Postmenopausal women who progress on fulvestrant ('Faslodex') remain
`Vergote, I;Robc1tson, JFR;Kleeberg, U;BuIton, G;et al
`Breast Cancer Research and Treatment; May 2003; 79, 2; ProQuest Central
`pg. 207
`
`K‘ Breast Cancer Research and Treatment 79: 207-211, 2003.
`w © 2003 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Report
`
`Postmenopausal Women who progress on fulvestrant (‘Faslodex’) remain
`sensitive to further endocrine therapy
`
`I. Vergotel, J.F.R. Robertsonl, U. Kleeberg3, G. Bu1ton4, C.K. Osborne5, and L. Mauriac6 (for
`the Trial 0020 and 0021 Investigators)
`UK;
`Nottingham,
`2Nottingham City Hospital,
`1University Hospitals,
`Leuven,
`Belgium;
`3Haematologische/Oncologische Praxis, Hamburg, Germany; 4Louisiana State University Health Science
`Center, Shreveport, LA; 5Breast Center at Baylor College ofMedicine and Methodist Hospital, Houston, TX, USA;
`6Bergonie Institute, Bordeaux, France
`
`Key words: advanced breast cancer, estrogen receptor downregulation, fulvestrant, sequential therapy
`
`Summary
`
`Purpose. This retrospective evaluation of data from two randomized, multicenter trials examined whether tumor
`responses to further endocrine therapy were seen in postmenopausal women with advanced breast cancer who
`had progressed on both initial endocrine therapy, usually tamoxifen, and on the estrogen receptor (ER) antagonist
`fulvestrant (‘Faslodex’).
`Patients and methods. A combined total of 423 patients received fulvestrant 250mg as a monthly intramus-
`cular injection. After progression on fulvestrant, some patients received another endocrine therapy. Responses to
`subsequent endocrine therapy were assessed using a questionnaire sent to the trial investigators. Best responses
`were classified as a complete or partial response (CR or PR), stable disease (SD) lasting :24 weeks, or disease
`progression.
`Results. Follow-up data were available for 54 patients who derived clinical benefit (CB, defined as CR, PR
`or SD) from fulvestrant and who received subsequent endocrine therapy, resulting in a PR in 4 patients, SD in
`21 patients, and disease progression in 29 patients. Data were available for 51 patients who derived no CB from
`fulvestrant and who received further endocrine therapy, resulting in a PR in 1 patient, SD in 17 patients, and disease
`progression in 33 patients. Aromatase inhibitors were used as subsequent endocrine therapy in >80% of patients.
`Conclusions. After progression on fulvestrant, patients may retain sensitivity to other endocrine agents. Ful-
`vestrant provides an additional option to existing endocrine therapies for the treatment of advanced or metastatic
`breast cancer in postmenopausal women, and may provide the opportunity to extend the sequence of endocrine
`regimens before cytotoxic chemotherapy is required.
`
`Introduction
`
`Despite advances in detection and treatment leading to
`improved survival, breast cancer represents a leading
`form of cancer-related death in women. In Europe,
`breast cancer was the major cause of cancer-related
`death, leading to approximately 17% of all deaths in
`1995 [1]. For hormone-sensitive breast cancers, endo-
`crine therapy is established as the treatment of choice.
`The selective estrogen receptor modulator (SERM)
`
`tamoxifen has for many years been the preferred initial
`treatment for hormone—sensitive, advanced breast can-
`cer, but aromatase inhibitors (Als) such as anastrozole
`and letrozole have been shown recently to be at least
`as effective [2, 3]. These therapies lead to tumor re-
`gression in 40-50% of estrogen receptor (ER)—positive
`patients [2, 3].
`Despite an initial response to tamoxifen, all pa-
`tients eventually undergo disease progression, ne-
`cessitating the use of a different therapy. Patients
`
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`208
`
`I Vergote et al.
`
`who respond to initial endocrine therapy may be
`responsive to subsequent endocrine intervention [4,
`5]. This sequential use of endocrine therapies offers
`significant quality—of—life advantages over cytotoxic
`chemotherapy [4], particularly in elderly patients or
`those patients with advanced disease, since they of-
`fer disease control without the marked adverse events
`associated with cytotoxic chemotherapy. This sequen-
`tial use of endocrine agents relies on them possessing
`different mechanisms of action to overcome cross-
`resistance, as seen between different SERMs [6]. As
`a result, the development of novel agents may extend
`the period of time during which endocrine therapy
`can be used,
`thereby deferring the decision to use
`chemotherapy.
`Fulvestrant (‘Faslodex’) is a new type of antiestro-
`gen, an ER antagonist that dramatically reduces cellu-
`lar levels of the ER and, importantly, does not possess
`the partial agonist activity associated with tamoxifen
`[7, 8]. In preclinical studies, fulvestrant was effective
`at inhibiting the growth of breast cancer models, both
`in vitro and in viva, including in models of tamox-
`ifen resistance [9, 10]. Phases I and II clinical studies
`in postmenopausal women with advanced breast can-
`cer who progressed on tamoxifen have demonstrated
`the efficacy of fulvestrant, with approximately 13/19
`(69%) patients showing clinical benefit (CB), without
`the adverse events associated with tamoxifen (such as
`hot flashes and night sweats) [11, 12].
`Two multicenter phase III trials, prospectively de-
`signed to allow the analysis of combined data, com-
`pared fulvestrant with anastrozole in postmenopausal
`women with advanced breast cancer [13, 14]. Ful-
`vestrant was at least as effective as anastrozole and
`was well tolerated. The work presented here repre-
`sents the retrospective analysis of combined data from
`these trials, to evaluate the effects of further endocrine
`therapies in patients whose tumors became resistant to
`fulvestrant.
`
`Patients and methods
`
`Trial 0020 was an open, randomized trial conducted
`in Europe, Australia and South Africa. Trial 0021 was
`a double-blind, double-dummy, randomized trial con-
`ducted in North America. Detailed methodology and
`results have been previously reported elsewhere [13,
`14]. Both trials were conducted with approval from
`the relevant ethics committees, and all patients gave
`written, informed consent.
`
`Patients
`
`Patients recruited to trials 0020 and 0021 were post-
`menopausal women with locally advanced or meta-
`static breast cancer not amenable to curative treatment
`who had progressed following prior endocrine therapy
`for advanced or early disease. Patients had histologi-
`cally or cytologically confirmed breast cancer, with
`objective evidence of disease recurrence or progres-
`sion, and at least one measurable lesion.
`In addi-
`tion, all patients demonstrated evidence of hormone
`sensitivity (either sensitivity to 31 prior hormonal
`treatment or known ER, or progesterone receptor pos-
`itivity), a life expectancy of 23 months, and a WHO
`performance status of 52.
`
`Treatment
`
`Patients received fulvestrant 250 mg once monthly and
`continued treatment until evidence of disease pro-
`gression or any other significant events warranting
`withdrawal (e.g., unacceptable adverse events, pro-
`tocol non-compliance, or withdrawal of patient con-
`sent). After this point, treatment ceased and patients
`undertook standard therapy as determined by their in-
`dividual clinician. Unless consent was withdrawn, pa-
`tients were monitored after withdrawal for progression
`and survival until death.
`
`Data collection
`
`investigators
`A questionnaire was sent to the trial
`caring for the fulvestrant-treated patients. Informa-
`tion requested included details of the response to
`fulvestrant during the trial, details of any subsequent
`endocrine therapy given after progression, and the best
`response to this therapy. The efficacy of subsequent
`endocrine therapy was determined from the investi-
`gators responses to the questionnaires. In practice, the
`treatments used were Als or megestrol acetate, with
`some patients receiving medroxyprogesterone acetate.
`
`Results
`
`Of the 423 patients who received fulvestrant in trials
`0020 and 0021, 186 derived CB, defined as complete
`response (CR), partial response (PR), or stable disease
`(SD) for 224 weeks, according to UICC criteria. Of
`these, retrospective follow-up data were available for
`66 patients who demonstrated CB on fulvestrant and
`
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`Endocrine theram after progression on fulvestrant
`Table 1. Age and site of disease at baseline in patients who did and did not derive CB from fulvestrant
`(combined data from trials 0020 and 0021)
`
`209
`
`Number of patients
`
`Who derived CB
`from fulvestrant
`(n = 54)
`
`61.5 (41-81)
`
`2 (3.7)
`8 (14.8)
`28 (51.8)
`7 (12.9)
`19 (35.2)
`16 (29.6)
`4 (7.4)
`
`Who did not derive CB
`from fulvestrant
`(n = 51)
`
`66.0 (42-85)
`
`6 (11.8)
`10 (19.6)
`26 (50.9)
`15 (29.4)
`12 (23.5)
`17 (33.3)
`8 (15.7)
`
`Median age (range), years
`
`Site of disease (%)‘"‘
`Breast
`Skin
`Bone
`Liver
`Lung
`Lymph node
`Other
`
`“Patients may be counted in more than one category.
`
`Table 2. Response to subsequent endocrine therapy in patients who derived CB from fulvestrant
`(combined data from trials 0020 and 0021)
`
`Number of patients
`
`PR
`
`4
`3
`1
`2
`0
`
`1
`
`SD
`324 weeks
`
`Progression
`
`Total
`
`21
`16
`13
`3
`0
`
`5
`
`29
`27
`23
`3
`1
`
`2
`
`54
`46
`37
`8
`
`8
`
`Endocrine therapy total
`Als
`Anastrozole
`Letrozole
`Formestane
`
`Megestrol acetate
`
`for 84 who did not achieve CB. Further endocrine ther-
`apy was received by 54 patients who achieved CB on
`fulvestrant and by 51 patients who did not achieve CB
`on trial therapy. These patients were generally well
`matched in terms of age and site of disease at baseline
`(Table 1).
`The majority of the patients who achieved CB on
`fulvestrant (46/54; 85%) (Table 2) subsequently re-
`ceived an AI, either anastrozole (n = 37), letrozole
`(n = 8) or formestane (n
`1), with the remaining
`patients (15%) receiving megestrol acetate (n = 8).
`Overall, subsequent endocrine therapy in this subset
`of patients resulted in an objective response (OR) in
`4/54 patients and CB in 25/54 patients.
`Eighty—two percent (42/51) of the patients who
`did not derive CB from fulvestrant received an AI as
`
`third—line therapy (Table 3): anastrozole (n = 34)
`or letrozole (n = 8). The remaining patients (18%)
`were treated with either megestrol acetate (n = 6) or
`medroxyprogesterone acetate (n = 3). The proportion
`of patients gaining an OR or CB in response to endo-
`crine therapy was lower (1/51 and 18/51, respectively),
`compared with patients who gained an initial CB from
`fulvestrant.
`
`A preliminary analysis of the duration of response
`data (defined as being from the start of treatment
`through to the date of progression; DOR) showed that
`the median DoR for patients (n = 24) who had CB
`with fulvestrant was 383 days. For patients (n = 18)
`who did not derive CB on fulvestrant, the DoR on sub-
`sequent endocrine therapy was 318 days. Further as-
`sessment of endocrine agents subsequent to fulvestrant
`
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`210
`
`I Vergote et al.
`Table 3. Response to subsequent endocrine therapy in patients who did not derive CB from fulvestrant
`(combined data from trials 0020 and 0021)
`
`Number of patients
`
`PR
`
`1
`1
`1
`0
`
`0
`0
`
`SD
`3 24 weeks
`
`Progression
`
`Total
`
`17
`15
`11
`4
`
`1
`1
`
`33
`26
`22
`4
`
`5
`2
`
`51
`42
`34
`8
`
`6
`3
`
`Endocrine therapy total
`AIs
`Anastroznle
`Letrozole
`
`Megestrol acetate
`Medroxyprogesterone acetate
`
`was not performed, due to an imbalance between the
`numbers of patients treated with each agent.
`
`Discussion
`
`Extending the period during which endocrine ther-
`apy may be used as an effective and viable treatment
`option for advanced or metastatic breast cancer in
`postmenopausal women is an important goal. No cura-
`tive treatment is currently available for many of these
`patients, and the ability of endocrine therapy to induce
`responses without producing debilitating toxicities is
`very valuable. Indeed, many patients are able to derive
`months, or even years, of high—quality life using se-
`quential endocrine treatment [4]. This sequential use
`depends on the availability of endocrine agents with
`differential mechanisms of action, thus avoiding prob-
`lems of cross-resistance between the various therapies.
`This report represents the first examination of
`sequential endocrine therapy incorporating the ER
`antagonist fulvestrant before AIs. The results demon-
`strate that after sequential treatment with tamoxifen
`and fulvestrant, many patients retain sensitivity to
`further endocrine therapy with third-generation AIs
`such as anastrozole and letrozole, or progestins such
`as megestrol acetate. The rates of CB reported here
`with endocrine therapy after fulvestrant are similar to
`those reported for therapy with other endocrine agents
`(30—50%) [15—17]. Similarly, the CB rates obtained
`after third-line use of Ms reported here are com-
`parable with previous studies [l8]. This indicates
`that there appears to be incomplete cross-resistance
`between the different endocrine therapies examined.
`
`The data in this report are limited by the retro-
`spective nature of their collection and the lack of
`randomization inherent in the use of a questionnaire.
`Nevertheless, within the limita1:ions imposed by the
`method used here, responsiveness to fulvestrant ap-
`pears to be associated with a slightly higher response
`to subsequent endocrine therapy, compared with those
`patients who failed to show CB on fulvestrant. Many
`of these observed responses were SD. The clinical rel-
`evance of SD has been demonstrated in a study which
`showed that patients whose disease stabilized for more
`than 24 weeks after receiving endocrine therapy, ex-
`hibited similar survival to patients who achieved an
`OR [19]. In addition, patients with an SD response
`to initial endocrine therapy appear to respond to treat-
`ment with subsequent endocrine agents equally as well
`as patients who derive a CR or PR to initial therapy
`[20]. Importantly,
`this suggests that despite the de-
`velopment of resistance, a response to one endocrine
`agent may predict a response to subsequent agents
`[20, 21]. Thus, only after failure of multiple prior
`endocrine therapies would patients be candidates for
`chemotherapy.
`Following progression on tamoxifen, fulvestrant
`provides an effective treatment option in addition to
`the currently available endocrine therapies for ad-
`vanced breast cancer. Progression following treatment
`with an SERM, and subsequent treatment with an anti-
`estrogen with pure antagonistic properties, does not
`appear to lead to complete cross-resistance with Als.
`Fulvestrant may therefore extend the opportunity for
`the use of endocrine therapies before reliance on cyto-
`toxic chemotherapy is necessary. In future studies it
`will be important to examine the activity of fulvestrant
`after disease progression on AIs, and initial results
`
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`Astrazeneca Ex. 2059 p. 4
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`indicate that CB is observed in patients receiving ful-
`vestrant subsequent to progression on prior treatment
`with AIs [22]. Data from this and similar trials will
`be important in further establishing the positioning of
`fulvestrant in the endocrine sequence for the treatment
`of advanced breast cancer.
`
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`Ignace Vergote, Uni-
`Address for ojfprints and carrespondence:
`versity Hospitals Leuven, Department of Gynecologic Oncol-
`ogy, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; Tel.:
`+32-16-34-46-35; Fax: +32-16-34-46-29; E-mail: Ignace.Vergote@
`uz.kuleuven.ac.be
`
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