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`JOURNAL OF CLINICAL ONCOLOGY
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`Phase III Trials With Docetaxel-Based Combinations
`for Metastatic Castration-Resistant Prostate Cancer:
`Time to Learn From Past Experiences
`
`Emmanuel S. Antonarakis and Mario A. Eisenberger, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
`University, Baltimore, MD
`See accompanying article on page 1740
`
`Ever since docetaxel was shown to be the first known agent to
`extend survival in men with metastatic castration-resistant prostate
`cancer (mCRPC),1 drug development efforts have focused on do-
`cetaxel as a pivot point for trial design and regulatory approval. To this
`end, the majority of phase III clinical trials conducted in the postdo-
`cetaxel era have investigated the use of novel agents either before
`docetaxel administration, combined with docetaxel, or after docetaxel
`exposure.2 Although this divide is an artificial one biologically, it has
`been embraced by regulatory agencies for the approval of several new
`drugs for mCRPC in the past 3 years. However, although new agents
`have been approved both in the predocetaxel setting (eg, sipuleucel-T,
`abiraterone) and in the postdocetaxel setting (eg, cabazitaxel, abi-
`raterone, enzalutamide) on the basis of improvements in overall sur-
`vival, no drug has yet demonstrated a survival benefit (or gained
`regulatory approval) when combined with docetaxel.
`In the article that accompanies this editorial, Fizazi et al3 report
`the final results of the ENTHUSE (Endothelin A Use) -M1C study, a
`randomized phase III trial of docetaxel plus zibotentan (an oral endo-
`thelin A receptor antagonist) versus docetaxel plus placebo. Despite
`the random assignment of 1,052 patients, this study failed to demon-
`strate a survival improvement in the docetaxel-zibotentan arm (haz-
`ard ratio, 1.00; 95% CI, 0.84 to 1.18), the primary end point of the trial.
`In addition, the combination arm was not associated with improve-
`ments in any of the secondary end points: prostate-specific antigen
`(PSA) response rate, time to PSA progression, progression-free sur-
`vival, time to new bone metastases, time to new skeletal-related events,
`pain response, or time to pain progression.3 Could these negative
`findings have been predicted before conducting a large phase III
`study? We sought to examine the evidence arguing for or against
`proceeding with a phase III trial.
`Before the design of the ENTHUSE-M1C study, a single phase
`I/II trial had been conducted examining the safety and efficacy of the
`docetaxel-zibotentan combination.4 In this trial, six patients were
`enrolled onto two dose-escalation cohorts followed by an expansion
`phase in which 31 additional patients were randomly assigned (2:1) to
`receive docetaxel-zibotentan (n ⫽ 20) or docetaxel-placebo (n ⫽ 11).
`The prespecified primary end points for the phase II expansion com-
`ponent were overall response rate and PSA response rate. There were
`no differences observed between arms in either of these end points.
`
`Objective response rates in the docetaxel-zibotentan and docetaxel-
`placebo groups were 22.2% and 16.7% respectively (difference, 5.5%;
`80% CI, ⫺23% to 30%; P ⬎ .05); PSA response rates were 85.0%
`and 72.7% respectively (difference, 12.3%; 80% CI, ⫺6% to 33%;
`P ⬎ .05). Despite these findings and perhaps encouraged by a separate
`randomized phase II trial of single-agent zibotentan versus placebo in
`asymptomatic patients with mCRPC, which showed a trend (P ⬎ .10)
`toward improved survival with zibotentan (a secondary end point in
`that study),5 the authors of the phase I/II trial commented that “suffi-
`cient preliminary activity was seen with this combination to merit
`continued development.” On the basis of the available clinical data, we
`do not believe that compelling evidence existed to justify proceeding
`with a phase III trial.
`In addition to this particular docetaxel-based combination, eight
`other decisive phase III trials have been designed in an attempt to
`improve on the efficacy of docetaxel in men with mCRPC. These trials
`are summarized in Table 1.6-18 Of the nine total trials (examining a
`range of agents including antiangiogenic drugs, bone microenviron-
`ment agents, immune modulators, and others), eight have been com-
`pleted, and one is still awaiting final results. Discouragingly, all eight of
`the studies with mature results failed to meet the primary end point of
`improving overall survival. Indeed, no docetaxel-based combination
`reported to date, to our knowledge, has been shown to extend survival
`compared with docetaxel alone. Notable as well is that a trial evaluat-
`ing another endothelin A receptor antagonist (atrasentan) also failed
`to improve survival beyond docetaxel alone.
`A more careful examination of this table reveals some sobering
`truths. Of the nine docetaxel-based combinations examined in the
`phase III setting, only three agents (bevacizumab, calcitriol, custirsen)
`had previously been tested in combination with docetaxel in dedicated
`phase II trials, whereas four agents (atrasentan, zibotentan, dasatinib,
`lenalidomide) were tested in expansion cohorts of phase I/II trials, and
`two agents (aflibercept, GVAX) were never tested in combination with
`docetaxel at all in the phase II setting. Moreover, of the seven
`docetaxel-based combinations that did have phase II data available,
`these phase II trials either did not define the metric for success that
`would prompt phase III development (dasatinib, lenalidomide) or
`did define the metric for success but did not achieve it (bevaci-
`zumab, atrasentan, zibotentan, calcitriol, custirsen). Therefore, it
`
`Journal of Clinical Oncology, Vol 31, No 14 (May 10), 2013: pp 1709-1712
`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
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`1709
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`JANSSEN EXHIBIT 2080
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`Primaryendpointnotmet18
`
`Primaryendpointnotmet17
`
`Metricforsuccessnotdefined15
`
`—
`
`Editorial
`
`Metricforsuccessnotdefined12
`
`Primaryendpointsnotmet4
`
`Primaryendpointnotmet10
`
`primaryendpoint
`82)usingPSAresponserateas
`
`RandomizedphaseIIstudy(n⫽
`
`asprimaryendpoint
`250)usingPSAresponserate
`RandomizedphaseIIstudy(n⫽
`
`Single-armphaseIIstudy(n⫽20;
`
`primaryendpoint
`usingPSAresponserateas
`expansionofphaseI/IItrial)
`
`NophaseIIcombinationstudies
`
`conducted
`
`Single-armphaseIIstudy(n⫽30;
`
`primaryendpoint
`usingPSAresponserateas
`expansionofphaseI/IItrial)
`
`endpoints
`PSAresponserateasprimary
`usingoverallresponserateand
`31;expansionofphaseI/IItrial)
`
`RandomizedphaseIIstudy(n⫽
`
`Single-armphaseIIstudy(n⫽23;
`
`primaryendpoint
`usingPSAresponserateas
`expansionofphaseI/IItrial)
`
`Abbreviations:HR,hazardratio;OS,overallsurvival;PFS,progression-freesurvival;PSA,prostate-specificantigen.
`
`Studyisongoing
`
`OSinferiorincombinationarm16;HR,
`
`1.42;95%CI,1.13to1.86
`
`OSinferiorincombinationarm14;HR,
`
`1.53;95%CI,1.17to2.00
`
`OSinferiorincombinationarm13;HR,
`
`1.70;95%CI,1.15to2.53
`
`OS
`
`OS
`
`OS
`
`OS
`
`800
`
`953
`
`1,059
`
`408
`
`Docetaxel⫾custirsen
`
`(NCT01188187)
`
`Docetaxel⫾calcitriol
`
`(NCT00273338)
`
`Miscellaneousagents
`
`Docetaxel⫾lenalidomide
`
`(NCT00988208)
`
`(NCT00133224)
`Docetaxel⫾GVAX
`Immunemodulators
`
`OSnotimprovedincombinationarm11;
`
`HR,0.99;95%CI,0.87to1.13
`
`OS
`
`1,380
`
`Docetaxel⫾dasatinib
`
`(NCT00744497)
`
`OSnotimprovedincombinationarm3;
`
`HR,1.00;95%CI,0.84to1.18
`
`OS
`
`1,052
`
`Docetaxel⫾zibotentan
`
`(NCT00617669)
`
`OSnotimprovedincombinationarm9;
`
`HR,1.01;95%CI,0.87to1.18
`
`OSandPFS
`
`991
`
`—
`
`Primaryendpointnotmet7
`
`NophaseIIcombinationstudies
`
`conducted
`
`usingPFSasprimaryendpoint
`Single-armphaseIIstudy(n⫽77)
`
`OSnotimprovedincombinationarm8;
`
`HR,0.94;95%CI,0.82to1.08
`
`OSnotimprovedincombinationarm6;
`
`HR,0.91;95%CI,0.78to1.05
`
`WasPrimaryEndPointMet?
`
`PrimaryEndPoint(s)Used
`
`Description,Including
`
`PrimaryResult
`
`PriorPhaseIITrial(s)
`
`PhaseIIITrial
`
`OS
`
`OS
`
`PrimaryEnd
`
`Point
`
`1,224
`
`1,050
`
`Sample
`
`Size
`
`Table1.CompletedorOngoingPhaseIIIStudiesExaminingDocetaxel-BasedCombinationsintheFirst-LineTreatmentofMetastaticCastration-ResistantProstateCancer
`
`Docetaxel⫾atrasentan
`
`(NCT00134056)
`
`Bonemicroenvironmentagents
`
`Docetaxel⫾aflibercept
`
`(NCT00519285)
`
`Docetaxel⫾bevacizumab
`
`(NCT00110214)
`
`Antiangiogenicdrugs
`
`Agent
`
`1710
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`JOURNAL OF CLINICAL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Editorial
`
`could be argued that none of the nine docetaxel-based combina-
`tion strategies shown in Table 1 had sufficient phase II data to
`warrant additional development.
`The decision-making process to proceed from phase II to phase
`III trials in oncology remains challenging. Oncologic clinical trials are
`becoming increasingly complex with the recognition of the molecular
`heterogeneity of tumors, even ones that originate from the same
`primary site. In addition, anticancer drugs are frequently designed to
`target specific cellular pathways and metastatic sites, which indicates a
`need for personalized treatment planning. Although accurate predic-
`tion of a positive phase III study is an impossible endeavor, there are
`several logical steps that can be taken in early-phase drug development
`to enhance our ability to identify potentially active treatments worthy
`of additional study in the phase III setting. First, and most simplisti-
`cally, phase III trials should not be pursued without the prior conduct
`of at least one phase II study that has met a prespecified rationally
`selected primary end point and its predefined metric for success (sig-
`nal for efficacy) in a safe manner. Our experience in phase III trials
`using docetaxel-based regimens in mCRPC in the past several years
`demonstrates that it is not appropriate to conclude that a regimen has
`sufficient activity to warrant phase III testing if the primary end point
`has not been met and the decision to proceed is based on whether a
`secondary end point has been achieved or on other post hoc consid-
`erations. Second, the most appropriate end point for defining a suc-
`cess in phase II trials should ideally be agent specific or at least class
`specific. For example, the choice of PSA response rate as the primary
`end point for phase II development of an androgen receptor–directed
`therapy (eg, abiraterone, enzalutamide) may be reasonable, whereas
`this might not be appropriate for a bone-targeting agent (eg, ziboten-
`tan, dasatinib). Third and most relevant to targeted therapies, early-
`phase studies should seek to confirm that the drug in question reaches
`its target, engages its target, and inhibits its target and that target
`inhibition produces a clinical effect. Fourth, phase II trials should use
`enrichment strategies to narrow down the target population to those
`patients who are most likely to benefit from a particular agent, on the
`basis of either clinical characteristics or molecular information. Along
`these lines, phase II trials should be designed with prospectively de-
`fined predictive biomarkers (ie, biomarker-stratified studies) in place;
`these trials would have the ability to investigate clinical outcomes to an
`experimental agent in patients both with and without a given biologic
`marker. Finally, because there are currently no established surrogate
`end points for overall survival in men with mCRPC,19 new efforts
`should focus on identification and validation of alternative interme-
`diate biomarkers of clinical benefit (eg, change in circulating tumor
`cell counts at 12 weeks after initiation of therapy), potentially shorten-
`ing the duration of phase III trials and allowing for an earlier signal
`of efficacy.
`In conclusion, Fizazi et al3 report that the results of the phase III
`ENTHUSE-M1C study “contradict earlier promising clinical data on
`the combination of zibotentan with chemotherapy.”3 On the basis of
`the information presented here, we would argue that the results of
`ENTHUSE-M1C confirm the phase II data that the combination
`of docetaxel and zibotentan has little clinical activity in men with
`mCRPC. We should be careful not to redefine our failures as successes.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
`Although all authors completed the disclosure declaration, the following
`author(s) and/or an author’s immediate family member(s) indicated a
`financial or other interest that is relevant to the subject matter under
`
`consideration in this article. Certain relationships marked with a “U” are
`those for which no compensation was received; those relationships marked
`with a “C” were compensated. For a detailed description of the disclosure
`categories, or for more information about ASCO’s conflict of interest policy,
`please refer to the Author Disclosure Declaration and the Disclosures of
`Potential Conflicts of Interest section in Information for Contributors.
`Employment or Leadership Position: None Consultant or Advisory
`Role: Emmanuel S. Antonarakis, sanofi-aventis (C), Dendreon (C),
`Janssen (C); Mario A. Eisenberger, sanofi-aventis (U) Stock
`Ownership: None Honoraria: Emmanuel S. Antonarakis,
`sanofi-aventis, Dendreon, Janssen Research Funding: Emmanuel S.
`Antonarakis, sanofi-aventis, Dendreon; Mario A. Eisenberger,
`sanofi-aventis, Genentech, Agensys, Oncology Trials Insights Expert
`Testimony: None Other Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`Manuscript writing: All authors
`Final approval of manuscript: All authors
`
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`
`www.jco.org
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`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
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`Editorial
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`patients with castrate-resistant prostate cancer: The MAINSAIL trial. Meeting of
`the European Society of Medical Oncology, Vienna, Austria, September 28-
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`17. Beer TM, Ryan CW, Venner PM, et al: Double-blind randomized study of
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`androgen-independent prostate cancer: A report from the ASCENT investigators.
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`
`DOI: 10.1200/JCO.2013.48.8825; published online ahead of print at
`www.jco.org on April 8, 2013
`
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`JOURNAL OF CLINICAL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 20, 2016. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
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