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`Volume 142
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`July 1989
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`Number 1
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`The lournal of
`UROLOGY'
`
`officiat ]ournal of the American urological Association, Inc.
`Founded Inl9l7 By Hugh Hampton Young
`
`I
`
`The,Inurnal,:f rrt'nlnqy
`Irl4L fur {ihel
`UilIIVERSiTY OI' CIILII.'O'iNIR'
`SRN DIEIIO '. I.ILTRARIE$
`Recei.red on: r)'7-"Et)-S'l
`.v, 1'- Ft'b, 1917"
`
`Annual Meeting, American UrologicalAssociation, Inc., New Orleans, Louisiana, May 13-12 1990
`
`JANSSEN EXHIBIT 2018
`Mylan v. Janssen IPR2016-01332
`
`

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`The |ournal of
`UROLOGY'
`
`Editor
`JohnT Grayhack
`1120 North Charles Street
`Baltimorg Maryl and, 2L20L
`
`Associate Editor
`Tbrry D. Allen
`Dallag lbxas
`
`Section Editor
`Stuart S Howards
`Charlottesville, Virginia
`
`Associate Editor
`Jay Y. Gillenwater
`Charlottesville, Virginia
`
`Sestion Editor
`Patrick C. Walsh
`Baltimorg Maryland
`
`EDITORIAL BOARD
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`Mid-Atlantic
`Fatrick C. Walsh
`Baltimore Maryland
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`NewEngland
`Bernard Lytton
`New Haven. Connecticut
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`NewYor*.
`Michael J. Droller
`New York, New York
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`North Central
`Joseph W Segura
`Rochester, Minnesota
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`Northeaetem
`Abraham T. K. Cockett
`Rochest€r, New York
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`South Central
`Robert E. Donohue
`Denver, Colorado
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`$outheastern
`Floyd A. Fried
`Chapel Hill, North Carolina
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`Duncan E. Govan
`Stanford, California
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`BOARD OF CONSUI.,XAT\ITS
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`Marc Garnick
`Boston, Massachusetts
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`Bruce McClennan
`St. Louis, Missouri
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`WilliamMurphy
`,-Memphis, Tbnnessee
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`Ryoichi Oyasu
`Chicagq Illinois
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`Howardhllack
`Cheltenham, Rnnsylvania
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`WilliamU. Shipley
`Boston, Massachusetts
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`Lynwood H. Smith, Jr.
`Rochester, Minnesota
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`ColinWhite
`New Haven. Connecticut
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`FORMER EDITORS
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`HughH. Young
`1917-1945
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`J. A. Campbell Colston
`1945-1966
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`Hugh J. Jewett
`1966-1977
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`WilliamW. Scott
`1977-1983
`
`Herbert Brendler
`1983-1985
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`oo22, 5:l 4i I f,g / r42 I (x)89$02.()0/0
`THE JoTTRNAL oF LjRoLocY
`Clopyright rc) 1989 by Williams & Wilkins
`
`Vol. 142, July
`Printed in U.S.A.
`
`HIGH DOSE KETOCONAZOLE FOR THE TREATMENT OF
`HORMONE REFRACTORY METASTATIC PROSTATE CARCINOMA:
`16 CASES AND REVIEW OF THE LITERATURE
`STEVEN J. JUBELIRER exo THOMAS HOGAN
`From the Cancer Care Center of Southern West Virginia, Charleston Area Medical Center, Charleston, West Virginia, and Department of
`Medicine, Section of Hematology/Oncology, West Virginia Uniuersity, Morgantown, West Virginia
`
`ABSTRACT
`- We treated 16 patients who had hormone refractory metastatic prostate cancer with 400 mg.
`ketoconazole orally every 8 hours. None ofthe patients had an objecfive response, although 6 (37:b
`per cent) had stable disease (2 of whom had a subjective decrease in bone pain). Thl median
`duration of stable disease was 6.8 months (range 2to 72 months) and side effects were seen in 14
`patients. Nausea, vomiting or anorexia was noted in 10 patients, rash and pruritus in 2, transient
`abnormal liver function tests in 1 and transient pulmonary infiltrates in 1.
`Nine prior studies inv^estigating the use of ketoconazole in hormone refractory metastatic prostate
`cancer were leviewed. Only 1 complete response was reported. A partial t".pon"" was noted in 14
`pe_r cent-of the patients. Most of the patients had stable or progressive disease.
`High dose ketoconazole_as a single agent appears to have li-It"d rrs. in patients who have failed
`prior systemic therapy. (J. Urol., j42: 8g-91, 19g9)
`
`since prior
`
`least 4 weeks
`radiotherapy, hormonal therapy or
`chemotherapy.
`The pre-treatment diagnostic evaluation consisted of historv
`and physical examination, complete blood count, liver function
`tests, total,and prostatic acid phosphatase, chest x_ray and
`bone scan. Subsequent evaluation inciuded history and physical
`examination, complete blood count and liver function tests
`every 3 weeks, total and prostatic acid phosphatase and chest
`x-ray (if a measurable lesion was present) every 6 weeks, and
`bone scan every 3 months (or earlier if there was increasing
`bone pain). Serum prostate specific antigen anci serum testos_
`terone were not evaluated.
`Tumor response was evaluated according to National pros-
`tatic Cancer Project criteria,rs
`
`RESULTS
`Patient characteristics and responses to therapy are noted in
`table 1. None of the 16 patients had an objeciive response
`
`Adenocarcinoma of the prostate is androgen dependent in
`the majority of cases.' Most of the circulating androgens in
`man are secreted by the testes and adrenal glands.z Conven-
`tional management of advanced prostate cancer has been ori-
`ented towards reducing circulating androgens by orchiectomy
`or estrogen therapy to attempt to induce disease remission.
`However, although 75 per cent of the patients respond to the
`aforementioned therapy, disease progression is associated with
`a 6-month survival of only 50 per cent and median over-all
`survival of 2.5 years."'' In men with hormone refractory disease,
`cytotoxic chemotherapy has been used with minor success and
`often is associated with toxicity."
`Ketoconazole is an orally administered bioad-$ectrum an-
`tifungal agent that blocks gonadal and adrenal synthesis of
`androgens,'and has a direct antitumor effect on prostatic
`cancer cells in vitro.'' Thus, high dose ketoconazole may be of
`potential value in the treatment of metastatic prostate cancer.
`Several investigators have reported good initial tumor re-
`sponses with ketoconazole in patients with untreated advanced
`prostate cancer, with few treatment-related side effects.,i't
`The poor response of hormone refractory prostate cancer to
`alternative systemic therapy and the promising results of the
`aforementioned pilot studies stimulated us to investigate the
`activity of ketoconazole in our patients with estrogen or or-
`chiectomy refractory metastatic disease.
`
`MATERIAL AND METHODS
`We studied 16 patients with estrogen or orchiectomy refrac-
`tory metastatic adenocarcinoma of the prostate. Ten patients
`had undergone orchiectomy, 4 had received diethylstilbestrol
`and 2 had received orchiectomy plus diethylstilbestrol. Keto-
`conazole (400 mg. every 8 hours orally) was given to all patients
`according to the dosage used in prior studies.6-1"
`Eligibility requirements for this study included histologically
`proved adenocarcinoma of the prostate with measurable or
`evaluable disease, life expectancy of at least 3 months, perform-
`ance status of 2 or better (Eastern Cooperative Oncology Group
`criteria),tt no prior treatment with ketoconazole, no hepatic
`dysfunction (that is total bilirubin less than 2 me./dlj and at
`
`Accepted for publication January 30, 1989.
`
`Tlsr,p 1. Patient characteristics and results
`No. pts. entered
`16
`Median age (range)
`71 (48-84)
`2 (0-2)
`Median performance status (range)*
`Prior treatment:
`Hormonal therapy only:
`Orchiectomy,4
`Diethylstilbestrol, 2
`Radiation and hormonal therapy:
`Orchiectomy,5
`Diethylstilbestrol, 2
`Orchiectomy plus diethylstilbestrol, 2
`Chemotherapy (cyclophosphamide) plus ra-
`diation plus hormonal therapy (orchiec
`tomy)
`Disease extent:
`Bone only
`Measurable sites:
`Lung, 2
`Lymph node, 2
`Response:
`Complete
`Partial
`Stable (decreased bone pain)
`Progression
`* Eastern Cooperative Oncology Group criteria.
`
`6
`
`9
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`I
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`72
`I
`
`0 06
`
`10
`
` (2)
`
`

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`JLTBELIRER AND HOGAN
`
`TABLE 2. Summary of studies on ketoconazolc in preuiously treated patients with ntetastatic prostate cancer
`Range of Response
`Duration (mos.)
`
`Response (No. pts.)
`
`Reference
`
`Total
`No. Pts.
`
`Complete
`
`Partial
`
`Subjective
`Improvement
`(decrease in bone pain)
`
`Conplete
`
`Partial
`
`5 3
`
`-8
`
`g-n
`3-4
`
`t-u
`
`7-12
`3-6
`3-4
`
`5
`
`2l
`IJ
`
`11j
`
`,
`
`oo
`
`0
`
`0
`
`11
`Pont8
`401*
`Vanultsel and associatese
`3900
`Debruyne and associatesro
`2202
`Johnson and associatesrt
`2015+
`Williams and associatesl2
`1508
`Bredt and associatesr3
`1404t
`Van Cangh and Opsomerr'
`1503
`Havlin and associatesru
`L201
`MacKintosh and associatest"
`1600
`Present study
`rEE T(o.se) u04.3')
`Totals (%)
`* National Prostatic Cancer Project criteria used for response.
`i European Organization for Research on Treatment of Cancer criteria used for response.
`f British Prostate Group criteria used for response.
`
`oa+
`7
`
`4 6
`
`10
`6*
`65 (sol
`
`TABLE 3. Side effects in patients treated with hetoconazole
`Nail
`Gastrointestinal Skin
`Dystrophy
`
`Cardiovascular
`
`Abnorlnal
`Liver Function Tests
`
`Fatigue, Lethar$'
`
`2
`10
`
`I
`
`Ia I 8
`
`- \
`
`_ =2
`
`94
`
`2-
`11
`
`4
`
`3 8
`
`14
`10
`11
`
`5 6 5 7
`
`10
`7s
`
`Reference
`
`J:f,i
`l1
`PontB
`22*
`Vanu5'tsel and associatese
`aq
`Debruyne and associatesro
`22
`Johnson and associatesrr
`20
`Williams and associates"
`l5
`Bredt and associatesrs
`Van Cangh and Opsomer"
`L4
`ID
`Havlin and associatesrs
`t2
`MacKintosh and associatesr6
`l6
`Present study
`Totals
`1E6
`* Includes treated and untreated patients'
`t Two patients had adrenal insufficiency.
`
`I
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`t
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`!.
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`3). Hepatotoxicity in these studies was rarer and usually re-
`solved quickly after stopping therapy.
`In summary, high dose ketoconazole as a single agent appears
`to have limited use in patients who have failed prior hormonal
`therapy for advanced prostate cancer. The use of this drug is
`limited further by its frequent side effects and high cost (ap-
`proximately $9 to $10 daily for 400 mg. 3 times per day).
`
`REFERENCES
`
`1. Lyss, A. P.: Systemic treatment for prostate cancer. Amer. J. Med.,
`83:1120,1987.
`2. Sonino, N.: The use of ketoconazole as an inhibitor of steroid
`production. New Engl. J. Med., 317: 812, 1987.
`3. Tannock, I. F.: Is there evidence that chemotherapy is of benefit
`to patients with carcinoma of the prostate? J. Clin. Oncol., 3:
`1013, 1985.
`4. O'Brien, W. M. and Lynch, J. H.: Current approaches to prostate
`cancer. Hosp. Pract., 23: 143, January 15, 1988.
`5. Trachtenberg, J. and Eichenberger, T.: Extra-hormonal effects of
`imidazoles on human prostatic cancer. J. Urol, part 2, L37:.
`115A, abstract 45, 1987.
`6. Trachtenberg, J., Halpern, N. and Pont, A.: Ketoconazole: a novel
`and rapid treatment for advanced prostatic cancer. J. Urol., 130:
`r52, 1983.
`7. Allen, J. M., Kerle, D. J., Ware, H., Doble, A., Williams, G. and
`Bloom, S. R.: Combined treatment with ketoconazole and lutein-
`ising hormone releasing hormone analogue: a novel approach to
`resistant progressive prostatic cancer. Brit. Med. J., 287:.1766,
`1983.
`Pont, A.: Long-term experience with high dose ketoconazole ther-
`apy in patients with stage D2 prostatic carcinoma. J. Urol., 13?:
`902,1987.
`Vanuytsel, L., Ang, K. K., Vantongelen, K., Drochmans, A., Baert,
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`prostatic cancer: feasibility and treatment results. J. Urol., 137:
`905, 1987.
`Debruyne, F. M. J., Witjes, J. and Metnbers of the Dutch South-
`
`8.
`
`q
`
`10,
`
`although 6 (3?.5 per cent) had stable disease, of whom 2 had
`subjective decrease in bone pain. The serum acid phosphatase
`was elevated in 12 patients but decreased in only 3 in response
`to ketoconazole. In the 3 patients in whom a palpable prostatic
`nodule could be evaluated no response to ketoconazole was
`noted. The median duration of stable disease was 6.8 months
`(range 2 to 12 months).
`Side effects were seen in 15 patients. Nausea, vomiting and
`anorexia were noted in 10 patients. One patient had abnormal
`Iiver function tests (for example serum glutamic oxaloacetic
`transaminase of 364 and total bilirubin 6.7) necessitating drug
`withdrawal 4 days after commencing therapy. These abnor-
`malities resolved after 1 week of treatment. Two patients had
`pruritus and an erythematous rash that resolved when the drug
`was temporarily discontinued. When these patients restarted
`therapy no further skin complications occurred. Severe dyspnea
`and pulmonary inberstitial infiltrates on chest x-ray occurred
`in 1 patient 4 days after starting treatment. These abnormali-
`ties subsided after 14 days offtherapy.
`
`DISCUSSION
`Table 2 compares prior studies with the present series.s 16
`The dose of ketoconazole used in all studies was 400 mg. every
`8 hours. In 3 of the studies the dose was reduced to 200 mg.
`every 8 hours in some patients.l0 r2 Only 1 complete response
`has been reported. Partial responses have been infrequent (14.3
`per cent over-all). In those studies in which it was noted the
`duration of response was short-lived, ranging from 3 to 13
`months.e' Ir' r3-r5 Most patients have had stable or progressive
`disease. A subjective improvement in bone pain was noted in
`some patients despite a Iack of objective response. In 4 of the
`studies a further significant decrease in serum testosterone
`concentration during ketoconazole therapy was noted.s r('r?
`Side effects have been frequent, most commonly nausea and
`vomiting @2 per cent over-all), fatigue, lethargy and rash (table
`
`l I
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`

`

`KETOCONAZOLE-HORMONE REFRACTORY METASTATIC PROSTATE CARCINOMA
`East Cooperative Study Group: Ketoconazole high dose (H.D.)
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`15. Havlin, K., Jordan, V. C._Cummings, K., Messing, E. and Trump,
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`D. L.: Ketoconazole (KC) in advanced prostalic ."".", (CuFj
`11. Johnson, D. E., Babaian, R. J., von Eschenbach, A. C., Wishnow.
`refractory to initial hormonal therapy: a clinical and endocrino-
`K. I. and Tenney, D.: Ketoconazole therapy for hormonally
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`refractive metastatic prostate cancer. Urology, 31: 182, 1g88.
`1987.
`12. Williams, G., Kerle, D. J., Ware, H., Doble, A., Dunlop, H., Smith,
`16. MacKintosh, F. R., Nicks, C. C., MacKintosh, C. L. and Hall, S.
`C., Allen, J., Yeo, T. and Bloom, S. R.: Objective responses to
`W.: High dose ketoconazole (K) therapy for metastatic prostatic
`ketoconazole therapy in patients with relapsed progressive pros-
`cancer (MPC): a clinico-pharmacologic phase II study. proc.
`tatic cancer. Brit. J. Urol., 58: 45, 1986.
`Amer. Soc. Clin. Oncol., 6: 101, abstract CaT. 1982.
`13. Bredt, A., Brughera, A., Girey, G., Schottinger, J., Helman, N. and
`17. Oken,-M. M., Creech, R. H-.,,Iormey, D. C., Horton, J., Davis, T.
`Weisz, J.: Ketoconazole therapy for metastatic prosrare cancer
`E., McFadden, E. T. and Carbon, p. p.: Toxicity'und re.porrse
`resistant to prior hormonal treatment. Proc. Amer. Soc. Clin.
`criteria of the Eastern Cooperative Oncology Group. Amer. J.
`Oncol., 5: 99, abstract 385, 1986.
`Clin. Oncol., 5: 649, 1982.
`14. Van Cangh, P. J. and Opsomer, R. J.: High dose ketoconazole as
`18. Torti, F. M.: Response criteria in urologic malignancies. Recent
`secondary form of therapy in metastatic prostatic cancer. J.
`Results Cancer Res., 8E: 50. 19g3.
`
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