical pro-
`gression event.
`
`Secondary Endpoints
`Baseline BAP values were similar in the 2 treatment
`arms. The mean change at final assessment was an
`increase of 13.2 ng/mL with atrasentan compared
`with an increase of 33.9 ng/mL with placebo (P 5
`.001). The time to PSA progression (requiring 2 con-
`secutive increases of 50% from nadir) was longer with
`atrasentan but did not reach statistical significance
`(HR, 0.84; 95% CI, 0.70–1.01). However, an additional
`26% of patients had a single 50% increase in PSA, and
`many of those men did not have a confirmatory test
`because their initial PSA increase occurred at Week 12
`or later, coincident with disease progression. Patients
`were not followed for the next PSA assessment once
`they experienced disease progression. In an explora-
`tory analysis of the time to first 50% increase in PSA,
`atrasentan significantly extended the time before PSA
`progression (HR, 0.86; 95% CI, 0.73–1.00).
`The survival analysis did not detect a difference
`between treatment arms based on initial randomiza-
`tion;
`the median survival was 20.5 months for
`patients who were randomized to the atrasentan arm
`and 20.3 months for patients who were randomized
`to the placebo arm. Interpretation of these results
`was confounded by the extension study,
`in which
`nearly 65% of patients from both randomized arms
`received open-label atrasentan.
`
`Tertiary Endpoints
`Results for the time to BAP progression and for the
`mean change from baseline PSA favored atrasentan
`(Table 3). The median time to BAP progression was
`nearly twice as long with atrasentan as with placebo
`(505 days vs 254 days; HR, 0.56; 95% CI, 0.42–0.75).
`Atrasentan significantly slowed the rise in mean PSA
`at Weeks 4, 8, 12 and at the final visit compared with
`placebo. The mean baseline PSA value for the atra-
`sentan arm was 200.1 ng/mL with a mean increase
`of 199.7 ng/mL at the final assessment; whereas the
`mean baseline PSA value was 215.0 ng/mL for the
`placebo arm with a greater mean increase from base-
`line of 290.7 ng/mL at the final assessment (P < .023).
`
`Safety
`Treatment with atrasentan was generally well toler-
`ated, with 9% (36 of 404 patients) of atrasentan-trea-
`ted patients discontinuing from the study primarily
`because of an adverse event and without disease
`progression compared with 6% (22 of 397 patients)
`of placebo-treated patients. The incidence of grade 3
`of 4 events (42% placebo, 40% atrasentan) was also
`
`Phase 3 Trial of Atrasentan in HRPC/Carducci et al.
`
`1963
`
`similar between treatment arms, as were serious
`adverse events (placebo arm, 26%; atrasentan arm,
`29%) and deaths from treatment-emergent adverse
`events
`(placebo arm, 5%; atrasentan arm, 6%)
`according to the National Cancer Institute Common
`Toxicity Criteria (NCICTC), version 2.
`Bone pain was the most common adverse event
`and was reported more frequently with placebo (Table 4).
`The most frequently reported adverse events that
`were more common with atrasentan were peripheral
`edema (40%), rhinitis (36%), and headache (21%),
`which reflect the vasodilatory and/or fluid-retention
`properties of ETA receptor antagonism (Table 4).
`Overall, the incidence of most grade 3 or 4 adverse
`events was similar between treatment groups. Bone
`pain was more common with placebo, and heart fail-
`ure was more common with atrasentan (Table 4).
`The incidence of heart failure was higher with
`atrasentan than with placebo (P 5 .002). Heart failure
`likely caused by fluid overload also was observed in
`the Phase 2 study and has been described in studies
`of other endothelin antagonists
`in cardiac dis-
`ease.21,26,27 Atrasentan recipients who experienced
`heart failure generally were older and weighed less at
`baseline than atrasentan-treated patients who did not
`develop heart failure (mean age, 78 years vs 72.1
`years; mean weight, 74.7 kg vs 84.3 kg). Most men (13
`of 18 patients; 72%) had a significant cardiovascular
`history, including previous congestive heart failure, is-
`chemic heart disease, cardiac arrhythmia, and/or val-
`vular heart disease. Heart failure tended to occur
`within the first 2 months of dosing with atrasentan
`(median time to onset, 35 days; range, 4–310 days).
`Heart failure resolved for 50% of the atrasentan-trea-
`ted patients, with most continuing or briefly inter-
`rupting atrasentan therapy and receiving appropriate
`medication. Events for 4 patients resolved after
`atrasentan discontinuation. Six atrasentan-treated
`patients died from complications related to heart fail-
`ure, although the clinical presentation was question-
`able for 3 of those patients, and 5 of them had very
`advanced cancer at baseline (3 patients had visceral
`metastases, and 2 had a BSI in the upper quartile).
`Myocardial
`infarction (MI) also was reported
`more frequently with atrasentan (9 of 404 patients;
`2.2%) than with placebo (2 of 397 patients; 0.5%).
`Five atrasentan recipients had MI concurrent with
`heart failure. The incidence of fatal MI was similar
`between treatment arms (2 deaths in the atrasentan
`arm; 1 death in the placebo arm).
`
`DISCUSSION
`The current study did not demonstrate a significant
`effect of atrasentan on delaying disease progression,
`
`

`

`1964
`
`CANCER November 1, 2007 / Volume 110 / Number 9
`
`TABLE 4
`Treatment-emergent Adverse Events Experienced by ‡10% of Patients in Either Treatment Group
`and Significant Cardiovascular Events
`
`No. of patients (%)
`
`Placebo (n 5 397)
`
`10-mg Dose of atrasentan (n 5 404)
`
`Event
`
`All events
`
`Grade 3/4 events
`
`All events
`
`Grade 3/4 events
`
`Greater incidence for atrasentan
`Peripheral edema
`Rhinitis
`Headache
`Constipation
`Infection
`Anemia
`Greater incidence for placebo
`Bone pain
`Pain
`Asthenia
`Prostatic carcinoma
`Nausea
`Anorexia
`Back pain
`Cardiovascular events
`{
`Heart failure
`Myocardial infarct
`
`47 (12)
`54 (14)
`57 (14)
`67 (17)
`30 (8)
`35 (9)
`
`215 (54)
`102 (26)
`69 (17)
`64 (16)
`55 (14)
`51 (13)
`46 (12)
`
`4 (1)
`2 (<1)
`
`5 (1)
`0 (0)
`0 (0)
`2 (1)
`0 (0)
`16 (4)
`
`y
`59 (15)
`8 (2)
`6 (2)
`29 (7)
`4 (1)
`3 (1)
`4 (1)
`
`3 (1)
`2 (1)
`
`160 (40)*
`144 (36)*
`y
`86 (21)
`77 (19)
`y
`52 (13)
`50 (12)
`
`191 (47)
`94 (23)
`63 (16)
`49 (12)
`51 (12)
`44 (11)
`41 (10)
`
`18 (5)
`9 (2)
`
`5 (1)
`0 (0)
`3 (1)
`5 (1)
`3 (1)
`16 (4)
`
`37 (9)
`7 (2)
`5 (1)
`23 (6)
`3 (1)
`2 (<1)
`4 (1)
`
`y
`
`12 (3)
`7 (2)
`
`* Statistically significant difference from placebo (P 5 .001).
`y
`Statistically significant difference from placebo (P 5.05).
`Includes combined Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) terms of ‘‘heart failure,’’ ‘‘congestive heart failure,’’ ‘‘left heart fail-
`ure,’’ and ‘‘lung edema’’ as well as the medical term ‘‘cardiogenic shock.’’
`
`{
`
`the primary endpoint, in the ITT population. Although
`it could be concluded that the drug was ineffective
`in this population, several aspects of the study, its
`design and the data, are of interest. The results of
`the earlier Phase 2 dose-ranging trial, which demon-
`strated that atrasentan was tolerable and delayed dis-
`ease progression significantly in evaluable patients,
`formed the basis for the current trial.21 From that
`study, the 10 mg per day dose was selected, and esti-
`mates of progression were used to generate the sta-
`tistical analysis for
`the current study. However,
`because of the potential for rising PSA to trigger dis-
`cretionary bone scans in patients with advanced
`prostate cancer, the Phase 3 protocol required us to
`schedule scans every 12 weeks. This singular differ-
`ence in protocol design between the dose-ranging
`study and the current study likely accounts for the
`unexpected and rapid progression rates noted in
`both the active and placebo treatment arms in this
`trial. The dose-ranging study allowed investigators to
`use clinical judgment to define progression and did
`not mandate radiographic studies except to confirm
`progression. In the study we report here, one conse-
`quence of the protocol-mandated bone scans was
`
`that >50% of the patients reached protocol-defined
`disease progression at
`the first scheduled scan,
`although 87% did not experience concurrent clinical
`progression. Although clinical practice varies widely
`among institutions and countries, many of
`these
`patients would not undergo 12-weekly scans in the
`absence of clinical symptoms. The finding of bone
`scan progression at the first 12-week time point in
`some patients may reflect radiographic changes that
`occurred before therapy was initiated or very early in
`the course of therapy when a treatment effect would
`not have been expected.
`Therefore, although the protocol mandated regu-
`lar scans to avoid PSA bias, the design actually preci-
`pitated endpoint acquisition. This, along with the
`finding that patients were not followed beyond bone
`scan progression for other progression events, ulti-
`mately limits the study’s ability to fully delineate the
`clinical benefit of atrasentan in these patients. In
`future studies, if bone scans are used, then changes
`in an otherwise asymptomatic patient should be
`deemed an endpoint only with a later confirmatory
`scan that shows evidence of additional lesions. This
`recommendation of a confirmatory second scan has
`
`

`

`Phase 3 Trial of Atrasentan in HRPC/Carducci et al.
`
`1965
`
`gression, particularly BAP, in this population, which
`may suggest targeted activity in the bone microenvir-
`onment. Multiple studies have demonstrated that
`alkaline phosphatase is of equal value in predicting
`prognosis for patients with advanced HRPC as the
`extent of bone disease, pain, or performance.29,30 Ex-
`ploratory subset analysis of the time to progression
`in men with bone metastases, excluding those
`patients with soft tissue disease only, demonstrated a
`modest 19% reduction in the risk of progression (HR,
`0.813; 95% CI, 0.658–0.965). Hence, this exploratory
`finding forces the hypothesis that the target popula-
`tion for this agent is men with bony metastatic dis-
`ease in the HRPC setting.
`The most common adverse events associated
`with atrasentan (peripheral edema,
`rhinitis, and
`headache) were consistent with the vasoactive pro-
`perties of the drug, and were generally mild, and
`typically did not lead to drug discontinuation. In sus-
`ceptible patients, however, fluid overload may result
`in heart
`failure.
`Identifying the most vulnerable
`patients—those aged >75 years with a significant
`cardiovascular history and early administration of
`diuretics—may mitigate the risk.
`Although this study did not meet the primary
`endpoint, the overall body of data, including the con-
`sistency across secondary, tertiary, and ad hoc analy-
`ses, provides evidence for
`the potential clinical
`benefit of atrasentan in men with metastatic HRPC.
`For all analyses, the outcomes favored atrasentan.
`Taken together, the results of the current trial are
`consistent with the mechanism of action of atrasen-
`tan. The ET axis plays a role in prostate cancer pro-
`gression as well as
`in the dysregulated bone
`remodeling typical of metastatic HRPC. The ETA re-
`ceptor mediates the epithelial cancer-related activ-
`ities of ET-1, including inhibition of apoptosis, bone
`matrix remodeling, and nociception.5,31–35 The results
`of the current trial add to this body of knowledge,
`demonstrating that atrasentan may slow the onset of
`morbidity manifest as cancer-related pain, skeletal-
`related events, and clinical complications of meta-
`static disease in men with HRPC. The study design
`and prior assumptions of progression rates may have
`limited the ability to fully define the benefit with atra-
`sentan. In addition, early endpoints of radiographic
`progression shortened the average duration of expo-
`sure to both atrasentan and placebo, thus limiting ob-
`servation of
`longer
`term treatment differences.
`However, the activity of atrasentan, particularly the
`potential effect on delaying disease progression
`measured by clinical criteria or the exploratory find-
`ing that suggests a modest clinical benefit in men
`with bone metastases, warrants further evaluation in
`
`FIGURE 2. This graph illustrates the time to clinical disease progression
`defined as the onset of pain requiring substantial opioids, pathologic fracture,
`spinal cord compression, or other cancer-related event resulting in intervention.
`
`been presented as part of the Prostate Cancer Clini-
`cal Trials Working Group consensus for Phase 2 trials
`in this patient population.28
`Despite the lack of definitive clinical benefit in
`the study, 2 results suggest potential activity with atra-
`sentan. Particularly noteworthy are exploratory ad hoc
`analyses of
`the separate radiographic and clinical
`components of disease progression. Patients were
`censored from subsequent analyses at the time of
`their first event. Of the 411 patients who progressed
`because of bone scan changes, only 42 patients (10%)
`had pain. Of the 177 patients who progressed because
`of a clinical event, only 65 patients (37%) progressed
`with simultaneous radiographic events (52 patients
`had a concurrent positive bone scan, 23 patients had
`a concurrent positive CT scan; 10 patients had both
`positive bone and CT scans). The time to onset of ra-
`diographic progression was similar between groups
`(HR, 90; 95% CI, 0.76–1.08). In contrast, fewer clinical
`progression events occurred with atrasentan (77 of
`408 patients; 18.9%) than with placebo (100 of 401
`patients; 24.9%), and atrasentan prolonged the onset
`of these events (HR, 74; 95% CI, 0.55–1.00) (Fig. 2).
`In these analyses, atrasentan reduced the risk of
`clinical progression as the first progression event by
`26%. Clinical progression, which was defined primar-
`ily as pain and skeletal-related events in this study,
`represents the morbidity of
`late-stage HRPC. The
`major limitation of these analyses, however, is that
`patients who had radiographic progression without
`clinical progression were censored when radio-
`graphic progression occurred. Therefore, these data
`are difficult to interpret and require confirmation in
`future studies.
`A biologic effect with atrasentan is evident from
`its slowing the increase of biomarkers of disease pro-
`
`

`

`1966
`
`CANCER November 1, 2007 / Volume 110 / Number 9
`
`prospective randomized controlled trials. A trial spon-
`sored by the Southwest Oncology Group (SWOG-
`0421) in patients with HRPC who have bone metasta-
`ses is underway to evaluate the possible synergistic
`effect of atrasentan in combination with docetaxel.
`
`9.
`
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