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`JOURNAL OF CLINICAL ONCOLOGY
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`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Flutamide Versus Prednisone in Patients With Prostate
`Cancer Symptomatically Progressing After Androgen-
`Ablative Therapy: A Phase III Study of the European
`Organization for Research and Treatment of Cancer
`Genitourinary Group
`
`By 5. D. Fossa, P. H.Th. Slee, M. Brousi, S. Horenblos, R. R. Hall, J. W. Hetherington. N. Aoronson. L. de Priiclc. and L. Collette
`
`flag-pose: Time to progression {'lTP], overall survival.
`and quality of life {0].} were compared in patients with
`hormone-resistant prostate cancer [HRPC] treated with
`prednisane {5 mg orally. foUr times a day} or flutamide
`[250 mg orally, three times a day].
`Patignl's—agd Methods: Symptomatic patients were
`randomized to receive either prednisone [10] patients}
`or flutamide [100 patients]. Subiective response was
`assessed based on performance status. the use of an-
`algesics, and the need to apply alternative palliative
`treatment. Prostate-specific antigen lPSAJ-based bio-
`chemical response (a 50% reduction of baseline PSA}
`was recorded. At baseline and at 6-week intervals
`during follow-up, patients completed the European Or»
`ganization for Research and Treatment of Cancer Qual-
`ity of Life Questionnaire C'SO.
`fiesults: There was no difference between the
`groups in median TI'P [prednisone, 3.4 months: flut-
`omide. 2.3 months] or overall survival [prednisone,
`10.6 months; fiutamide. 11.2 months].
`In the pred-
`
`nisone group. 56% of the patients experienced a subs
`iective response, compared with 45% in the flutamide
`group (P = .13]. The median response duration was 4.8
`months for prednisone and 4.2 months for flutarnide. A
`biochemical response was observed in 21% and 23% of
`the prednisone and flutamide groups, respectively.
`Gastrointestinal toxicity was the reason for trial discon-
`tinuation in seven patients receiving flutamide and two
`patients receiving prednisone. The GI. assessment pa-
`rameters favored the use of prednisane with statisti-
`cally significant differences in pain, fatigue, role func-
`tioning. appetite loss, gastrointestinal distress, and
`overall at.
`In symptomatic HRPC, treatment with
`Concflsn:
`prednisone or llutamide leads to similar rates of TTP
`and overall survival and no difference in subjective or
`biochemical response. The GL results favor the use of
`low-cost prednisane in patients with HRPC.
`J Clin Oncol 19:62-71. o 200! by American
`Society of Clinical Oncology.
`
`DEF-ABIRA-0000103
`
`will progress in 60‘}? to 80‘}?- ol‘ the responding patients
`during the first 3 y‘ars alter the start of treatment.l 3 in a
`recent meta—analysis.
`the addition of an antiandrogen to
`initial
`androgen SUppression {total androgen blockade
`[TABIJ was shown to have a limited effect. if any at all.4
`11' the malignancy progresses despite androgen ablation
`after castration.
`three biologically dil'l‘erent subgroups ol‘
`hormone—resistant prostate cancer tHRI’C) can be identified.
`l. HRPC‘ with t‘t’j‘lrllt‘ttl rtntt'rogcn .t‘ctts‘itit-r'ty. The cancer
`cells are still sensitive to residual circulating androgens
`produced mainly in the adrenal glands. and the malignam.‘_\.’
`may respond beneficially if the effect ol‘ these. remaining
`androgens is removed. This can be achieted by medical
`suppression of adrenal corticosteroid production or. if nol
`used previously. by the application of antiandrogens which
`block the androgen receptors of the cancer cells.
`2. Hot'titwtc—.rett.tltl1-'r HRPC: The disease is no longer
`andl'ogen—sensitive. but
`it may still be inllucnced by
`hormones such as tnedroxy-progestcrone acetate or high—
`dose estrogens.
`
`to 80% of patients with
`AI’PROXIMA'I‘ELY 709::
`advanced prostate cancer respond initially or remain
`stable when treated by medical or surgical castration. but in
`20% to 30%. of the patients.
`the malignancy progresses
`despite primary androgen deprivation. In addition. disease
`
`
`
`()trt'tllogr tttttt Rtalintltt’rttltrt',
`From .ltllt' Depurmmtt at Medical
`Norwegian Rttcllttttt Hm‘pitttl.
`(lilo. NUt'lt't’llt‘f St Antonlm llm‘pttttl.
`.-Wmort{ceitt. (ltttl .-'\-'etttert’tnttls {"tttrt'er Hospital. .‘itltwtl TH” chtttt't’n-
`lltic’k Hmpitttt'. :ittl.\'fc‘t‘cltttit. the Nrtltrrttttttls.‘ .S'tttt h’ttjtitrlc. ti-tilutt. ttrtlr.‘
`Ft't’c’rtttitt
`.llm'pt'tttl.
`.-Ve’tl't'tt.\'tlt’.
`tttttl Princess Nirvttl Hospital. Hull.
`Urtttctt Kittettwtt: and European (try:tniztttiturtirr tit-search mat 't'rmt—
`tttc’tll tit'tTtmcer Dttttt (‘rrttrra Brussels. Belgium.
`Submitted March 24. EENJI‘J: accepted July l 5'. Eliot}.
`through 5 Ullt
`.S'ttppurtrrl
`lay grunts
`no. Stilt)
`(ft-1H 4834!
`(It’ll l Hamil/lilo!” tllt’ .’\"tttt'ott.rtl ("(tttt't’t'
`.ltt.rtt'ttttt’.
`lit’tltt'n‘tltt. till).
`tile contents til-Ilth article are solely the t't”.i'}'lr’Jtl.\'lIl?lllll_\' of the authors
`ttrttl do not necessarily represent the official
`t'it-n'r of tire National
`(\(Hlt‘c‘l' ltls'titttl't’.
`
`(ff.
`.f)t‘l"tll'l."lt¢"ttl
`l). Frtn'ti. Ml).
`t'c’ttt'llll rt'qttt’n'tn' to .‘lttpltt't’
`titlrlt't’s‘a'
`.'\"r’!t'll‘l£’§,’ltlli Rtttlltttti Hm‘pltttl.
`fzrtflf’l'tl('Jrl'tllf.".\'t.’{’l'l 70. Hill}
`Oncology,
`Ulnar. Nttt‘it'tit'.‘ t’tttttll .t'.tl._lltt.¢.s'u(t?l'ltlttttttt’tl.ttltutn.
`('3' 2l’lt}.l by .titttt’t'lt'tttt Society tfl Clinical Oncology
`EJ1732-ltS'.iA?‘f}lt’l9lll-63
`
`3. i-‘ltltlt‘ttgt’tt- rtitil ltormmtc-refractory HRPC: The disease
`has become completely lionnone—insensitit-e. Chemotherapy
`or int-'esligational treatment modalities may he considered.
`
`62
`
`Journal of Clinical Oncology, Voi l9, No l
`
`lJonuary l], 200i: pp 62-7l
`
`DEF-ABIRA-0000103
`
`MYLAN PHARMS. INC. EXHIBIT 1100 PAGE 3
`
`

`

`FLI "AMIDE v PREDNISONE FOR ADVANCED PROSTATE CANCER
`
`..t the individual patient with HRPC. most often a mixture
`or these three cell populations is present
`in unknown
`proportions. Patients witlt prostate cancer who progress
`alter primary androgen deprivation present with increasing
`somatic and psychologic distress.
`including pain due to
`bone metastases, anemia. and fatigue. Ten percent to 20% of
`in patients develop inicturition problems caused by a
`growing primary tumor. Radiotherapy and analgesics can
`relieve local symptoms. but effective systemic therapies are
`n .- :ded to slow down or reverse the progressive develop—
`merit of the malignancy.
`Several end points can be considered during the treatment
`or HRPC: overall survival.
`time to progression ('I‘TP).
`objective response. physician-assessed subjective response,
`and quality of life (QL).
`The evaluation of objective response according to the
`World Health Organization (WHO) criteria" is problematic
`b-.--cause only 10% to 20% of the patients have easily
`measurable metastatic lesions. Objective response based on
`assessment of bone scans is also difficult due to frequent
`i:.terobserver and interexamination variation." Relief of
`metastatic bone pain and improvement of the patient’s
`general condition are the most
`important parameters of
`silijcctive response in patients with HRPC and should be
`recorded routinely. During recent years. patient—based mon-
`itoring of QL has been introduced into clinical oncology,
`and appropriate questionnaires have been developed? Bio—
`chetnical response based on measurements of serum pros—
`late-Specific antigen (PSA) should be monitored as a sepa—
`rate entity. A recent consensus meeting has published
`guidelines for the evaluation of PSA-based response. thereby
`enabling more uniform reporting of observed changes.8 In
`:‘tldltion to the above methodologie problems, trials of chemo-
`therapy to treat HRPC have been hantpeted by relatively
`.requent
`toxicity problems in the elderly prostate cancer
`patients who often present with major eomorbidity.
`in this
`situation.
`it seems reasonable to influence the disease widi
`
`hormones as long as possible, because hormonal manipulation
`is easily applied and has limited toxicity.
`Surgical and medical adrenalectomy, the latter by hydro-
`..'ortisone or prednisone. has been used in the treatment of
`l—lRPC for many years)” to suppress the adrenal production
`of androstenedione attd dehydroepiandrosterone. Up to the
`-:ariy 1990s, however. only a few well-designed phase I[ or
`III studies were published that evaluated medical adrenal-
`cctomy in HRPC.
`Flutarnide exhibits antiandrogenic effects by binding to
`the cellular androgen receptors and thus reducing the cell‘s
`androgen uptake. This drug has been used extensively in
`previously untreated patients, as a part of TAB or as
`monotherapy. ' ‘3‘” In limited series, flutamide has also been
`
`63
`
`evaluated in the treatment of HRPC. with subjective re—
`
`sponse rates of IS% to 30%.11'3
`In [990.
`the European Organization for Research and
`Treatment of Cancer (EORTC) Genitourinary Group initi-
`ated a phase Ill study to compare the effectiveness of
`predttisone and llutamide as secondary hormone manipula—
`tion in patients with metastatic HRPC. At
`that time. the
`expectation was that Hutamide would be more effective than
`prednisone because of its specific activity in the cancer cell.
`The present report represents the final analysis of this study.
`
`PATIENTS AND METHODS
`
`Patients with histologically confirmed prostate cancer were eligible
`for the trial
`if they fulfilled the following criteria: (1) presence of
`symptomatic metastatic disease that had progressed after medical
`castration with luteinizing Immune-releasing hot-meme {LHRH} alta—
`logs tnot estrogens} or bilateral orchiectomy. The pretrial serum
`testosterone level had to be within the range of the institution‘s
`castration levels.
`in the present study, symptomatic disease implied
`cancer-induced deterioration of the patient‘s general condition andfor
`painful. progressive metastatic disease with or without
`the use of
`analgesics, with or without complete pain relief: (2,1 WHO performance
`status of 0 to 3: t3: no previous use of prednisonc. flutamide. or any
`other oral antiandrogen. but patients were eligible if they had received
`an antiattdrogen transiently {for a maximum of 4 weeks) during their
`LHRH treatment in order to prevent a flare reaction; [4] Ito previous
`systemic anticancer treatment. except
`the above primary hormonal
`manipulation: and {5} certainty of clinical disease progression after
`prior surgery or previous radiotherapy. The patients were not allowed
`to receive radiotherapy at the time of trial entry.
`Patients with a second primary tumor {except basal cell skin cancer}.
`serious cardiovascular problems. or insulin—dependent diabetes mellitus
`were ineligible for the trial. as were those who were unable to comply
`with regular follow—up.
`The trial was approved by the institutions‘ local ethical committee.
`and patients provided written informed consent before randomization.
`The trial was open for patient entry from January [992 to March i998.
`In October 1995. an independent data—monitoring committee approved
`continuation of the trial without modification. At the time of the present
`analysis, the median follow-up was 33d]I days.
`
`Trial Design
`Patients were randomized to receive either fiutamide 250 mg orally
`three times a day {the F group) or prednisone 5 mg orally four times a
`day {the P group). Patients receiving LHRH analogs continued with this
`treatment.
`
`All patients were examined for acute toxicity 3 weeks after trial
`entry. Response was evaluated at 6-week intervals from the start of
`treatment. Patients had to remain in the trial for at least 6 weeks to be
`assessable for response. They were otherwise included in the analysis
`as "non-assessable." Patients who progressed during the first 6 weeks
`were included in the progression category. Patients remained on the
`trial until subjective progression or unacceptable toxicity was recorded
`or until
`they wished to discontinue participation for any reason.
`Therapeutic interventions in patients who had gone off protocol
`treatment were chosen by the individual clinical
`investigator. All
`patients were followed until death.
`
`DEF-ABIRA-0000104
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`

`Fossil ET Al
`
`"No change" was defined as an unchanged pain score
`No change.
`with less than a 35% reduction in the prescribed daily analgesic dose as
`compared With the pretreatment situation. and unchanged performanct-
`status.
`
`l’rognrssion was evaluated relative to the best condi-
`Progressiott.
`titttt. observed at start of treatment or obtained during treatment.
`Progression was determined to have occurred if patients met at leas
`one of the following conditions: increase of the pain score by at least
`one level. increase ofthe daily analgesic dose by at least 25%. any neeo
`to give addilional pain treatment. such as radiotherapy. and WHO
`performance status deterioration by at least one level.
`Duration of subjective response was calculated from trial entry to the
`date of progression. Bioclteittical response was defined as a decrease ot
`the serum PSA level by 2 50% as compared with the baselinr
`value.”"" However. Ito duration was required for biochemical response.
`Statistics
`
`The main end points for this trial were TTP and duration of survival.
`Sincc virtually all patients entered onto the trial were expected to
`progress and die during follow—up. either of these end points could be
`chosen for calculating the sample sire. A total of I92 patients followed
`until death were required in order to detect a difference of 50% in the
`median duration of survival between the two treatment arms (lmin ‘-'
`months with predtiisonc to |3.S months with llutamidet. using a
`two-sided log—rank test [alpha — 0.5. beta = 0.20). Two hundred
`patients were sufficient to detect a difference of 20% in the response
`rate in the two arms {alpha = 0.05. beta = 0.20).
`Given an anticipated median survival time of 8 to 10 months (based
`on the published literature on Hle and the number of available
`observations at each subsequent assesslttent point. the Q1. analysis was
`restriclcd to the 6-month period following entry onto the study. Means
`and confidence intervals were calculated for the QL scores of both
`treatment groups
`at each assessment poiitt. yielding a series of
`descriptive profiles that could be displayed in graphic form. In order ir-
`adjust for multiple comparisons over' time. 99% confidence intervals
`were calculated to maintain an overall 95% confidence interval for each
`QL outcome, A linear mixed model analysis of variance was used that
`accounts for serial correlations between observations. as well as for
`intennittent missing forms. The main effects of treatment and time
`were tested on a reduced model [without an interaction term} whenever
`the interaction effect was found not to be statistically significant.
`The intention-to-treat principle was followed in all statistical analy—
`sis tie. including ineligible altd nonassessnble patients in the analysis
`and considering patients in the treatment group they were allocated to
`by randomization].
`
`RESULTS
`
`Patients
`
`A total of 201 patients were randomized to receive
`prednisone (IOI patients) or flutamide {100 patients, Table
`I). Presumed prognostic factors and coinorbidities were
`equally distributed between the two treatment groups (P 3‘
`.05). Almost all patients used analgesics. with approxi—
`mately 25% regularly using narcotics for pain level 4. The
`median number of hot Spots on bone scans was 12 in both
`groups. and approximately 25% of the patients displayed
`supei‘scans. The initial PSA level was elevated to more than
`
`64
`
`El
`trial entry and at each follow—up visil. patients underwent
`At
`clinical examination. including assessment of pain using a five-point
`scale (level I]. analgesiCs not required: level I. ttonnarcotic analgesics
`occasionally irx'uired:
`level 2. nonnarcot'tc ztnalgestcs regularly re—
`quired;
`level 3. oral or parenteral narcotic analgesics occasionally
`required;
`level 4. oral or parenteral narcotic analgesics regularly
`required). Types and doses of the prescribed analgesics were recorded.
`A chest x—ray and radioisotope bone scan were mandatory: other
`I'adiolugic examinations were optional. "Super-scan" was defined as 2
`7'59}.- mctastatic involvement of the central skeleton.
`Blood samples were taken for analysis of hemoglobin. WBC count.
`and llironibocytes. together with the determination of PSA. alkaline
`phosphatase. creatittitte. liver enzyme. and testosterone levels.
`Clinical examinations and blood tests were repeated at each fol-
`
`low-up
`t. Patiettts' performance status. weight. and degree of
`vomiting and diarrhea were recorded using the WHO criteria for
`toxicity} The performance of other tests was left to the discretion of the
`clinical investigator.
`
`
`
`Quality of Mfr:
`
`QL. as assessed by the patient. was a secondary and point of the
`study. but
`there was no a prior-i stated hypothesis. Thus.
`the Q].
`evaluation was exploratory, with global QL representing the primary
`variable.
`
`At trial entry and at each follow-up visit. patients were asked to
`complete the EOR'I‘C Quality of Life Questionnaire {QLQ} (2—30
`{version LU).7 The QLQ (3—30 is a 30-item questionnaire that was
`developed to assess a range of physical. emotional. and social health
`issues relevant to a broad spectrum of cancer patients.
`[I has been
`shown to be reliable and valid in a wide range of patient populations
`and trcattttent settings and is currently being used in a large number of
`oncology clinical trials. The questions are organized into a number of
`multi—item scales and single-item symptom measures (live functioning
`scales [physicaL role. cognitive. emotional. and sociall. three symptom
`scales lfatigue. nausea and vomiting. and pain}. and six single items
`lassessing dyspnea. sleep disturbance. appetite loss. constipation.
`diarrhea. and financial impactll. The last two questions ask patients to
`rate their overall health and Ql... The QLQ C-3ll was supplemented by
`three questions pertaining to analgesic use (Did you take any riiedica-
`tion for pain? It so. how much did it ltelp‘.’ Have you had pain despite
`the use of analgesics?) All scales and single—item measures were
`linearly transformed to a U to IOU scale.“ For the funclioning scales
`and the global QL scale. a higher score represents a higher level of
`funciioninngl.; for the symptom measures. a higher score conesponds
`to a greater degree of symptoms.
`
`Response Criteri‘rt
`
`Objective response was not assCSScd. On the basis of the physician's
`evaluation,
`three categories for subjective response were defined:
`response. no change. and progression. No minimum duration of
`response was required.
`Response. At least one of the following three conditions had to be
`fulfilled: {1} reduction of the pain score (WHO criteria) by at least one
`level. with no deterioration of performance status: {2: unchanged pain
`level and reduction of the prescribed daily dose ofanalgcsics by at least
`25% as compared with the pretreatment situation. with no deterioration
`of performance status: and [3} inlpmvement of the WHO performance
`status by at least one level without either an increase of the daily dose
`of analgesics by 3: 25% or art increase in the pain level.
`
`DEF-ABIRA-0000105
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`

`

`HUT,“ tv’tiDE v PREDNISONE FOR ADVANCED PROSTATE CANCER
`
`65
`
`
`Table 2. Reasons for Going OH Study and Type of Clinical Toxicity
`Tobie 1. Patient Demographics and Clinical Data
`Prednisone
`Fiulamide
`Prednisone
`FILrchmide
`
`Group
`Group
`lolai
`Group
`Group
`Total
`
`
`
`
`
` Reason in 10!] in - 100i [N = 20]!
`
`
`
`201
`A
`72
`19
`
`i5
`5i
`77
`9
`49
`
`i0]
`2
`72
`l9
`
`6
`29
`35
`5
`26
`
`lot)
`2
`72
`21
`
`9
`2?
`42
`11
`23
`
`:‘soiienis
`No.
`ineligible patients, n
`Mac'.
`:-- age, years
`Median time since castration, monlhs
`min“. pain score
`0
`|
`i?
`3
`a.
`WHO perionnonce status
`2?
`13
`i4
`C"
`i 16
`57
`59'
`i
`4?
`23
`24
`p
`i l
`7
`d
`3
`12
`1'2
`12
`Me..";in no. oi hot spots
`43
`3?
`50
`Initiai PSA level, median, ng/mL
`i7
`ii
`6
`- 2.5 X N
`20
`i3
`7
`2.5i-i0 K N
`27
`10
`i7
`- I-25 X N
`oi
`33
`28
`296-100 .M N
`53
`24
`29
`. 100 .5; N
`
`Missing 23 14 9‘
`
`
`Abbreviation: N, normal.
`
`172
`86
`36
`Progression only
`i0
`7
`3
`Toxicity only
`6
`2
`4
`Progression v toxicity
`3
`ii
`2'
`Other
`4
`2
`2
`inaiigible
`1
`0
`1
`Unknown
`
`Death [due to inter-current disease! 5 3 2
`
`
`NOTE.
`In the prednisane group, the clinical toxicities were gastrointestinai
`ldyspepsia, peptic ulceri tn - '2}, cardiovascular [Fluid retention, deep venous
`Il'rrombosis} [n = 3], Cushing’s syndrome in = i], and unspecified In - i}. In
`liie liulomide group, they were gastrointestinal lnouseo, vomiting, and diar-
`rhea] In 2 7} and cardiovascular lrnyocordiac iniorclion] In 1 2].
`'Patients reiused trial participation immediately ailer randomization.
`‘i'Biochemicoi PD, protocol violation.
`
`retention. venous thrombosis} were observed, and in two
`patients, increasing dyspepsia or peptic ulcer caused treat-
`ment discontinuation.
`
`No grade 3 or grade 4 lcukopenia or [l'll‘Ol'l'lboclepttl'iia
`was observed. except
`in one patient in the F group. This
`patient developed grade 4 thrombocylopenia, which most
`probably was related to disease progression. There was no
`difference between the two groups in liver function during
`the trial period.
`
`Response
`
`Subjective response was not assessable in 10 patients. In
`56% of the available patients from the P group and 45 5/5 of
`the F group. a subjective response was recorded at least at
`one follow—up visit (P = .IS: Table 3).
`In 15% of the
`patients in the P group and 2] '54.- of the F group, disease had
`progressed at the time of their first response evaluation. if a
`minimum response duration off: weeks had been required in
`the original protocol,
`the subjective response rate would
`have been 49% for the P group and 34% for the F group.
`Subjective responses lasted for 4.8 months (median) in the
`P group and for 4.2 months in the F group (P: 0.21).
`A biochemical response was observed in 21% of the
`patients in the P group and 23% of patients in the F group.
`Responding patients from the P group had significantly
`higher baseline PSA values than those from the F group
`(Table 4). in nine of the patients in the P group and ID in the
`F group. the Z 50% PSA reduction was confirmed after 4
`weeks. Both subjective and biochemical
`responses were
`available in 180 patients.
`When both groups were combined, there was a Significant
`association between PSA response at anyr lime and subjec-
`tive response at any time (Table 5) {P 4 .001]. However,
`
`In“ times the upper limit of the normal range in 29% of the
`P—group patients and 24% of the F~group patients.
`Fwo patients in each group were finally deemed to be
`ineligible [prior treatment with prednisone. l; no metastases
`at
`trial entry.
`1; palliative radiotherapy at
`the time of
`randomization.
`I;
`testosterone level above the castration
`range,
`l).
`
`T-n-rtrnwm Compliance and Side Effi’r‘rs
`
`No attempt was made to regularly monitor :1 patienl‘s
`daily intake of prednisone or fiutaniide. except for the
`I';'..‘=.Jr(.iitlg of dose reductions. prescribed at
`the 6—week
`follow—up visits. Treatment-related modifications of drug
`doses {without drug discontinuation} were recorded in two
`|.‘- :tients from the P group (reduction to Ii] mg daily) and in
`eight patients from the F group. Serious nonhemalologic
`side effects (grade 3 or 4} contributing significantly to trial
`1
`.-attnent discontinuation were recorded in seven patients
`from the P group and nine patients from the F group (Table
`L}.
`in the F group. gastrointestinai side effects (diarrhea.
`it-iusea) were most frequent. Two patients had a myocardial
`infarction while receiving flutamide treatment. Two patients
`in the P group refused triai participation immediately after
`randomization and were given flutamide.
`in three patients
`from the P group. cardiovascular side effects (edema. fluid
`
`DEF-ABIRA-0000106
`
`MYLAN PHARMS. INC. EXHIBIT 1100 PAGE 6
`
`DEF-ABIRA-0000106
`
`MYLAN PHARMS. INC. EXHIBIT 1100 PAGE 6
`
`

`

`66
`
`Parameter
`
`Response'.‘l
`No chonge‘l‘
`ProgreSsioi-il
`Early death, malignant disease
`Early death, other cause
`Not ossesmble
`Ineligible
`
`56
`21
`16
`1
`I
`11
`2
`
`£15
`29
`21
`0
`1
`2
`2
`
`
`Table 5. Subiective and Biochemical Response lot any time!
`Table 3. Efficacy Evaluation
`Prednisone
`Flutamide
`Na. d Pane”; With
`No. of Patients With Biochemical Response
`Group
`Group
`
`Subiective Response Tore-E- No Yes
`
`
`ln = 101]
`In -- 100]
`No
`71
`1 0
`3 1
`Yes
`65
`34
`99
`
`136 AdTotal 18?
`
`
`NOTE. P = .001 for the correlation.
`
`rossA ET AL
`
`Total
`{N = 2011
`
`101
`50
`3?
`l
`'2
`6
`4
`
`4,6
`4.2
`21.8?
`Duration of response, monll'ls
`2.9
`2.3
`341*
`Progression-flee survival, monllws§
`
`Overall survival. months 10.9 10.6%: 11.2
`
`
`
`'P = .13 for response {A52 test}.
`lSubiech've response.
`fMedion.
`§TTP from trial entry in all patients will'l subiective response.
`
`33% of the patients had a subjective response without a
`biochemical response. and 5% of the patients had 2 50%
`decrease from baseline PSA without a subjective response.
`Most often. subjective responses preceded biochemical
`responses or were recorded simultaneously with biochemi-
`cal responses. In only 18% of the available cases was a
`subjective response observed after a biochemical response
`had been reported.
`
`QL
`
`At baseline. QLQ C-30 data were available for 90% of
`patients in both treatment arms. Patients without baseline
`QL data were excluded from further serial analyses. During
`the subsequent 24-week period. compliance with QL asseSs-
`ment decreased to approximately 70%, equally in both arms
`
`Table 4. Baseline o! Serum PSA levels and Number of Biochemicth
`Responding Patients [HA 2 50% reduction}
`Biochemical Response
`Prednisone Group
`Flutemide Group
`Toto!
`
`{n =1011
`ln =100]
`{N ' 201]
`
`’21
`
`23
`
`44
`
`702
`0.2-2.350
`
`.775
`0.22.039
`
`135
`0.2-2.350
`
`No. of responding patients
`Baseline PSA.
`,tLg/l.
`Median
`Range
`PSA level
`10
`6
`15 2.5 X N
`5
`3
`251-10 X N
`5
`3
`11-25 x N
`6
`6
`26400 X N
`17
`d
`> 100 X N
`1
`1'
`Missing
`
`Total 414 {22%} 21 [21%] 23 [23%]
`
`
`'Missing baseline FSA, but PSA within normal range during follow-up.
`
`4
`2
`2
`—
`
`13
`
`(Table 6). Progression of the disease andi’or death was the
`main reason for noncompliance in both arms.
`Overall. scores on the functioning scales tended to
`declincjust before dropout. whereas scores on the symptom
`Scales tended to increase, indicating a nonrandom pattern of
`missing data. This held for both treatment arms of the trial.
`
`The pattern of QL scores overtime for the P group anti
`F group are presented graphically in Figures 1 and 2.
`Statistically significant treatment effects favoring the P
`group were noted for pain {P < .005). nausea and
`vomitin