`0 1989 British Journal of Urology
`
`007-1 33 1/89/00634634/S10.00
`
`Anti- hormone Treatment for Prostate Cancer Relapsing
`after Treatment with Flutamide and Castration
`Addition of Aminoglutethimide and Low Dose Hydrocortisone to
`Combination Therapy
`
`F. LABRIE,A. DUPONT,A. BELANGER, L. CUSAN, M. BROCHU, E.TURINA, S. PINAULT,
`Y. LACOURCIERE and J. EMOND
`
`Departments of Molecular Endocrinology, Medicine, Nuclear Medicine, Radiology and Urology, Laval
`University Medical Center, Quebec, Canada
`
`Summary-The effect of further adrenal androgen blockade with aminoglutethimide (AG) plus low
`dose hydrocortisone (HC) was studied in 1 19 patients with clinical stage D2 prostate cancer who
`previously progressed after standard hormone therapy and were under progression while receiving
`the combination therapy with Flutamide and castration. Using the objective criteria of the US
`NPCP, 1 complete, 2 partial and 14 stable responses were obtained for a total response rate of
`14.3%, while 102 patients continued to progress. The 50% probability of survival was 21 .O months
`androgen blockade with AG + low dose HC is well tolerated and can be of benefit to a significant
`for the responders and 9.2 months for the non-responders. The present data indicate that further
`proportion of patients in progression at a very late stage of the disease.
`
`A major problem facing the treatment of advanced
`prostate cancer is the lack of response as well as
`interruption of response to first-line endocrine
`therapy. Since the observation of Huggins and
`Hodges (1941), first-line endocrine therapy has
`been the neutralisation of testicular androgens by
`orchiectomy or oestrogens (Mettlin et al., 1982)
`and, more recently, by LHRH agonists (Labrie et
`al., 1980, 1986). Following such neutralisation of
`testicular androgens, 20 to 40% of patients are left
`in progression with no response at the start of
`treatment, while relapse of the disease is generally
`seen within 6 to 24 months in all of those who
`initially respond (Resnick and Grayhack, 1975). At
`the time of relapse, the median life expectancy is
`only 6 months (Johnson et al., 1977). Our approach
`for these patients showing disease progression
`following treatment by orchiectomy, oestrogens or
`LHRH agonists alone has been the addition of the
`antiandrogen Flutamide with an objective positive
`response rate of 34% (Labrie et al., 1988).
`
`Accepted for publication 16 June 1988
`
`An important advance in the first-line endocrine
`therapy of advanced prostate cancer has been
`combination therapy or the association of a pure
`antiandrogen to castration at the start of treatment.
`As shown by open (Labrie et a[., 1986, 1987a) and
`randomised (Labrie et al., 1985; Ojasoo, 1987;
`Benson et al., 1988) trials, the rate and duration of
`response as well as survival are improved by the
`additional blockade of androgens achieved by a
`pure antiandrogen. However, 5 to 10% of patients
`do not respond to combination therapy and relapse
`of the disease, although markedly delayed com-
`pared with standard monotherapy, occurs in 60%
`of patients within 2 years (Labrie et al., 1987).
`'The next and most difficult question is which
`treatment should be used in those patients showing
`lack of response or relapse of the disease under
`combination therapy. The present study investi-
`gated the effect of adding the inhibitor of adrenal
`steroid biosynthesis, aminoglutethimide, plus a low
`replacement dose of hydrocortisone to combination
`therapy in stage D2 patients in relapse or not
`responding to the association of Flutamide and
`634
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`ANTI-HORMONE TREATMENT FOR RELAPSING PROSTATE CANCER
`
`castration. All of these patients had previously
`failed to respond to standard endocrine therapy.
`
`350
`
`635
`
`0 SUPPLETIVE THERAPY
`0 NORMAL
`
`h
`
`T
`
`I
`
`6
`
`I
`10
`
`I
`6
`
`MIDNIGHT
`I
`I
`1
`1
`22
`2
`18
`14
`TIME (HOURS)
`Fig. 1 Profile of serum cortisol concentration in 15 prostate
`cancer patients receiving the indicated doses of hydrocortisone
`acetate compared with control circadian rhythm in 20 untreated
`patients of similar age.
`
`2 250
`L
`(3 t 200-
`d
`9
`8
`I-
`
`150-
`
`100-
`
`50 -
`
`0 1
`
`Patients and Methods
`All patients with biopsy-proven stage D2 prostatic
`carcinoma had disease progression following or-
`chiectomy or treatment with diethylstilboestrol
`(DES) or an LHRH agonist alone. They were
`entered into the study after written informed
`consent. Flutamide 250 mg (orally every 8 h) was
`then given alone in castrated patients or in
`combination with the LHRH agonist [D-Trp6, des-
`Gly-NH2'O]LHRH ethylamide (LHRH-A) 500 pg
`S.C. daily for the first month, followed by 250 pg S.C.
`daily, to those previously treated with DES or
`another LHRH agonist. The oestrogen or other
`LHRH agonist was replaced by LHRH-A in all
`cases.
`Patients who did not respond or who relapsed
`while receiving the combination therapy with
`Flutamide received aminoglutethimide and hydro-
`cortisone. Aminoglutethimide 250 mg 3 times a day
`was given orally for the first 3 weeks followed by
`250 mg 4 times a day, unless the patient complained
`of lethargy associated with the soporific side effects
`of the drug. If side effects such as lethargy, nausea,
`ataxia or dizziness became clinically significant,
`the dose of AG was temporarily reduced until the
`signs and/or symptoms disappeared or became
`acceptable. The dose was then re-established to
`lOOOmg/day in 4 divided doses. A low dose of
`hydrocortisone acetate was given as glucocorticoid
`replacement, namely 20 mg daily (10 mg at 0700 h,
`5 mg at 1500 h and 5 mg at 2300 h). As shown in
`Figure 1, this schedule and dose of HC was used in
`an attempt to reproduce the physiological nycto-
`hemeral cycle of cortisol secretion.
`Complete clinical, urological, biochemical and
`radiological evaluation of the patients was per-
`formed before the start of treatment and during the
`study as described (Labrie et al., 1985). The initial
`evaluation included medical history, physical ex-
`amination, haematology, serum biochemistry, ur-
`ine analysis, flowmetry, chest X-ray, bone scan,
`skeletal survey, ultrasonography of the prostate and
`abdomen and, when indicated, computed axial
`tomography (CAT), nuclear magnetic resonance
`imaging (NMI) and intravenous urography (IVU).
`The same tests were performed after 3 and 6 months
`of treatment and then every third or sixth month or
`more frequently, depending upon the evolution of
`the disease.
`Classification of response was performed accord-
`ing to the objective criteriaof the National Prostatic
`
`Cancer Project (NPCP) (Slack et al., 1984). Bone
`scans were evaluated by an independent group of
`radiologists unaware of the treatment of the
`patients. All measurements of serum prostatic acid
`phosphatase (PAP) and prostatic specific antigen
`(PSA) as well as serum levels of testicular steroids,
`adrenal steroids and pituitary hormones were
`performed at the Laboratory of Molecular Endocri-
`nology, Lava1 University Medical Center, Quebec
`City.
`The first reported evaluation of positive objective
`response was after 3 months' treatment. Patients
`were considered as non-responders if there was no
`objective stabilisation or regression of their disease
`at that time, even though there had been subjective
`benefits. Performance status and pain were evalu-
`ated on a scale of 0 to 4 according to the ECOG
`criteria.
`In 72 patients (5773, orchiectomy was the first
`treatment. In those previously treated with an
`LHRH agonist alone or DES, serum testosterone
`levels were all in the orchiectomised range; 34
`patients (27%) had received at least 1 course of
`radiotherapy for metastatic disease but none had
`received chemotherapy. Among the 126 patients
`entered into the study, 7 were not evaluated: 5
`stopped therapy on their own and 2 were lost to
`follow-up. Thus 119 patients with an age range of
`48 to 83 years (mean 66) were evaluated for their
`objective response to the addition of aminoglute-
`thimide and low dose hydrocortisone to combina-
`tion therapy.
`
`DEF-ABIRA-0000194
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`MYLAN PHARMS. INC. EXHIBIT 1115 PAGE 2
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`
`
`636
`
`Among the patients included in the study, 94
`(74.6%) complained of pain (58 had pain permitting
`normal activity, 29 had pain interfering with daily
`activity and/or sleep, 5 were constantly suffering
`from pain and 2 had intolerable pain requiring
`100% of time in bed); 35 patients (27.7%) were
`ambulant but symptomatic, 17 (13.5%) were bedrid-
`den less than 50% of the time, 5 (3.9%) were
`bedridden more than 50% of the time and 2 (1.6%)
`were 100% bedridden. Loss of body weight and
`appetite was present in 50 patients (40%). Location
`of metastases prior to the addition of aminoglute-
`thimide and hydrocortisone included bone metas-
`tases in all patients, lung involvement in 10 (7.9%),
`pelvic and distant lymph nodes in 10 (7.973 liver
`in 4 (3.2%), central nervous system in 1 (0.8%) and
`bone marrow in 1 (0.8%); 79 patients (62.7%) had
`elevated levels of serum prostatic acid phosphatase
`(PAP).
`Calculations
`Radioimmunoassay data were analysed using a
`program based on model I1 of Rodbard and Lewald
`(1 970). Statistical significance was measured ac-
`cording to the multiple-range test of Kramer (1956).
`The probability of continuing response and survival
`was calculated according to Kaplan and Meier
`(1958).
`
`Results
`As shown in Table 1 and Figure 2, the addition of
`AG+HC to combination therapy led to a 14%
`objective response rate in patients progressing
`under combination therapy with Flutamide; 1
`patient (0.8%) had a complete response, 2 (1.7%)
`had a partial response, 14 (1 1.8%) had a stable
`response and 102 (85.8%) continued to progress. In
`the latter group, 2 patients showed simultaneous
`disappearance of old lesions and appearance of new
`ones, thus suggesting heterogeneity of the androgen
`sensitivity of the tumours. As illustrated in Figure
`2, the 50% probability of survival was 21 .O months
`
`BRITISH JOURNAL OF UROLOGY
`
`for responders (curve A) and 9.2 months for non-
`responders, the difference between the 2 curves
`being highly significant ( P = 0.0056, log rank test)
`(Knudsen and Strom, 1986).
`The most frequent side effect was lethargy (12
`patients) (Table 2). Nausea was seen in 5 patients
`and skin rash and fever occurred in 4 cases; 1
`patient needed replacement therapy with Florinef
`for symptomatic low blood pressure.
`Discussion
`The present data show that an objective response
`can be obtained in a small but significant (14%)
`proportion of patients in progression under combi-
`nalion therapy (Flutamide and castration) by
`additional blockade of adrenal androgen secretion
`achieved by AG + HC and that the therapy is well
`tolerated. We found that the addition of Flutamide
`to patients in relapse after standard endocrine
`therapy produced an objective response in 34.5%
`of 209 patients (Labrie e? al., 1988). The present
`data indicate that an additional 14% can benefit
`from further adrenal androgen blockade achieved
`by AG and low dose HC, making a total response
`rate of 48% in this difficult group of patients with
`disease progression after standard hormonal
`therapy.
`Since most of the objective responses were in the
`stable category, it was important to establish that
`treatment with AG + HC and not already stable. In
`every patient was in real progression at the start of
`this regard it should be recalled that all of the
`patients were first seen in progression under
`standard endocrine therapy, namely blockade of
`testicular androgens by orchiectomy, DES or an
`LHRH agonist alone. Combination therapy with
`Flutamide was then given to all patients and a
`AG + HC was not taken until 3 to 6 months later.
`decision about further androgen blockade with
`In patients already castrated, Flutamide was given
`alone, and for those treated with DES: Flutamide
`was given in combination with the LHRH agonist
`
`Table 1 Effect of Addition of Aminoglutethimide and Low Dose Hydrocortisone on the Objective Response Rate
`
`85.7% -
`
`Stable
`
`14
`1 1.8%
`J
`
`Progression
`
`I02
`
`Totul
`ecaluuted
`
`1 I9
`
`Day r of
`treatment
`mean
`(limits J
`
`323
`(85-943)
`
`Objectice response
`
`Complete
`
`Purtiaf
`
`1
`0.8%
`
`2
`1.72,
`
`* 10 8"" to 17 2% (95'?,, confidence limits)
`
`14.3%*
`
`DEF-ABIRA-0000195
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`MYLAN PHARMS. INC. EXHIBIT 1115 PAGE 3
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`
`
`ANTI-HORMONE TREATMENT FOR RELAPSING PROSTATE CANCER
`
`637
`
`such therapy. All 119 evaluated patients who
`received AG + HC were thus in clear progression
`under our observations for a minimal period of 3
`months before the addition of AG + HC. It is thus
`unlikely that any of the stable responses observed
`correspond to patients already having stable disease
`before further blockade of adrenal androgens was
`achieved by AG + HC.
`The present approach, namely blockade of
`adrenal androgen secretion in patients relapsing
`under combination therapy, is based on the premise
`that tumours remain sensitive to the low concentra-
`tion of androgens remaining free to activate the
`androgen receptor in castrated patients receiving
`Flutamide, and that aminoglutethimide associated
`with a low and near-physiological dose of hydrocor-
`tisone efficiently blocks adrenal androgen produc-
`tion.
`Clinical data demonstrate that androgen-sensi-
`tive tumours are also present in patients who relapse
`after castration. These pertain to the findings that
`34% of patients already castrated or treated with
`oestrogens or LHRH agonists alone show a positive
`objective response to the addition of Flutamide
`(Labrie et al., 1988). That more than 95%of patients
`at the time of relapse have androgen-sensitive
`tumours is shown by the observation of a rapid
`exacerbation (within 3 days) of symptoms in 97%
`of relapsing patients treated with exogenous testos-
`terone (Fowler and Whitmore, 1981).
`Although AG has never been used in patients
`relapsing under combination therapy, the benefits
`of this drug have been observed in 30 to 60% of
`patients in progression after orchiectomy or treat-
`ment with DES (Robinson er al., 1974; Drago et
`al., 1984). Using the objective criteria of response
`of the NPCP, Drago er af. (1984) reported positive
`objective responses in 17 of 43 patients (40%) and
`Murray and Pitt (1985) observed 33% positive
`objective responses in 58 patients. In a study of 129
`patients relapsing after castration, treatment with
`AG (1000 mg/day) and HC (40mg/day) caused
`objective partial and stable remission in 9 and 33%
`of patients respectively, making a total objective
`response rate of 42% while 58% had disease
`progression (Crawford et af., 1988).
`A potentially important characteristic of the
`regimen AG-HC used in this study is the low dose
`of hydrocortisone used (20 mg/day), while all other
`reported studies used 40 or more mg HC/day as
`glucocorticoid replacement therapy. Crawford et
`a/. (1988) used 100 mg HC during the first 2 weeks
`followed by 40 mg daily, Ponder et al. (1 984) used
`cortisone acetate 50 mg/day and Drago et al. (1984)
`
`A-RESPONDERS
`8-NON-RESPONDERS
`
`2.0
`
`0.0
`
`1 .o
`1.5
`0:5
`TIME UNDER TREATMENT,AG+HC(YEARS)
`Fig. 2 Comparison of the probability of survival in stage D2
`prostate cancer patients progressing under combination therapy
`and responsive to the addition of aminoglutethimide and
`hydrocortisone (AG + HC) (curve A) and the non-responders to
`the same treatment (curve B). The numbers on the curves
`indicate the number of patients assessed at each time interval.
`The two curves are statistically different (P=0.0056, log route
`test (Knudsen and Strom, 1986).
`
`[D-Trph, ~ ~ s - G ~ ~ - N H , ~ O ] L H R H ethylamide. In a
`
`study of 209 evaluable patients relapsing after
`standard monotherapy, 6.2,9.6 and 18.7% achieved
`complete, partial and stable responses respectively,
`i.e. a total objective response rate of 34.5% to
`combination therapy (Labrie et al., 1988). Coupled
`with the patients’ excellent tolerance of this
`treatment, this response rate appears to make it the
`treatment of choice for prostate cancer patients in
`relapse after standard endocrine therapy.
`Unfortunately, 65.5% of patients relapsing after
`monotherapy do not respond to the addition of the
`antiandrogen (Labrie et al., 1988). Moreover, for
`the 34.5% of patients who initially respond, the
`mean duration of response is 24 months before a
`second progression occurs. The patients included
`in the present study are those who did not respond
`to the combination therapy as well as those who
`progressed after a variable period of response to
`
`Table 2 Side Effects of Treatment with AG and HC
`
`Adrenal insufficiency
`Nausea
`Rash
`Lethargy
`Fever
`Dizziness
`Throm bocytopenia
`Leucopenia
`Mineralocorticoid deficiency
`
`No. of
`patients
`
`0
`5
`4
`12
`4
`0
`0
`0
`1
`
`%
`
`0
`4.2
`3.4
`10. I
`3.4
`0
`0
`0
`0.8
`
`DEF-ABIRA-0000196
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`MYLAN PHARMS. INC. EXHIBIT 1115 PAGE 4
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`
`
`638
`
`and Murray and Pitt (1985) used 40mg HC and
`37.5 mg cortisone acetate daily respectively.
`Although greater inhibition of adrenocortical
`activity could be achieved with higher doses of
`glucocorticoids, it is likely that such an approach
`has potential harmful effects on the immune system
`and on the evolution of cancer itself. It is of interest
`to recall the immunosuppressive properties of
`glucocorticoids. The secretion of interleukin-1 (IL-
`1) originating from monocytes as well as interleu-
`kin-2 and lymphotoxin from T-lymphocytes is
`suppressed by glucocorticoids (Mishell et ul., 198 1).
`These steroids also block natural killer cell activity,
`possibly by inhibiting the production or release of
`specific cytotoxic factors. It has been shown that
`corticosteroids inhibit IL-1 production through an
`inhibition of the transcription of 1L-1 encoding
`mRNA and thereby blocking cell-mediated immu-
`nity (Knudsen and Strom, 1986). With this knowl-
`edge of the role of the immune system in cancer, it
`seems logical to avoid the use of high doses of
`glucocorticoids, an approach which might have
`apparent short-term benefits but may well be
`responsible for an accelerated growth of the cancer.
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`The Authors
`F. Labrie, MD. PhD, FRCP(C), Professor of Endocrinology,
`Departments of Molecular Endocrinology and Medicine.
`A. Dupont, MD, PhD, Endocrinologist, Departments of
`Molecular Endocrinology and Medicine.
`A. Btlanger, PhD, Biochemist, Department of Molecular
`Endocrinology.
`L. Cusan, MD, PhD, Endocrinologist, Departments of Molecu-
`lar Endocrinology and Medicine.
`M. Brochu, PhD, Biochemist, Department of Molecular Endo-
`crinology.
`E. Turina, MD, Urologist.
`S. Pinault, MD, Radiologist.
`Y . Lacourciere, MD, Internist, Department of Nuclear Medi-
`cine.
`J . Emond, MD, Urologist.
`Requests for reprints to: F. Labrie, Department of Molecular
`Endocrinology, Lava1 University Medical Center, 2705 Laurier
`Boulevard, Quebec G 1V 4G2, Canada.
`
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