Correspondence
`
`for patients with HPV16-positive OPC is currently intensive and re-
`sults in substantial morbidity, albeit with a high survival rate, ongoing
`trials are evaluating radiation deintensification among patients with
`HPV-positive OPC. Thus, there may be less intensive treatment op-
`tions in the future, especially for HPV-driven cancers diagnosed at an
`earlier stage.
`On the basis of available data, we estimate that, in regions like the
`United States where rates of HPV-driven OPC are rare but increasing,
`the number of individuals in the population needed to be screened to
`detect one case of OPC is approximately 5,000 (assuming 70% of
`tumors are HPV16 positive and 90% assay sensitivity), and the num-
`ber of individuals who screened positive that would yield one case is
`approximately 50 (assuming 99.0% specificity); this value decreases to
`approximately 11 if specificity increases to 99.8% (Table 1). To put this
`into context, in comparison with cervical cancer screening,7,8 the
`number of individuals needed to screen to detect one cancer would be
`higher for OPC because of differences in incidence, whereas the num-
`ber of individuals who screen positive needed to detect one case would
`be lower for OPC because of the high specificity of the HPV16 E6
`assay, especially if test characteristics can be further improved.
`It is too early to judge the suitability of HPV16 E6 antibody as a
`screening tool for OPC, and we will continue to evaluate this poten-
`tially important cancer prevention opportunity. However, because
`OPC is only a subset of head and neck cancers, even if this marker is
`proven successful as a screening test, efforts to evaluate markers for
`non-HPV–related head and neck cancer are also important if we are to
`have a global and meaningful impact.
`
`Aime´e R. Kreimer
`National Cancer Institute, National Institutes of Health, Bethesda, MD
`
`Mattias Johansson
`International Agency for Research on Cancer, Lyon, France
`
`Michael Pawlita
`German Cancer Research Center, Heidelberg, Germany
`
`Paul Brennan
`International Agency for Research on Cancer, Lyon, France
`
`ACKNOWLEDGMENT
`We thank Dr Anna Coghill for her input in the calculations related to
`HPV16 E6 positivity as a screening tool for oropharyngeal cancer.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
`The authors indicated no potential conflicts of interest.
`
`REFERENCES
`1. Castle PE: Teaching moment: Why promising biomarkers do not always
`translate into clinically useful tests. J Clin Oncol 32:359-360, 2014
`2. Kreimer AR, Johansson M, Waterboer T, et al: Evaluation of human
`papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin
`Oncol 31:2708-2715, 2013
`3. McShane LM, Altman DG, Sauerbrei W: Identification of clinically useful
`cancer prognostic factors: What are we missing? J Natl Cancer Inst 97:1023-
`1025, 2005
`4. de Martel C, Ferlay J, Franceschi S, et al: Global burden of cancers
`attributable to infections in 2008: A review and synthetic analysis. Lancet Oncol
`13:607-615, 2012
`5. Anantharaman D, Gheit T, Waterboer T, et al: Human papillomavirus
`infections and upper aero-digestive tract cancers: The ARCAGE study. J Natl
`Cancer Inst 105:536-545, 2013
`6. Ribeiro KB, Levi JE, Pawlita M, et al: Low human papillomavirus prevalence
`in head and neck cancer: Results from two large case-control studies in
`high-incidence regions. Int J Epidemiol 40:489-502, 2011
`7. Nanda K, McCrory DC, Myers ER, et al: Accuracy of the Papanicolaou test
`in screening for and follow-up of cervical cytologic abnormalities: A systematic
`review. Ann Intern Med 132:810-819, 2000
`8. Meijer CJ Berkhof J, Castle PE, et al: Guidelines for human papillomavirus
`DNA test requirements for primary cervical cancer screening in women 30 years
`and older. Int J Cancer 124:516-520, 2009
`
`Allan Hildesheim
`National Cancer Institute, National Institutes of Health, Bethesda, MD
`
`DOI: 10.1200/JCO.2013.53.2697; published online ahead of print at
`www.jco.org on December 23, 2013
`
`■ ■ ■
`
`US Food and Drug Administration
`Approval of Drugs for the Treatment
`of Prostate Cancer: A New Era
`Has Begun
`
`TO THE EDITOR: Before 2002, only three drugs were approved by
`the US Food and Drug Administration (FDA) for the treatment of
`prostate cancer (PC),1-3 as shown in Table 1, and only one of these
`approvals3 was based on a prolongation of survival from a randomized
`clinical trial (RCT). Since then, that number has risen to 12,4 with
`nearly all new drug approvals (NDAs) a result of a survival benefit that
`was documented in an RCT. What changed?
`In 1993, under the umbrella of the newly formed organization
`called the Prostate Cancer Foundation (PCF),5 formerly the Associa-
`tion for the Cure of Cancer of the Prostate (CaP CURE), leading
`scientific and clinical experts in the treatment of PC were assembled
`on a board whose mission was to use the resources of PCF to find a way
`to expedite new treatments and improve outcomes for men facing a
`
`diagnosis of advanced PC. Significant resources were initially pro-
`vided by the founder and chairman of this group, Michael Milken,
`who had been diagnosed with PC in 1993. This was followed by a large
`fundraising effort by PCF to perpetuate the revenue stream that was
`needed to support ongoing research initiatives. To date, $510 million
`have been raised for PC research, making this organization the largest
`private sponsor of PC research in the world, funding more than 1,600
`proposals at nearly 200 research centers in 16 countries.
`The NDA for zoledronic acid4 was issued by the FDA in 2002.
`This was the first agent shown to decrease skeletal-related events (eg,
`compression fractures) in an RCT of men with PC whose primary site
`of metastasis is the skeleton. The impetus for this RCT was a PCF-
`funded survivorship study that elucidated the relationship between
`declining bone mineral density and hormonal therapy use in PC.
`Next, work by clinical leaders in the PCF Clinical Consortium contrib-
`uted to our understanding that PC was sensitive to taxane-based
`chemotherapy regimens (ie, docetaxel; sanofi-aventis, Bridgewater,
`NJ)4; docetaxel was FDA approved in 2004 after the publication of two
`RCTs, one of which was led by a PCF clinical investigator and showed
`an improvement in survival in men with castration-resistant and
`metastatic PC. Moving forward, during this new era of NDAs for PC,
`
`362
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at INFOTRIEVE on June 19, 2014 from 216.33.62.90
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`002004
`
`AVENTIS EXHIBIT 2011
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Correspondence
`
`Fundedthebasicscienceresearchleadingtoour
`
`investigator
`ThelandmarkRCTwasledbyaPCF
`fundedinvestigatorstodiscoverenzalutamide.
`overexpressiondrivesCRMPC,leadingPCF-
`understandingthatandrogenreceptor
`
`PCFclinicalinvestigatorsthatledtoapproval
`enthusiasmforthephaseIIandIIItrialsledby
`actionofabiraterone,whichgenerated
`
`Fundedthestudythatdefinedthemechanismof
`
`conductedbyaPCFclinicalinvestigator
`thephaseIIIRCTthatledtoapprovalwas
`companythenturneditsattentiontoPC,and
`anexpertPCFclinicalinvestigator.The
`rightsondenosumabwithbonebiologistsand
`
`Broughttogetherthecompanywhohadpatent
`
`whichsipuleucel-Twasapproved
`RCTledbyaPCFclinicalinvestigatorafter
`immunotherapyinPC,leadingtothephaseIII
`FundedthephaseIIstudysuggestingefficacyof
`None
`
`Foundation;RCT,randomizedcontrolledtrial.
`Abbreviations:CRMPC,castration-resistantmetastaticprostatecancer;FDA,USFoodandDrugAdministration;LHRH,luteinizinghormone–releasinghormone;PC,prostatecancer;PCF,ProstateCancer
`
`None
`
`Survival
`
`CRMPCafterdocetaxel
`
`2013
`
`Radium-223
`
`Survival
`
`CRMPCafterdocetaxel
`
`2012
`
`Enzalutamide
`
`Survival
`
`CRMPCafterandbeforedocetaxel
`
`2012
`
`Abiraterone
`
`Skeletal-relatedevents
`
`Nonmetastaticprostatecancerbeingtreated
`
`withandrogendeprivationtherapy
`
`Survival
`Survival
`
`Asymptomaticorminimallysymptomatic
`CRMPCafterdocetaxel
`
`CRMPC
`
`None
`
`Notestosteroneflareaswith
`
`LHRHagonist
`
`AdvancedPC
`
`2013
`
`2010
`2010
`
`2008
`
`Denosumab
`
`Sipuleucel-T
`Cabazitaxel
`
`Degarelix
`
`afterwhichdocetaxelwasapproved
`todocetaxel,leadingtothephaseIIIRCTs
`investigatorsrevealingthatPCwassensitive
`
`FundedphaseIIstudiesrunbyPCFclinical
`
`Fundedsurvivorshipstudiesuncoveringdeclining
`Pre-PCF
`Pre-PCF
`Pre-PCF
`
`wasapproved
`thephaseIIIRCTafterwhichzoledronicacid
`bonemineraldensitywithHTuse,leadingto
`
`PCFContribution
`
`Survival
`
`CRMPC
`
`2004
`
`Docetaxel
`
`Skeletal-relatedevents
`Survival
`Qualityoflife
`Clinicalresponserate
`
`EndPointLeading
`
`toApproval
`
`MetastaticPC
`LocallyadvancedPC
`MetastaticPC
`MetastaticPC
`
`DiseaseState
`
`2002
`1998
`1996
`1981
`
`YearofFDA
`
`Approval
`
`Zoledronicacid
`GoserelinacetateLHRHagonist
`Mitoxantrone⫹prednisone
`Estramustine
`
`Drug
`
`Table1.ChronologicalSummaryofNewDrugApprovalsGrantedbytheFDAforTreatmentofProstateCancer,IncludingContributionbyPCFThatLedtoApproval
`
`www.jco.org
`
`© 2013 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at INFOTRIEVE on June 19, 2014 from 216.33.62.90
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`363
`
`

`
`Correspondence
`
`avoiding a testosterone flare became possible with a single agent in
`2008 with the approval of degarelix,4 a pure luteinizing hormone–
`releasing hormone antagonist. Then, in 2010 and 2011, three new
`agents were approved by the FDA for patients with PC: sipuleucel-T
`(Provenge; Dendreon, Seattle, WA),4 the first immunotherapy to
`stimulate the body’s immune system and prolong survival, remark-
`ably, in the absence of a prostate-specific antigen response; Jevtana
`(cabazitaxel; sanofi-aventis),4 another taxane-based chemotherapy
`that prolonged survival after disease progression during treatment
`with docetaxel; and finally, on September 16, 2011, the FDA granted
`approval for Xgeva (denosumab; Amgen, Thousand Oaks, CA)4 as a
`treatment to increase bone mass in patients who are at high risk of
`fracture from receiving androgen deprivation therapy for nonmeta-
`static PC. PCF’s sentinel contributions leading to FDA approval for
`two of these three agents are described in Table 1. During the last 2
`years, abiraterone acetate4 and enzalutamide,4 two novel forms of
`hormonal therapy that have been shown in the context of multi-
`institutional RCTs to prolong survival and improve patient-reported
`health-related quality of life for men with castration-resistant and
`metastatic PC, have been approved by the FDA and are now being
`tested in earlier stages of the disease by cooperative groups around the
`world. The expectation is that these agents will increase the probability
`of cure for men with newly diagnosed high-risk and nonmetastatic
`PC. PCF played the major role in defining the mechanism of action
`of these drugs, and in one case, supported the research that led to
`the discovery of the drug. In both cases, PCF clinical investigators
`led the RCTs that resulted in FDA approval, as detailed in Table 1.
`Finally, on May 15, 2013, the first radiopharmaceutical, radium-
`223,4 was found to prolong survival in men with PC and bone
`metastasis refractory to conventional hormonal therapy.3 By selec-
`
`tive uptake in bone and the short distance (⬍ 1 mm) over which
`the charged particle (ie, alpha particle) acts, damage to surround-
`ing hematopoietic tissues was minimal.
`Therefore, of the nine NDAs that occurred after 2002, six were
`driven by research and collaborations that existed because of PCF, as
`shown in Table 1. Today, with federal funding initiatives for cancer
`research continuing to decline, the need for novel approaches, such as
`that used by PCF to fund the research that lead to NDAs, are needed
`across all cancers.
`
`Anthony V. D’Amico
`Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA
`
`AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
`The author(s) indicated no potential conflicts of interest.
`
`REFERENCES
`1. Perry CM, McTavish D: Estramustine phosphate sodium: A review of its
`pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in
`prostate cancer. Drugs Aging 7:49-74, 1995
`2. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without
`mitoxantrone in men with hormone-refractory prostate cancer: Results of the
`cancer and leukemia group B 9182 study. J Clin Oncol 17:2506-2513, 1999
`in patients with
`3. Bolla M, Gonzalez D, Warde P, et al: Improved survival
`locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl
`J Med 337:295-300, 1997
`4. Leibowitz-Amit R, Joshua AM: The changing landscape in metastatic
`castration-resistant prostate cancer. Curr Opin Support Palliat Care [epub ahead
`of print on June 28, 2013]
`Foundation.
`5. Prostate Cancer
`b.5699537/k.BEF4/Home.htm
`
`http://www.pcf.org/site/c.leJRIROrEpH/
`
`DOI: 10.1200/JCO.2013.53.9528; published online ahead of print at
`www.jco.org on December 16, 2013
`
`■ ■ ■
`
`364
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2013 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at INFOTRIEVE on June 19, 2014 from 216.33.62.90
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.