Original Article
`
`Chemohormonal Therapy in Metastatic
`Hormone-Sensitive Prostate Cancer
`Christopher J. Sweeney, M.B., B.S., Yu-Hui Chen, M.S., M.P.H.,
`Michael Carducci, M.D., Glenn Liu, M.D., David F. Jarrard, M.D.,
`Mario Eisenberger, M.D., Yu-Ning Wong, M.D., M.S.C.E., Noah Hahn, M.D.,
`Manish Kohli, M.D., Matthew M. Cooney, M.D., Robert Dreicer, M.D.,
`Nicholas J. Vogelzang, M.D., Joel Picus, M.D., Daniel Shevrin, M.D.,
`Maha Hussain, M.B., Ch.B., Jorge A. Garcia, M.D., and Robert S. DiPaola, M.D.
`
`ABS TR ACT
`
`BACKGROUND
`Androgen-deprivation therapy (ADT) has been the backbone of treatment for
`metastatic prostate cancer since the 1940s. We assessed whether concomitant
`treatment with ADT plus docetaxel would result in longer overall survival than that
`with ADT alone.
`
`METHODS
`We assigned men with metastatic, hormone-sensitive prostate cancer to receive
`either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface
`area every 3 weeks for six cycles) or ADT alone. The primary objective was to test
`the hypothesis that the median overall survival would be 33.3% longer among
`patients receiving docetaxel added to ADT early during therapy than among pa-
`tients receiving ADT alone.
`
`RESULTS
`A total of 790 patients (median age, 63 years) underwent randomization. After a
`median follow-up of 28.9 months, the median overall survival was 13.6 months
`longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6
`months vs. 44.0 months; hazard ratio for death in the combination group, 0.61;
`95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to bio-
`chemical, symptomatic, or radiographic progression was 20.2 months in the com-
`bination group, as compared with 11.7 months in the ADT-alone group (hazard
`ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen
`level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination
`group versus 16.8% in the ADT-alone group (P<0.001). In the combination group,
`the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4
`infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy
`and of grade 3 motor neuropathy was 0.5%.
`
`CONCLUSIONS
`Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer re-
`sulted in significantly longer overall survival than that with ADT alone. (Funded by
`the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.)
`
`From the Department of Medicine (C.J.S.)
`and the Department of Biostatistics and
`Computational Biology (Y.-H.C.), Dana–
`Farber Cancer Institute, Boston; Harvard
`Medical School, Boston (C.J.S.); Johns
`Hopkins University, Baltimore (M.C., M.E.);
`University of Wisconsin Carbone Cancer
`Center (G.L., D.F.J.) and School of Medi-
`cine and Public Health (D.F.J.), Madison;
`Fox Chase Cancer Center, Temple Univer-
`sity Health System, Philadelphia (Y.-N.W.);
`Indiana University Melvin and Bren Simon
`Cancer Center, Indianapolis (N.H.); Mayo
`Clinic, Rochester, MN (M.K.); University
`Hospitals Case Medical Center, Seidman
`Cancer Center (M.M.C.), and Cleveland
`Clinic Taussig Cancer Institute (J.A.G.)
`— both in Cleveland; University of Virginia
`Cancer Center, Charlottesville (R.D.); Com-
`prehensive Cancer Centers of Nevada, Las
`Vegas (N.J.V.); Siteman Cancer Center,
`Washington University School of Medi-
`cine, St. Louis (J.P.); NorthShore University
`HealthSystem, Evanston, IL (D.S.); Univer-
`sity of Michigan Comprehensive Cancer
`Center, Ann Arbor (M.H.); and Rutgers
`Cancer Institute of New Jersey, New Bruns-
`wick (R.S.D.). Address reprint requests to
`Dr. Sweeney at christopher_sweeney@ dfci
`. harvard . edu.
`
`This article was published on August 5,
`2015, at NEJM.org.
`
`N Engl J Med 2015;373:737-46.
`DOI: 10.1056/NEJMoa1503747
`Copyright © 2015 Massachusetts Medical Society.
`
`n engl j med 373;8 nejm.org August 20, 2015
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`737
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`The New England Journal of Medicine
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`Downloaded from nejm.org at SIDLEY AUSTIN LLP on March 16, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`JANSSEN EXHIBIT 2163
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Regressions of metastatic prostate
`
`cancer were first documented in the 1940s
`and were achieved with surgical castra-
`tion; subsequently, androgen-deprivation therapy
`(ADT) became the mainstay of therapy.1 Attempts
`to improve the efficacy or decrease the treatment
`burden of ADT have included the use of anti-
`androgens alone, intermittent dosing of ADT,
`and the use of an antiandrogen combined with
`medical or surgical castration.2-4 A meta-analysis
`revealed an increase in survival of 3 percentage
`points at 5 years with concurrent use of a non-
`steroidal antiandrogen at the time of initiation
`of ADT.2 However, resistance to ADT occurs in
`most patients, with the result that the median
`survival among patients with metastatic prostate
`cancer is approximately 3 years.5,6 In patients
`with resistance to ADT, docetaxel therapy re-
`sulted in a median survival that was approxi-
`mately 2.5 months longer than that with mito-
`xantrone and prednisone.7,8
`Prior studies of chemotherapy plus ADT, which
`did not show a benefit, were small studies that
`involved primarily patients with a relatively low
`tumor burden.9,10 Definitions of a high burden of
`disease have included the presence of visceral
`metastases, a bone-metastasis burden categorized
`by site (beyond the axial skeleton) or by a high
`number of lesions, or a combination of these.9,11,12
`In this study, the E3805 study, patients received
`ADT alone or ADT plus docetaxel at the begin-
`ning of ADT for metastatic hormone-sensitive
`prostate cancer, and stratification was performed
`prospectively according to high or low burden of
`metastatic disease.
`
`Methods
`
`Study Oversight
`The primary objective of the E3805 study was to
`determine whether docetaxel therapy at the be-
`ginning of ADT for metastatic hormone-sensitive
`prostate cancer would result in longer overall
`survival than that with ADT alone. The study was
`designed in 2005 by the Eastern Cooperative On-
`cology Group (ECOG; now part of ECOG-ACRIN)
`and was approved by the institutional review
`board at each participating institution. The study
`was coordinated by the ECOG-ACRIN Cancer
`Research Group. The ECOG-ACRIN Statistical
`Center collected the data and was the leading
`cooperative group and data coordinating center.
`
`The first two authors attest that the study was
`conducted and monitored as specified by the
`protocol. The first author wrote the first draft of
`the manuscript, with subsequent contributions
`by all the coauthors. The authors vouch for the
`accuracy and completeness of the data presented.
`The protocol with the statistical analysis plan
`is available with the full text of this article at
`NEJM.org. Sanofi donated the docetaxel for
`early use (i.e., before progression during ADT)
`and provided a grant to ECOG-ACRIN but had
`no role in the design of the protocol, the collec-
`tion or analysis of the data, or the preparation of
`the manuscript.
`
`Patients
`Patients were enrolled by ECOG-ACRIN, the
`Southwest Oncology Group, the Alliance for
`Clinical Trials in Oncology, and NRG Oncology
`(a merged group that includes the National Sur-
`gical Adjuvant Breast and Bowel Project, the Ra-
`diation Therapy Oncology Group, and the Gyne-
`cologic Oncology Group) and through the Clinical
`Trials Support Unit. Eligible patients had a
`pathological diagnosis of prostate cancer or a
`clinical scenario consistent with prostate cancer
`with an elevated prostate-specific antigen (PSA)
`level; radiologic evidence of metastatic disease;
`and an ECOG performance-status score of 0, 1,
`or 2 (on a scale from 0 to 5, with higher scores
`indicating greater disability; patients with a score
`of 2 were eligible if the decrement in function-
`ing was due to prostate cancer). Prior adjuvant
`ADT was allowed if the duration of therapy was
`24 months or less and progression had occurred
`more than 12 months after completion of ther-
`apy. Patients who were receiving ADT for meta-
`static disease were eligible if there was no evidence
`of progression and treatment had commenced
`within 120 days before randomization. Organ
`function that was adequate for doce taxel treat-
`ment was required (details are provided in the
`protocol). All patients provided written informed
`consent in accordance with institutional and
`federal guidelines.
`
`Treatment Plan, Stratification,
`and Randomization
`Patients were randomly assigned to ADT alone
`or to combination therapy with ADT plus doce-
`taxel at a dose of 75 mg per square meter of
`body-surface area given every 3 weeks for six
`
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`
`

`

`Chemohormonal Therapy in Prostate Cancer
`
`cycles, with premedication with 8 mg of oral
`dexamethasone at 12 hours, 3 hours, and 1 hour
`before docetaxel infusion. Daily prednisone was
`not required. Patients were stratified according
`to age (<70 years vs. ≥70 years), ECOG perfor-
`mance-status score (0 or 1 vs. 2), and planned
`use of combined androgen blockade for more
`than 30 days (yes vs. no) or agents approved for
`prevention of skeletal-related events in castration-
`resistant disease (zoledronic acid or denosumab)
`(yes vs. no). Patients were also stratified accord-
`ing to the duration of prior adjuvant ADT (<12
`months vs. ≥12 months) and the extent of metas-
`tases (high volume [defined as the presence of
`visceral metastases or ≥4 bone lesions with ≥1
`beyond the vertebral bodies and pelvis] vs. low
`volume). Patients were required to take at least
`500 mg of oral calcium carbonate and at least
`400 IU of vitamin D per day.
`
`Dose Modifications
`No dose modifications of ADT were allowed,
`and the use of a nonsteroidal antiandrogen with
`castration (medical or surgical) at the time of
`initiation of therapy was at the discretion of the
`investigator. Intermittent hormonal therapy was
`not allowed. For docetaxel, no more than two
`dose modifications (decreases to 65 mg per
`square meter and 55 mg per square meter) were
`allowed. Dose adjustments were made according
`to the organ system that showed the greatest de-
`gree of toxic effects, which were graded accord-
`ing to the National Cancer Institute (NCI) Com-
`mon Terminology Criteria for Adverse Events
`(CTCAE; version 3.0 until September 2011 and
`version 4.0 thereafter). Details on dosing are
`provided in the protocol. If a dose was reduced
`owing to toxic effects, it was not increased sub-
`sequently, and docetaxel was discontinued if
`administration was delayed longer than 3 weeks
`from the scheduled day of dosing. The use of
`growth factors was at the discretion of the inves-
`tigator.
`
`Monitoring of Toxic Effects and Efficacy
`Patients assigned to combination therapy were
`seen every 3 weeks during the period of docetaxel
`administration and then every 3 months. Patients
`assigned to ADT alone were seen every 3 months.
`For the reporting of serious adverse events to the
`NCI and to guide dose modifications, CTCAE
`version 3.0 was used until September 2011, at
`
`which time the study began using version 4.0. To
`ensure consistency, case-report forms for toxic
`effects that were recorded in the study database
`retained the use of version 3.0. All grade 3 or
`higher toxic effects in the combination group
`were captured, and an attribution of relatedness
`to study therapy was made by the local investiga-
`tors. Adverse events among patients assigned to
`ADT alone were not routinely documented, al-
`though major adverse events were to be reported.
`PSA levels were measured at each scheduled
`visit. Imaging (computed tomography [CT] of
`the abdomen and pelvis, technetium-99m bone
`scanning, and radiography or CT of the chest)
`was performed at baseline and at the time of
`documented castration resistance or as clinically
`indicated. Disease progression on imaging was
`determined according to the Response Evaluation
`Criteria in Solid Tumors (RECIST), version 1.013
`(the criteria are summarized in the protocol). A
`complete serologic response was defined as a
`PSA level of less than 0.2 ng per milliliter on two
`consecutive measurements at least 4 weeks apart.
`Serologic progression was defined as an increase
`in the PSA level of more than 50% above the
`nadir reached after the initiation of ADT, with
`two consecutive increases at least 2 weeks apart.
`The date of a first recorded increase of more
`than 50% above the nadir was deemed the date
`of progression. If the nadir level was less than
`2 ng per milliliter, a minimum increase of more
`than 2 ng per milliliter was required.
`All time-to-event end points were determined
`from the time of randomization. Overall survival
`was defined as the time until death from any
`cause. The time to castration-resistant prostate
`cancer was defined as the time until document-
`ed clinical or serologic progression with a testos-
`terone level of less than 50 ng per deciliter (or
`source documentation of medical castration or
`surgical castration). The time to clinical pro-
`gression was defined as the time until increas-
`ing symptoms of bone metastases; progression
`according to RECIST, version 1.0; or clinical
`deterioration due to cancer according to the in-
`vestigator’s opinion.
`
`Statistical Analysis
`The study underwent two major amendments
`(details are provided in the protocol); in all ver-
`sions, an intention-to-treat analysis plan was
`used. With each amendment, the sample size
`
`n engl j med 373;8 nejm.org August 20, 2015
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`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`was adjusted so that the study would have 80%
`power to detect a 33.3% difference in median
`overall survival between the combination group
`and the ADT-alone group, with the use of a
`stratified log-rank test at a one-sided alpha level
`of 2.5%. At study inception, only patients with
`high-volume disease were to be enrolled, and the
`sample size was to be 568 patients. After com-
`pletion of enrollment in the NCI-sponsored
`S9346 trial,4 an amendment to the E3805 study
`was made in July 2008, after 53 patients had been
`enrolled, to include patients with low-volume
`disease. A prospective stratification of high vol-
`ume versus low volume of metastatic disease
`was added, and the sample size was increased to
`600 patients. The final amendment was made in
`December 2011, after 579 patients had been en-
`rolled, to reflect new data documenting an in-
`crease in median overall survival owing to the
`use of PSA in the detection and monitoring of
`disease activity5 (initial projections were based
`on studies from the pre-PSA era) and to address
`the September 2011 report of the data and safety
`monitoring committee, which noted that 70% of
`enrolled patients had high-volume disease. The
`final design required the enrollment of 780 pa-
`tients, with projections of median overall sur-
`vival with ADT alone of 33 months among pa-
`tients with high-volume disease and 67 months
`among patients with low-volume disease.
`Interim analyses were to be performed before
`all semiannual meetings of the data and safety
`monitoring committee starting when approxi-
`mately 25% of the planned full information was
`obtained and continuing until either the criteria
`for early stopping were met or full information
`was obtained (after 399 deaths). The study was
`monitored for early stopping for futility with the
`use of repeated-confidence-interval methods.14 At
`each interim analysis, the nominal (1 − [2 × alpha])
`confidence interval for the hazard ratio for death
`in the comparison of the combination-therapy
`group with the ADT-alone group was computed.
`For a given analysis time (information fraction),
`alpha was set at the nominal one-sided signifi-
`cance level of the use function boundary. Infor-
`mation from interim analyses was reviewed by
`members of the independent data and safety
`monitoring committee, who determined wheth-
`er efficacy or futility had been demonstrated and
`who decided whether the study should be stopped
`and the results reported early.
`
`Descriptive statistics were used to characterize
`patients at study entry. Kaplan–Meier estimates15
`were used for event-time distributions. Cox pro-
`portional-hazard models,16 stratified according
`to the factors described above, were used to esti-
`mate hazard ratios for time-to-event end points.
`Stratified log-rank tests17 were used to compare
`event-time distributions between the two groups.
`Response rates were compared with the use of
`Fisher’s exact test.18 An intention-to-treat analy-
`sis was conducted that included all randomly
`assigned patients regardless of eligibility and
`treatment status. P values are two-sided, and con-
`fidence intervals are at the 95% level.
`
`R esults
`
`Patients
`From July 2006 through December 2012, a total
`of 790 patients were enrolled and underwent ran-
`domization. Ten patients were ineligible, 7 had
`incomplete information to assess eligibility, and
`6 patients in the combination group did not
`start the assigned therapy (Fig. S1 in the Supple-
`mentary Appendix, available at NEJM.org). All
`randomly assigned patients were followed and
`included in the primary analysis of their assigned
`group. At the planned interim analysis in Octo-
`ber 2013, a total of 53% of the planned full in-
`formation had been obtained, prespecified crite-
`ria for significance had been met, and the data
`were released by the data and safety monitoring
`committee. This report represents data with a
`cutoff date for survival of December 23, 2013;
`the median follow-up was 28.9 months, with
`136 deaths in the ADT-alone group and 101
`deaths in the combination group. All other data
`reflect the database as of December 23, 2014.
`Patient characteristics were well balanced be-
`tween the two groups (Table 1). The median age
`was 64 years (range, 36 to 88) in the combina-
`tion group and 63 years (range, 39 to 91) in the
`ADT-alone group. In both groups, approximately
`85% of the patients were white, approximately
`70% had an ECOG performance-status score of 0,
`approximately 65% had high-volume disease, and
`approximately 60% had a Gleason score of 8 or
`higher (on a scale from 2 to 10, with higher
`scores indicating a more aggressive form of pros-
`tate cancer and a worse prognosis). In both
`groups, 73% of the patients had received no
`prior local therapy for prostate cancer with cura-
`
`740
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`n engl j med 373;8 nejm.org August 20, 2015
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`The New England Journal of Medicine
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`Downloaded from nejm.org at SIDLEY AUSTIN LLP on March 16, 2017. For personal use only. No other uses without permission.
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`
`

`

`Chemohormonal Therapy in Prostate Cancer
`
`Table 1. Baseline Characteristics of the Patients.*
`
`Characteristic
`Age — yr
`Median
`Range
`Race — no. (%)†
`White
`Black
`Other
`Unknown
`ECOG performance status — no. (%)‡
`0
`1
`2
`Volume of metastases — no. (%)§
`Low
`High
`Visceral metastases — no. (%)
`Gleason score — no. (%)¶
`4–6
`7
`8–10
`Unknown
`PSA level at start of ADT — ng/ml
`Median
`Range
`Prior treatment for prostate cancer — no. (%)
`No local therapy
`Primary radiation
`Prostatectomy
`Missing data
`Adjuvant ADT — no. (%)
`Time from start of ADT to randomization — mo‖
`Median
`Range
`No ADT before randomization — no. (%)
`
`ADT plus Docetaxel
`(N = 397)
`
`ADT Alone
`(N = 393)
`
`64
`36–88
`
`344 (86.6)
`39 (9.8)
` 4 (1.0)
`10 (2.5)
`
`277 (69.8)
`114 (28.7)
` 6 (1.5)
`
`134 (33.8)
`263 (66.2)
` 57 (14.4)
`
`21 (5.3)
` 96 (24.2)
`241 (60.7)
`39 (9.8)
`
`63
`39–91
`
`330 (84.0)
`37 (9.4)
` 6 (1.5)
`20 (5.1)
`
`272 (69.2)
`115 (29.3)
` 6 (1.5)
`
`143 (36.4)
`250 (63.6)
` 66 (16.8)
`
`21 (5.3)
` 83 (21.1)
`243 (61.8)
` 46 (11.7)
`
`50.9
`0.2–8540.1
`
`52.1
`0.1–8056.0
`
`289 (72.8)
`27 (6.8)
` 81 (20.4)
`0
`18 (4.5)
`
`1.2
`0.03–3.9
` 51 (12.8)
`
`286 (72.8)
`33 (8.4)
` 73 (18.6)
` 1 (0.3)
`16 (4.1)
`
`1.3
`0.03–3.9
` 52 (13.2)
`
`* There were no significant differences in characteristics between the two groups when analyzed with the use of the
`Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables, with the categories for
`“unknown” or “missing data” excluded. ADT denotes androgen-deprivation therapy, and PSA prostate-specific antigen.
`† Race was self-reported.
`‡ Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores indicat-
`ing greater disability. One patient assigned to ADT alone did not have an on-study form submitted, so the ECOG per-
`formance-status score was unknown, but the stratification by the site placed the patient into the stratum of a perfor-
`mance-status score of 2 at randomization.
`§ A high volume of metastases was defined by the presence of visceral metastases or four or more bone lesions with at
`least one beyond the vertebral bodies and pelvis. One patient assigned to ADT alone did not have an on-study form
`submitted, so the volume of metastases was unknown, but the stratification by the site placed the patient into the high-
`volume stratum at randomization.
`¶ Gleason scores range from 2 to 10, with higher scores indicating a more aggressive form of prostate cancer and a
`worse prognosis.
`‖ Time from start of ADT to randomization is among patients who started ADT before randomization.
`
`n engl j med 373;8 nejm.org August 20, 2015
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`741
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`The New England Journal of Medicine
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`Downloaded from nejm.org at SIDLEY AUSTIN LLP on March 16, 2017. For personal use only. No other uses without permission.
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`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Figure 1. Kaplan–Meier Estimates of Overall Survival.
`The median duration of follow-up was 28.9 months
`among all patients (Panel A), 29.2 months among pa-
`tients with high-volume disease (Panel B), and 27.6
`months among patients with low-volume disease (Pan-
`el C). ADT denotes androgen-deprivation therapy, and
`NR not reached.
`
`tive (rather than palliative) intent. Among pa-
`tients who started ADT before randomization,
`the median time from the start of ADT to ran-
`domization was 1.2 months (range, 0 to 3.9) in
`the combination group and 1.3 months (range,
`0 to 3.9) in the ADT-alone group.
`
`Survival
`The median overall survival was 13.6 months
`longer with the addition to ADT of early docetax-
`el than with ADT alone (57.6 months vs. 44.0
`months; hazard ratio for death in the combina-
`tion group, 0.61; 95% confidence interval [CI],
`0.47 to 0.80; P<0.001) (Fig. 1A). There were 85
`prostate-cancer deaths in the combination group
`and 114 prostate-cancer deaths in the ADT-alone
`group (Table S1 in the Supplementary Appen-
`dix). The benefit at the last analysis was more
`apparent in the subgroup with high-volume dis-
`ease than in the overall study population
`(Fig. 1B), with a median overall survival that was
`17.0 months longer in the combination group
`than in the ADT-alone group (49.2 months vs.
`32.2 months; hazard ratio for death, 0.60; 95%
`CI, 0.45 to 0.81; P<0.001). The median survival
`at the time of the analysis had not been reached
`in the subgroup with low-volume disease in ei-
`ther study group (Fig. 1C). A benefit of docetax-
`el treatment was detected in all the subgroups
`analyzed (Fig. 2).
`
`Secondary End Points and Toxic Effects
`The proportion of patients who had a decrease
`in the PSA level to less than 0.2 ng per milliliter
`at 12 months was 27.7% in the combination
`group, as compared with 16.8% in the ADT-
`alone group (P<0.001) (Table 2). The median
`time to the development of castration-resistant
`prostate cancer (biochemical, symptomatic, or
`radiographic) was 20.2 months with combina-
`tion therapy, as compared with 11.7 months
`with ADT alone (hazard ratio in the combina-
`tion group, 0.61; 95% CI, 0.51 to 0.72; P<0.001)
`
`Hazard ratio for death with ADT+docetaxel,
`0.61 (95% CI, 0.47–0.80) P<0.001
`
`ADT+docetaxel
`(median overall survival, 57.6 mo)
`
`ADT alone
`(median overall
`survival, 44.0 mo)
`
`A AllPatients
`
`100
`
`80
`
`60
`
`40
`
`20
`
`PatientsSurviving(%)
`
`0
`
`0
`
`12
`
`24
`
`36
`48
`Months
`
`60
`
`72
`
`84
`
`00
`
`21
`
`53
`
`397
`393
`
`333
`318
`
`189
`168
`
`89
`71
`
`46
`27
`
`No.atRisk
`ADT+docetaxel
`ADT alone
`
`B PatientswithHigh-VolumeDisease
`100
`
`Hazard ratio for death with ADT+docetaxel,
`0.60 (95% CI, 0.45–0.81) P<0.001
`
`ADT+docetaxel
`(median overall survival, 49.2 mo)
`
`ADT alone
`(median overall
`survival, 32.2 mo)
`
`80
`
`60
`
`40
`
`20
`
`PatientsSurviving(%)
`
`0
`
`0
`
`12
`
`24
`
`36
`48
`Months
`
`60
`
`72
`
`84
`
`00
`
`21
`
`53
`
`263
`250
`
`213
`193
`
`123
`92
`
`56
`40
`
`31
`14
`
`No.atRisk
`ADT+docetaxel
`ADT alone
`
`C PatientswithLow-VolumeDisease
`100
`
`ADT+docetaxel
`(median overall survival, NR)
`
`ADT alone
`(median overall
`survival, NR)
`
`Hazard ratio for death with ADT+docetaxel,
`0.60 (95% CI, 0.32–1.13) P=0.11
`
`60
`
`00
`
`12
`
`120
`125
`
`24
`
`66
`76
`
`Months
`
`36
`
`33
`31
`
`48
`
`15
`13
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`PatientsSurviving(%)
`
`No.atRisk
`ADT+docetaxel
`ADT alone
`
`134
`143
`
`742
`
`n engl j med 373;8 nejm.org August 20, 2015
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on March 16, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`

`

`Chemohormonal Therapy in Prostate Cancer
`
`No.ofPatients
`
`HazardRatio(95%CI)
`
`790
`
`612
`178
`
`549
`241
`
`674
`116
`
`277
`513
`
`123
`389
`
`221
`484
`
`575
`214
`
`459
`331
`
`443
`347
`
`0.61 (0.47–0.80)
`
`0.68 (0.50–0.91)
`0.43 (0.23–0.78)
`
`0.71 (0.50–1.01)
`0.42 (0.26–0.67)
`
`0.62 (0.47–0.83)
`0.32 (0.11–0.89)
`
`0.60 (0.32–1.13)
`0.60 (0.45–0.81)
`
`0.52 (0.25–1.07)
`0.64 (0.46–0.89)
`
`0.41 (0.21–0.80)
`0.60 (0.43–0.83)
`
`0.66 (0.50–0.89)
`0.55 (0.23–1.31)
`
`0.69 (0.49–0.99)
`0.52 (0.34–0.79)
`
`0.58 (0.40–0.84)
`0.65 (0.45–0.96)
`
`Subgroup
`
`All patients
`Age
`<70 yr
`≥70 yr
`ECOG performance-status score
`
`0 1
`
` or 2
`Race
`White
`Other or unknown
`Volume of metastases
`Low
`High
`Type of metastases
`Visceral metastases with or without bone metastases
`High-volume disease with bone metastases alone
`Gleason score
`<8
`≥8
`Previous local therapy
`No
`Yes
`Combined androgen blockade >30 days
`No
`Yes
`Therapy for skeletal-related events at time of starting ADT
`No
`Yes
`
`0.125
`
`0.25
`
`0.50
`
`1.00
`
`2.00
`
`4.00
`
`ADTplusDocetaxelBetter
`
`ADTAloneBetter
`
`Figure 2. Hazard Ratios for Death in Subgroups.
`Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores indi-
`cating greater disability. Patients were stratified on the basis of an ECOG performance-status score of 0 or 1 versus
`2, but because there were so few patients with a score of 2, the analysis was performed on the basis of a score of 0
`versus 1 or 2. Race was self-reported; other or unknown race includes black (76 patients), Asian (8), Native Ameri-
`can (2), and unknown (30). A high volume of metastases was defined by the presence of visceral metastases or four
`or more bone lesions with at least one beyond the vertebral bodies and pelvis. Gleason scores range from 2 to 10,
`with higher scores indicating a more aggressive form of prostate cancer and a worse prognosis. The x axis of the
`forest plot is scaled according to the natural logarithm of the hazard ratio. The size of the squares is proportional to
`the inverse of the variance of the log hazard ratio (small squares correspond to large variances).
`
`(Table 2, and Fig. S2A in the Supplementary
`Appendix). The median time to clinical progres-
`sion was 33.0 months with combination therapy,
`as compared with 19.8 months with ADT alone
`(hazard ratio, 0.61; 95% CI, 0.50 to 0.75; P<0.001)
`(Table 2, and Fig. S2B in the Supplementary Ap-
`pendix).
`Among the patients who received combina-
`tion therapy, approximately 2% had a treatment-
`related grade 3 or 4 allergic reaction; grade 3
`fatigue occurred in 4% of the patients, and
`grade 3 diarrhea, stomatitis, motor neuropathy,
`
`and sensory neuropathy each occurred at a rate
`of 1% or less (Table 3). Approximately 1% of the
`patients in the combination group had a throm-
`boembolic event. One patient died suddenly at
`home of an unknown cause during the course of
`docetaxel therapy; the death was considered to
`be possibly related to docetaxel according to the
`Adverse Event Expedited Reporting System. Ap-
`proximately 6% of the patients in the combina-
`tion group had neutropenic fever, and approxi-
`mately 2% had grade 3 or 4 infection with
`neutropenia.
`
`n engl j med 373;8 nejm.org August 20, 2015
`
`743
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at SIDLEY AUSTIN LLP on March 16, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 2. Secondary End Points.
`
`End Point
`
`PSA level <0.2 ng/ml at 6 mo — no. (%)
`
`PSA level <0.2 ng/ml at 12 mo — no. (%)
`
`Time to castration-resistant prostate cancer — mo*
`
`Median
`
`95% CI
`
`Time to clinical progression — mo†
`
`Median
`
`95% CI
`
`ADT plus Docetaxel
`(N = 397)
`
`ADT Alone
`(N = 393)
`
`127 (32.0)
`
`110 (27.7)
`
`20.2
`
`17.2–23.6
`
`33.0
`
`27.3–41.2
`
`77 (19.6)
`
`66 (16.8)
`
`11.7
`
`10.8–14.7
`
`19.8
`
`17.9–22.8
`
`Hazard Ratio
`(95% CI)
`
`P Value
`
`<0.001
`
`<0.001
`
`<0.001
`
`0.61 (0.51–0.72)
`
`<0.001
`
`0.61 (0.50–0.75)
`
`* The time to castration-resistant prostate cancer was the time until documented clinical or serologic progression with a testosterone level of
`less than 50 ng per deciliter (or source documentation of medical castration or surgical castration).
`† Clinical progression was defined by increasing symptoms of bone metastases; progression according to the Response Evaluation Criteria in
`Solid Tumors, version 1.0; or clinical deterioration due to cancer according to the investigator’s opinion.
`
`Table 3. Adverse Events of Grade 3 or Higher among the 390 Patients Who
`Received the Docetaxel-Containing Regimen and Had Follow-up Data
`Available.*
`
`Event
`
`Grade 3
`
`Grade 4
`
`Grade 5
`
`Allergic reaction
`
`Fatigue
`
`no. of patients (%)
`
` 7 (1.8)
`
`16 (4.1)
`
` 4 (1.0)
`
`1 (0.3)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Assigned Therapy Administered
`and Subsequent Therapy
`Approximately 86% of the 390 patients in the
`combination group who started the assigned
`therapy completed six cycles of docetaxel therapy
`(Table S2 in the Supplementary Appendix), and
`approximately 74% of all the treated patients
`received all planned cycles without dose modifi-
`cations. At the time of this analysis, castration-
`resistant prostate cancer with at least biochemi-
`cal progression had developed in 287 patients
`assigned to ADT alone; 137 patients of these
`patients had received docetaxel for castration-
`resistant prostate cancer, and another 10 patients
`had received docetaxel before castration resis-
`tance was confirmed. In addition, 104 patients
`had received abiraterone or enzalutamide after
`confirmed castration resistance (9 of these pa-
`tients may have received placebo as part of a
`trial). Table S3 in the Supplementary Appendix
`documents the use of other therapies that have
`been shown to prolong overall survival in patients
`with castration-resistant prostate cancer.
`
`Discussion
`
`Improvements in outcomes in men with meta-
`static castration-resistant prostate cancer have
`been achieved with the use of cytotoxic chemo-
`therapy, next-generation hormonal therapies,
`immunotherapy, and therapy with radiopharma-
`ceutical agents.19-25 This study showed that
`
`Diarrhea
`
`Stomatitis
`
`Neuropathy, motor
`
`Neuropathy, sensory
`
`Thromboembolism
`
`Sudden death
`
`Anemia
`
`Thrombocytopenia
`
`Neutropenia
`
`Febrile neutropenia
`
`Infection with neutropenia
`
` 2 (0.5)
`
` 2 (0.5)
`
` 2 (0.5)
`
` 1 (0.3)
`
`0
`
` 4 (1.0)
`
`0
`
`12 (3.1)
`
`15 (3.8)
`
` 5 (1.3)
`
`0
`
`0
`
`0
`
`2 (0.5)
`
`0
`
`1 (0.3)
`
`1 (0.3)
`
`35 (9.0)
`
`9 (2.3)
`
`4 (1.0)
`
`0
`
`0
`
`0
`
`0
`
`1 (0.3)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Any event
`
` 65 (16.7)
`
`49 (12.6)
`
`1 (0.3)
`
`* Patients were classified according to the worst grade reported across all body
`systems. Patients assigned to ADT plus docetaxel were monitored every 3
`weeks during the time docetaxel was administered and then every 3 months,
`whereas patients assigned to the ADT-alone group were seen every 3 months
`after randomization. Toxic effects in the group that received ADT plus
`