`
`European journal ochmcer, Vol. 35, No. 2, pp. 214~218, 1999
`© 1999 Elsevier Science Ltd. All rights reserved
`Printed in Great Britain
`0959-8049/99/35 - see front matter
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`Original Paper
`
`Onapristone, a Progesterone Receptor Antagonist, as First-line
`Therapy in Primary Breast Cancer
`
`].F.R. Robertson,1 P.C. \Willsher,1 L. \Winterbottom,1 R.W. Blamey1 and S. Thorpe2
`
`1Professorial Unit of Surgery, City Hospital, Hucknall Road, Nottingham, NG5 lPB, and 2Schering Health Care,
`Burgess Hill, West Sussex, U.K.
`
`The progesterone receptor antagonist, Onapristone, is an efl'ective endocrine agent in experimental
`breast cancer models. This study aimed to investigate this agent as first-line endocrine therapy in
`patients with breast cancer. However, owing to the recognition in this and other clinical studies that
`some patients on Onapristone developed liver function test abnormalities, the development of this
`drug and recruitment to the study stopped in 1995. 19 patients either with locally advanced breast
`cancer (11 = 12) or who were elderly, unfit patients with primary breast cancer (11: 7) received Ona-
`pristone 100 mglday. Seventeen of the 19 tumours expressed oestrogen receptors (ER) whilst 12 of the
`18 tumours tested expressed progesterone receptors (PgR). Tumour remission was categorised by
`International Union Against Cancer criteria. One patient was withdrawn after 4.5 months while her
`disease was static. Of the remaining 18 patients, 10 (56%) showed a partial response and 2 (11%) dur-
`able static disease (2 6 months), giving an overall tumour remission rate of 67%. The median duration
`of remission was 70 weeks. Transient liver function test abnormalities developed in a number of
`patients, mainly during the first 6 weeks of treatment. In conclusion Onapristone can induce tumour
`responses in human breast cancer. © 1999 Elsevier Science Ltd. All rights reserved.
`
`Key words: breast cancer, progesterone antagonists, onapristone
`Eur} Cancer, Vol. 35, No. 2, pp. 214—218, 1999
`
`INTRODUCTION
`
`BREAST CANCER is the most common female malignancy in the
`western world, with a lifetime risk of at least 1:12 at present.
`At some point in their disease most patients will receive sys—
`temic therapy. The endocrine therapy of choice in post—
`menopausal or oophorectomised patients
`is
`the
`anti—
`oestrogen, tamoxifen [1]. Tamoxifen gives a tumour remis—
`sion rate of approximately 60% in selected patients [2], e.g.
`those with tumours which are oestrogen receptor (ER) and
`progesterone receptor (PgR) positive. However,
`tamoxifen
`has a partial oestrogen agonistic activity on some tissues and
`organs. The second—line hormonal agents used in relapse
`after tamoxifen include aromatase inhibitors (e.g. Aminoglu—
`tethamide, Lentaron and, Arimidex) and high—dose proges—
`tins
`(e.g. medroxyprogesterone
`acetate
`and megestrol
`acetate). These drugs are less well tolerated than tamoxifen.
`
`Correspondence to J.F.R. Robertson,
`nottingham.ac.uk
`Received 20 Jul. 1998; accepted 8 Oct. 1998.
`
`e—mail:
`
`john . robertson@
`
`Progesterone antagonists offer a new therapeutic strategy
`in the treatment of invasive breast cancer. Furthermore, if the
`molecular studies on the effects of these compounds on
`breast cancer in animals are confirmed their potential clinical
`utility may extend back into preneoplastic disease (e.g. atypi—
`cal ductal hyperplasia).
`The progesterone antagonist Onapristone was developed
`by Schering AG [3,4]. It was reported to have strong anti—
`progestational and antitumour activity. Onapristone (ZK
`98.299) showed tumour inhibitory effects in several hor—
`mone—dependent mammary tumours in animal models. Its
`antitumour activity is as potent or even more potent than that
`of tamoxifen or oophorectomy in the MXT mammary
`tumour of the mouse and DMBA— and NMU—induced
`
`mammary tumours of the rat [5,6]. Although binding to
`tumour progesterone receptors is a prerequisite for its anti—
`proliferative effects, there is evidence that the mechanism of
`its antitumour effects does not depend on a classical anti—
`hormonal mechanism. While the mechanism of action of this
`
`new antiprogestin is poorly understood, it has recently been
`reported that when Onapristone was given to mice bearing
`
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`Onapristone as Initial Therapy in Breast Cancer
`
`215
`
`hormone—dependent MXT mammary tumours, in addition to
`causing tumour regression, the compound caused histological
`changes suggestive of differentation to a more benign and
`mature status [6]. Further in vivo work has suggested that the
`antitumour action of Onapristone is a direct, progesterone—
`mediated antiproliferative effect at the cell level, probably via
`the induction of terminal differentiation associated with cell
`
`death [5].
`The aim of this study was to investigate the clinical and
`biological effects of this agent as first—line endocrine therapy
`in patients with breast cancer.
`
`PATIENTS AND METHODS
`
`In September 1994 a phase II study was commenced to
`assess Onapristone as first—line therapy in postmenopausal
`patients with primary breast cancer. Patients were eligible to
`enter the study if they had a locally advanced tumour or were
`elderly with tumours suitable for endocrine therapy. In all
`patients endocrine therapy was deemed the initial treatment
`of choice. A primary goal of the study was to assess by
`sequential
`tumour biopsies the effect of Onapristone on
`tumour biology. The recruitment
`target was 30 patients.
`However, owing to the recognition in this and other clinical
`studies that some patients on Onapristone developed liver
`function test (LFT) abnormalities, the development of this
`drug was discontinued and recruitment to the study stopped
`in 1995. At this time 19 patients had entered the study: 12
`patients had locally advanced primary tumours and 7 were
`elderly patients in whom endocrine therapy was the initial
`treatment of choice.
`
`trial programme on Onapristone was
`When the clinical
`halted all 19 patients were informed of the new data on LFT
`abnormalities. Since these changes appeared to be transient
`in all breast cancer patients treated, the 19 patients in this
`study were offered the option of continuing Onapristone with
`increased frequency of monitoring LFT measurements or
`changing to tamoxifen therapy. All patients elected to con—
`tinue with Onapristone.
`This paper reports the clinical response rate and duration
`of remission in these 19 patients. The minimum follow—up
`since randomisation was now 24 months and the maximum
`32 months. The data on liver function tests in these 19
`
`patients are also reported. These data are particularly important
`since, unlike the phase II/III studies in patients with metastatic
`disease, changes in LFT can be attributed to Onapristone
`rather than to metastatic involvement of liver or bone.
`
`Oestrogen receptors
`ER were routinely measured in all pretreatment tumour
`biopsies by oestrogen receptor immunocytochemical assay
`(ERICA), as reported previously [7]. Two tumours showed
`no expression of ER. Of the remaining 17 tumours, four
`showed ER expression on between 10 and 50% of tumour
`cells and 13 showed ER expression on between 70 and 100%
`of tumour cells. PgR was also measured by immunocy—
`tochemistry (Abbott Laboratories, Maidenhead, Berkshire,
`U.K.). 12 patients had PgR—positive tumours and 6 patients
`had PgR—negative tumours. In the remaining patient PgR
`status was unavailable.
`
`Therapeutic assessment
`Patients were assessed for therapeutic remission using the
`International Union Against Cancer (UICC) criteria [8].
`
`Since all patients commenced with only a palpable breast
`tumour the assessment involved measurement of the tumour.
`
`The largest diameters of the tumour in two directions were
`then multiplied together. Similar measurements were made
`of any regional lymph nodes and the sums of primary tumour
`and lymph node(s) added. All measurements were carried out
`by two breast surgeons (IFRR and PCW).
`Complete response (CR) was regarded as complete dis—
`appearance of the tumour. Partial
`response (PR) was a
`reduction of > 50% in the sum of the product of the two lar—
`gest diameters of palpable tumour (i lymph nodes). Objec—
`tive response (OR) combines the CR and PR categories. A
`tumour was classified as static disease (SD) if any change in
`size ranged between < 50% reduction and < 25% increase in
`the pretreatment measurements. In all cases (CR, PR or SD)
`there had to be no new lesions either in the breast or at dis—
`
`tant sites. Progressive disease (PD) de novo was defined as an
`increase in tumour size > 25% of the pretreatment value or
`the appearance of new lesions, or both. PD after a period of
`response or SD was defined as an increase in tumour size
`> 25% of the smallest recorded size or the appearance of new
`lesions, or both.
`A further criterion to be fulfilled before patients were clas—
`sified as CR, PR or SD was the British Breast Group recom—
`mendation that tumours had to be in CR, PR or SD after at
`least 6 months of treatment [9]. This requirement was intro—
`duced to prevent reporting short remissions of doubtful clin—
`ical benefit. Subsequently, studies have supported this 6—
`month figure by reporting that patients who show SD for 6
`months have a statistically similar survival to patients who
`show PR or CR. All three groups show a significantly longer
`survival than the PD group [10—12].
`
`RESULTS
`
`showed PD.
`the 3—month assessment no patient
`At
`Patients’ tumours were either in PR (n = 3) or in SD (n = 16).
`By 6 months the results were: PD (n = 6). SD (n: 2) and PR
`(n: 10). One patient discontinued Onapristone after 4.5
`months when the tumour was static (see below). The median
`duration of response for the 12 patients with PR or SD was
`70 weeks, compared with 20 weeks for the patients where the
`tumours showed de novo progression. 2 patients remain on
`Onapristone at a median time of 26 months from entry into
`the study.
`Some patients during therapy developed LFT abnormal—
`ities. The number of patients with abnormalities in each test,
`either before Onapristone treatment or at any time during
`therapy, is detailed in Table 1. Changes in each of the four
`liver
`function measurements are shown over
`time, and
`presented in two ways. Figure
`1(a)—(d)
`shows values
`pretreatment and regular 6—weekly values, as planned in the
`original protocol. Figure 2(a)—(d) show values pretreatment
`and at each time point at which blood was obtained
`during the patient’s first year of treatment. Figure 2 reflects
`the increased frequency of blood sampling in the patients
`recruited later in the study, when liver dysfunction became
`known.
`
`function abnormalities appeared mainly during
`Liver
`the first 6 weeks of follow—up. In only 3 out of 19 patients did
`the abnormality in LFT start after 6 weeks with a slight
`elevation of bilirubin (n: 1)
`(weeks 18 and 24), a 4—fold
`rise in gamma—glutaryltransferase (GGT) at week 18 (n: 1)
`and
`a
`slight
`elevation
`of
`alkaline
`phosphatase
`and
`
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`216
`
`].F.R. Robertson ei al.
`
`GGT (n = 1) (week 15 onwards). One patient discontinued LFT were starting to fall. Nevertheless, Onapristone was not
`Onapristone at 4.5 months owing to rising LFT abnor— restarted.
`malities. At the point of discontinuing the drug a further
`In the 12 patients who had OR or SD 8 were both ER and
`blood test was taken, which subsequently showed that the
`PgR positive, 3 were ER positive and PgR negative and one
`
`Table 1. Number of patients with liver function test abnormalities
`
`No. of patients with elevated tests
`
`Bilirubin
`Alkaline transferase
`Alkaline phosphatase
`Gamma—glutamyltransferase
`
`Normal range
`
`Pretreatment
`
`During treatment
`
`5717umol/l
`5410 U/l
`807280 U/l
`10750 U/l
`
`0/18
`0/19
`1 1/19
`4/19
`
`4/19
`12/19
`18/19
`14/19
`
`
`
`(a)
`j 60
`g
`E
`3 40
`E
`5 20
`
`m
`
`
`0 I
`I
`I
`I
`I
`O
`6
`1 2
`1 8
`24
`
`(b) 200 —
`
`g 150 4
`I)
`I: 100 —
`(5
`>
`
`50 _,
`
`0
`
`_
`0
`
`I
`6
`
`I
`12
`
`I
`18
`
`I
`24
`
`(n) 18
`
`18
`
`13
`
`Weeks
`
`13
`
`13
`
`(n) 19
`
`18
`
`13
`
`Weeks
`
`13
`
`13
`
`7
`
`(c)
`
`80
`
`Q 60
`I—
`3 40
`—'
`< 20
`
`(d) 500 3
`
`g 400 —
`»
`o
`I 300 —
`“E 200 —-
`—_v< 100 -
`
`
`
`0 I
`O
`
`I
`6
`
`I
`12
`
`T"
`1 8
`
`1
`24
`
`O
`
`0
`
`I
`6
`
`I
`1 2
`
`I
`1 8
`
`I
`24
`
`(n) 19
`
`18
`
`13
`Weeks
`
`13
`
`13
`
`(n) 19
`
`18
`
`13
`
`13
`
`13
`Weeks
`
`Figure 1. LFT measurements (6 weekly). ALT, alkaline transferase; GT, gamma-glutamyltransferase; Alk, alkaline phosphatase.
`
`A3
`
`
`
`
`
`Bilirubin(UMoI/L)
`
`AE
`
`ALT(U/L)
`
`50-
`
`40—
`
`30—!
`20—
`
`1O
`
`0
`
`
`
`lllllllllllllll||||l|1|||||l||||
`4
`8
`12
`16
`20
`25
`29
`41
`
`O
`
`||||11|I11|1||111|1111ll|
`4
`8
`12
`16
`2O
`25
`
`29
`
`O
`
`41
`
`(n) 18
`
`4
`
`6
`
`13
`
`5
`Weeks
`
`3
`
`1
`
`7
`
`3
`
`(n) 19
`
`4
`
`6
`
`13
`
`5
`Weeks
`
`3
`
`2
`
`1
`
`3
`
`250
`
`200
`
`1 50
`
`100
`50
`
`g
`
`600
`
`400
`
`200
`
`
`
`Alkphos(U/L)
`
`
`0IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`0IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`0
`4
`8
`12
`16
`2O
`25
`29
`41
`0
`4
`8
`12
`16
`2O
`25
`29
`41
`
`(n) 19
`
`4
`
`6
`
`13
`
`5
`Weeks
`
`3
`
`2
`
`1
`
`3
`
`(n) 19
`
`4
`
`6
`
`13
`
`5
`Weeks
`
`3
`
`2
`
`1
`
`3
`
`Figure 2. LFT measurements (weekly). For abbreviations, see Figure 1.
`
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`Onapristone as Initial Therapy in Breast Cancer
`
`217
`
`PgR unknown was weakly ER positive. In the 6 patients who
`showed de novo progression, 3 were ER and PgR positive, one
`was ER positive and PgR negative, one was ER negative and
`PgR positive and one was negative for both receptors.
`
`DISCUSSION
`
`clinically relevant
`Two—thirds of patients obtained a
`tumour remission: 10 out of 18 (56%) showed a PR and 2
`out of 18 (11%) SD. These figures are at least as good as
`published remission rates
`for
`the
`anti—oestrogen agent
`tamoxifen [12—14], synthetic progestogen, megestrol acetate
`[13—15] and aromatase inhibitors such as aminoglutethamide
`[16—18] or Lentaron [19] used as first—line endocrine thera—
`pies. The high remission rate is in part related to the fact that
`17 out of 19 patients were ER and or PgR positive. Similarly,
`most of the studies referenced above entered only patients
`with ER—positive tumours or ER status unknown.
`It is known that the remission rate is lower to second—line
`
`than to first—line endocrine therapy. Recently, 225 patients
`were reviewed who received both first—line and second—line
`
`the remission rates were 72% (10%
`endocrine therapies,
`CR+ 22% PR+ 40% SD) and 53% (3% CR+ 8% PR+ 42%
`SD), respectively. In this latter review over 90% of patients
`received tamoxifen as first—line and megestrol acetate as sec—
`ond—line therapies [20]. Overall, Onapristone appears an
`effective first—line endocrine agent, with tumour remission
`rates similar to more established therapies. However, with
`only 19 patients in the study there were insuflicient numbers
`to draw conclusions about equivalence with other agents.
`One or more LFT was elevated in the majority of patients
`on Onapristone. The abnormalities became apparent in the
`first 6 weeks of treatment and usually declined thereafter at a
`steady rate. In 1 patient Onapristone was discontinued and
`even in this patient the LFT had started to show a downward
`turn in the sample taken on the day on which therapy was
`stopped.
`The comparison between PgR status and remission needs
`to be interpreted with caution for the following reasons. In
`this group of patients,
`the majority were ER and/or PgR
`positive. If the same group were treated with an anti—oestro—
`gen such as tamoxifen, not all would respond, despite the
`presence of ER. In fact, one would expect
`tamoxifen to
`induce OR and SD in around 60—70% of ER—positive
`tumours. In this study 9 out of 14 (64%) patients with PgR—
`positive tumours showed OR or SD to Onapristone as first—
`line endocrine therapy.
`A recent publication on the progesterone antagonist Mife—
`pristone reported an objective response rate (CR or PR) of
`10.7% with a stable disease (duration range 2—17 months)
`rate of 39.3% [21]. The authors stated that these results were
`in patients with untreated metastatic breast cancer. However,
`the majority of patients had received adjuvant hormone ther—
`apy (43%) or chemotherapy (32%). This would have influ—
`enced the response rates they reported. As noted above, the
`long—term results have been reported of 250 patients where
`first— and second—line endocrine therapies were their initial
`systemic therapies for measurable disease [20], i.e. none had
`received adjuvant endocrine therapy. Patients received endo—
`crine therapy either
`for metastatic disease or
`for
`local
`tumours (e.g. elderly, unfit patients or locally advanced dis—
`ease). The results in the study by Perrault and colleagues
`appear more reflective of response rates that the present
`authors have reported to second—line therapy,
`i.e. 11%
`
`OR+42% SD [20]. These results are also similar to a recent
`randomised study of megestrol acetate 40 mg four times daily
`versus anastrozole 1mg daily given as second—line endocrine
`therapy. The OR rates were 12% for both agents and the SD
`rates were 28% and 30% for megestrol acetate and anastro—
`zole, respectively.
`A further point to be considered when comparing results of
`this study with Onapristone and the study reported by Per—
`rault and colleagues with Mifepristone is the effect of these
`drugs on the level of oestradiol. In a study by Klijn and col—
`leagues, Mifepristone was reported to cause up to a 5—fold
`increase in serum oestradiol [22]. Mifepristone in that study
`was given as second—line therapy and induced an objective
`response rate of 9% and SD rate of 54%. Onapristone in the
`present study resulted in no increase in serum oestradiol
`(data not shown). These latter data are the subject of a
`separate publication. However,
`if a 50—90% reduction in
`serum oestradiol by aromatase inhibitors induces clinical
`responses, a 5—fold increase by Mifepristone may have an
`adverse effect on tumour growth. This difference between
`Onapristone and Mifepristone may be clinically important.
`Future studies on the effect of pure progesterone antagonists
`should include an assessment of their effect on sex hormone
`levels.
`
`The results of this small study of Onapristone as first—line
`therapy support the preclinical data that Onapristone is a new
`class of endocrine agent that could have a significant impact
`on endocrine treatment of breast cancer. From a clinical
`
`viewpoint the results of this study support the development of
`second—generation progesterone receptor antagonists for use
`in the treatment of breast cancer. Studies are starting to
`assess whether the sequential tumour biopsies from this study
`during Onapristone treatment show evidence of the occur—
`rence of tumour differentiation. If confirmed, this would fur—
`ther support preclinical data indicating that progesterone
`antagonists exert a differentiation effect
`through a novel
`mechanism of action. This would further support a develop—
`ment programme of new progesterone antagonists.
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`1989, 49, 285172856.
`
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`AstraZeneca Exhibit 2036 p. 5
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