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Fulvestrant: Expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer
ARTICLE IN PRESS THE BREAST The Breast 17 (2008) S16–S21 www.elsevier.com/locate/breast
Original article
Fulvestrant: Expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer Stephen Chiaa,, William Gradisharb a
Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada b Northwestern University Feinberg School of Medicine, USA
Abstract With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptorpositive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (FaslodexTM) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment. r 2008 Published by Elsevier Ltd. Keywords: Fulvestrant; Endocrine therapy; Advanced breast cancer; Early breast cancer
Introduction In 2005, adjuvant endocrine treatment guidelines for postmenopausal breast cancer were changed. For the first time, it was proposed that adjuvant endocrine therapy for postmenopausal women with early hormone receptorpositive breast cancer should include a third-generation aromatase inhibitor (AI).1–5 Consequently, an increasing number of patients in clinical practice today will be treated with an AI as the preferred treatment option. However, despite the superior efficacy profile of the AIs compared with tamoxifen, some patients with early disease will eventually experience a recurrence of their breast cancer and progress to advanced disease and all those with preCorresponding author. Tel.: +1 604 877 6098; fax: +1 604 877 0585.
E-mail address: [email protected] (S. Chia). 0960-9776/$ - see front matter r 2008 Published by Elsevier Ltd. doi:10.1016/j.breast.2007.12.004
existing advanced disease will experience further progression events. Therefore, there is a need to evaluate appropriate endocrine treatment options following AI failure. Until recently, clinical trial research in advanced disease focused on treatment following tamoxifen failure, with the AIs and fulvestrant all shown to be effective treatment options in this setting. As clinical practice changes and AIs replace tamoxifen as the treatment of choice in postmenopausal women, a shift in clinical trial design is also needed. Several endocrine therapy options with varying modes of action are now available, and it is often standard practice that following the failure of one endocrine option another is introduced. Resistance to subsequent endocrine therapies is thought to be reduced if an endocrine treatment from a different class or with a differing mode of action is used. Fulvestrant (FaslodexTM) is an oestrogen receptor (ER)
ARTICLE IN PRESS S. Chia, W. Gradishar / The Breast 17 (2008) S16–S21
antagonist that binds to and downregulates the ER in a mechanism that is distinct from that of the AIs or tamoxifen (a selective ER modulator). Fulvestrant is at least as effective as anastrozole in postmenopausal women with advanced breast cancer who had progressed while on anti-oestrogen therapy (predominantly tamoxifen), while Phase II data have indicated it also has efficacy against breast cancers that progressed during therapy with an AI.6,7 Recently, fulvestrant was compared with exemestane in the Evaluation of Faslodex and Exemestane Clinical Trial (EFECT), which investigated these two agents in postmenopausal women who had progressed or recurred following non-steroidal AI treatment (anastrozole or letrozole).8 The EFECT trial EFECT is a randomised, double-blind, double-dummy, multicentre study, and the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and exemestane following the failure of a non-steroidal AI.8 Women who had hormone receptor-positive locally advanced or metastatic breast cancer and had progressed during nonsteroidal AI therapy or recurred while receiving adjuvant therapy with a non-steroidal AI were enrolled. In total, 693 patients were randomised to receive either fulvestrant (n ¼ 351) or exemestane (n ¼ 342). Patients who were randomised to fulvestrant received 2 250 mg IM injections on Day 0, 250 mg on Days 14 and 28, and 250 mg every 2873 days thereafter (plus exemestane placebo). Exemestane was administered at a dose of 25 mg orally per day (plus fulvestrant placebo). Approximately 60% of patients had received X2 prior endocrine therapies and approximately 60% had visceral involvement. Patients were followed until progression, withdrawal or death. Median time to progression, which was the primary endpoint of EFECT, was 3.7 months in both the fulvestrant and exemestane groups (Table 1) (hazard ratio (HR) 0.963; 95% confidence intervals (CI) 0.819, 1.133; p ¼ 0.6531). A prospective analysis in patients who were evaluable for response revealed 7.4% achieved an objective response (OR) in the fulvestrant group compared with 6.7% in the exemestane group (OR 1.120; 95% CI 0.578, 2.186; p ¼ 0.7364), and 32.2% of fulvestrant patients gained clinical benefit (CB; defined as an OR or stable disease X6 months) compared with 31.5% of patients receiving exemestane (OR 1.035; 95% CI 0.720, 1.487; p ¼ 0.8534) (Table 1). In those who responded to endocrine treatment, duration of response was 13.5 months with fulvestrant versus 9.8 months with exemestane (Table 1). In patients experiencing CB, median duration of CB with fulvestrant compared with exemestane was 9.3 months versus 8.3 months, respectively (Table 1; Fig. 1). In a retrospective subgroup analysis of second-line AI-sensitive patients, there was a visual separation in the curves for time to progression between fulvestrant and exemestane from approximately 6 months onwards
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Table 1 Time to progression (TTP), objective response (OR), clinical benefit (CB) and duration of CB, for patients receiving fulvestrant and exemestane in EFECT, overall and according to visceral metastases8,9 Median TTP, months
Total population Fulvestrant Exemestane
3.7 3.7
Patients with visceral metastases Fulvestrant 3.1 Exemestane 2.8 Patients with no visceral metastases Fulvestrant 4.1 Exemestane 5.2 a
OR, n (%)
CB, n (%)
Median duration of CB, monthsa
20 (7.4) 18 (6.7)
87 (32.2) 85 (31.5)
9.3 8.3
13 (7.1) 8 (4.4)
53 (29.1) 50 (27.2)
9.9 8.1
7 (8.0) 10 (11.6)
34 (38.6) 35 (40.7)
8.0 8.6
Retrospective analysis.
Fig. 1. Duration of clinical benefit in patients receiving fulvestrant or exemestane in the EFECT trial.
(Fig. 2). Although median time to progression was similar for both groups (3.8 months versus 3.7 months, respectively; HR 0.73; 99.8% CI 0.45, 1.19), it raises the question of whether there is a potential benefit for fulvestrant over exemestane in this setting. Both agents also demonstrated good CB in the subgroup of patients who had visceral metastases (Table 1), although median duration of CB (9.9 months versus 8.1 months) in these patients was slightly longer in the fulvestrant group compared with the exemestane group.9 Patients with visceral metastases are widely acknowledged to be less responsive to hormonal therapy than non-visceral metastases, with the result that they are commonly treated with cytotoxic chemotherapy,10 and so activity of endocrine therapy in this group is encouraging and raises the profile of hormonal therapy in this cohort of patients.11 Fulvestrant and exemestane were both well tolerated in EFECT. Withdrawals due to adverse events were low in both treatment groups (2.0% fulvestrant; 2.6% exemestane), and there were no differences in the reported adverse
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steroidal AI. The results from EFECT corroborate the efficacy findings reported for fulvestrant in the posttamoxifen setting. No other endocrine agent has been shown to be more effective than fulvestrant in either of these scenarios. In addition, in both settings fulvestrant was associated with a prolonged duration of response and duration of CB, and was effective in patients with visceral metastases who are traditionally more difficult to treat with endocrine therapies. Which patients are candidates for treatment with fulvestrant?
Fig. 2. Time to progression in a subset of patients from EFECT who were AI-sensitive and receiving fulvestrant or exemestane as second-line endocrine treatment.8 [Reprinted with permission from the American Society of Clinical Oncology. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo-controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. Published online March 3, 2008 10.1200/JCO.2007.13.5822].
Table 2 Analysis of pre-specified adverse event categories in EFECT
Weight gain Increased appetite Hot flushes Joint disorders Nausea and/or vomiting Diarrhoea Androgenic effects Injection-site reactions
Fulvestrant, n (%)
Exemestane, n (%)
p-Value
4 (1.1) 2 (0.6) 47 (13.4) 93 (26.5) 88 (25.1) 46 (13.1) 15 (4.3) 56 (16.0)
3 (0.9) 1 (0.3) 54 (15.9) 99 (29.1) 84 (24.7) 46 (13.5) 12 (3.5) 46 (13.5)
40.999 40.999 0.389 0.446 0.930 0.911 0.6966 0.392
events for fulvestrant or exemestane. The most common events included joint disorders and hot flushes, which are expected with anti-oestrogen therapies, and nausea and diarrhoea (Table 2). Clinical implications of EFECT Until EFECT, our knowledge of fulvestrant in controlled clinical trials predominantly came from the posttamoxifen setting, including two large Phase III trials versus anastrozole (Trials 0020/21)12,13 and supportive data published from the fulvestrant compassionate use programme.14 With the shift in current treatment paradigms to include AIs earlier in the treatment sequence, data from EFECT are essential in increasing our understanding of the use of fulvestrant in the endocrine treatment sequence. EFECT confirmed that fulvestrant and exemestane are effective and safe treatment options for patients who have progressed or recurred following treatment with a non-
The data from Trials 0020/21 and EFECT show that fulvestrant is a valid option for all patients progressing or recurring while on tamoxifen or a non-steroidal AI. Additionally, there may be particular groups of patients who will be especially well-suited to fulvestrant treatment, not least because of its requirement for once-monthly injections, but also for its favourable tolerability profile, as shown in Phase III trials.12,13 Compliance to oral medication is generally a major challenge for clinical practice and remains an issue even in potentially life-threatening conditions such as cancer. In one study where 131 patients with stable breast cancer were interviewed, 55% admitted being non-compliant to their breast cancer medication frequently or occasionally.15 Patients may choose not to comply with medication for several reasons, including side effects, the benefits of treatment not being immediately obvious, patients not wanting a daily reminder of the disease, and a lack of psychological adaptation to needing the medication. However, Atkins and Fallowfield reported that of the patients who were non-compliant to medication, 83.3% were unintentionally non-compliant.15 This may happen for many reasons but a common factor may be the level of polypharmacy occurring in the advanced breast cancer setting. Many patients with advanced breast cancer, particularly the elderly, are prescribed multiple concomitant oral medications for comorbid conditions.16 Additional prescriptions for tablets can cause confusion and difficulty in remembering to take the correct medication— such patients may find the IM route of administration of fulvestrant attractive, as may patients who have difficulty in swallowing tablets. Although the majority of patients prefer oral medications, few patients have true injection phobias and most are happy to receive IM injections. In fact, in a recent study 25% of breast cancer patients stated that they preferred receiving their medication via this route.17 Furthermore, monthly injections mean more regular contact with healthcare professionals and so the parenteral administration route of fulvestrant may also be preferred by patients who like the support of regular clinic visits. Special consideration should also be given to patients with low bone mineral density, arthralgia or other musculoskeletal problems. The AIs have been associated with increased levels of arthralgia and fractures compared with tamoxifen.18–20 Fulvestrant was associated with
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significantly lower levels of joint disorders compared with anastrozole,21 although in EFECT the incidence was similar between fulvestrant and exemestane.8 It is possible that the residual effect of prior AI therapy may have masked any difference between treatments in the EFECT trial. In addition, bone marker data from postmenopausal women with breast cancer who were treated with fulvestrant over a 6-month treatment period indicate stability of bone turnover in patients receiving fulvestrant.22 Therefore, fulvestrant may also be a preferable option for patients with pre-existing bone or joint issues, or those who have encountered such problems during prior AI treatment. Where next for fulvestrant? Is there potential for a high-dose regimen? The approved dosing regimen for fulvestrant is a 250 mg IM injection once per month. While this dose is effective, it takes approximately 3–6 months to achieve steady-state plasma levels of fulvestrant. The loading-dose regimen used in EFECT successfully achieved steady-state plasma levels within 1 month. But is there also potential for a high-dose regimen of fulvestrant? An early study of the effects of fulvestrant versus tamoxifen or placebo on tumour ER and progesterone receptor (PgR) content revealed that fulvestrant induces ER downregulation in a dose-dependent manner.23 Fulvestrant 50 mg reduced the ER content from baseline by 39%, while fulvestrant 125 and 250 mg led to reductions of 50% and 59%, respectively. In addition, clinical data have shown a longer median time to progression in patients receiving higher doses (250 mg versus 125 mg) of fulvestrant.24,25 All these data suggest that increasing doses of fulvestrant achieve greater ER downregulation.26 The high-dose (500 mg/month) regimen for fulvestrant is being investigated in the ongoing Comparison of Faslodex in Recurrent or Metastatic breast cancer (CONFIRM) trial (Fig. 3). In CONFIRM, 720 postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have progressed on one prior endocrine therapy are being randomised to either the approved dose or the high-dose regimen of fulvestrant and followed until progression. This will be the first Phase III trial to directly compare these two dosing regimens and should determine any benefit from an increased monthly fulvestrant dose. Could additional benefits be gained by combining fulvestrant with an AI? Preclinical data suggest that fulvestrant may be particularly effective in a low-oestrogen environment such as that produced in the presence of an AI.27 In line with this, it has now been shown that fulvestrant plus letrozole is more active than either agent alone in murine tumour xeno-
Fig. 3. Ongoing clinical trials (schemas for CONFIRM, SWOG, FACT, and NEWEST).
grafts,28 and several Phase III clinical trials are underway to investigate the combination of fulvestrant with an AI. The Southwestern Oncology Group (SWOG) S0266 and Fulvestrant and Anastrozole Clinical Trial (FACT) studies are currently evaluating the efficacy of fulvestrant plus anastrozole versus anastrozole alone as first-line treatments for patients with advanced disease (Fig. 3). Who benefits most from fulvestrant? Not all tumours expressing hormone receptors will respond to endocrine therapy, and the quality and quantity of response amongst responsive patients may differ between treatments. Although the mechanisms are not fully understood, it has been observed that patients who respond to fulvestrant generally demonstrate a good duration of response and duration of CB.24 From a clinical standpoint, it would be useful if the patients most likely to respond to fulvestrant treatment could be identified upfront as these are the patients who are likely to gain maximum benefit. In addition, biological markers may be
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S. Chia, W. Gradishar / The Breast 17 (2008) S16–S21
useful in this respect and some will be investigated in studies such as the NEWEST (Neoadjuvant Endocrine therapy for Women with Estrogen-Sensitive Tumors) trial. NEWEST is a randomised Phase II study comparing the approved fulvestrant dose (250 mg/month) and the fulvestrant high dose (500 mg/month plus 500 mg on Day 14 of Month 1) as neoadjuvant therapy for postmenopausal women with newly diagnosed, locally advanced breast cancer (Fig. 3). In addition to biological endpoint (ER, PgR and Ki67) analyses, exploratory biomarker and expression gene array analyses will be performed in order to explore their prognostic and/or predictive value in relation to response and dose of fulvestrant treatment.
3.
4.
5.
6.
7.
Conclusions EFECT has significantly broadened our understanding of the role of fulvestrant in the endocrine treatment sequence. Along with exemestane, fulvestrant now has confirmed activity in the treatment of advanced disease following non-steroidal AI failure. Although both agents provide valid treatment options in this setting, certain patients, for example, those with compliance issues or those with bone or joint problems, may be particularly wellsuited to fulvestrant treatment. Fulvestrant has now demonstrated efficacy in the post-tamoxifen and post-AI settings. The ability to identify those patients who are more likely to respond, using baseline clinical and/or biological markers will be invaluable for the optimal clinical use of this novel endocrine treatment. Results from ongoing trials evaluating new dosing and combination regimens, as well as assessing the utility of clinical or biological markers of response, are awaited with interest.
8.
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12.
13.
Conflict of Interest Statement Honorarium received for speaking engagements and Advisory Boards by Astra-Zeneca Canada by AstraZeneca Canada for prospective clinical and tissue bank of post-menopausal women starting aromatase inhibitors in British Columbia. Acknowledgement
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15.
16. 17.
The authors would like to thank Nicole Jones from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. References 1. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptorpositive breast cancer: status report 2004. J Clin Oncol 2005;23: 619–29. 2. Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmeno-
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pausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007;25:486–92. Coombes RC, Paridaens R, Jassem J, Van de Velde CJ, Delozier T, Jones SE, et al. First mature analysis of the Intergroup Exemestane Study. J Clin Oncol 2006;24(Part I):18S. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349: 1793–802. Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366:455–62. Ingle JN, Suman VJ, Rowland KM, et al. Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial n0032. J Clin Oncol 2006;24:1052–6. Perey L, Paridaens R, Hawle H, et al. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss group for clinical cancer research trial (SAKK 21/00). Ann Oncol 2007;18:64–9. Chia S, Gradishar W, Mauriac L, et al. A Double-blind, randomized, placebo-controlled trial of fulvestrant compared with exemestane after prior non steroidal aromatase inhibitor therapy in post menopausal women with hormone receptor-positive advanced breast cancer: Results from EFECT. J Clin Oncol Published online March 3, 2008, 10.1200/JCO.2007.13.5822. Romieu G, Bines J, Mauriac L. Activity of fulvestrant in patients with visceral metastases: results from EFECT. Eur J Cancer Suppl 2007;5: 222 abs 2126. Ellis MJ, Hayes DF, Lippman M. Treatment of metastatic breast cancer. In: Harris JR, editor. Diseases of the breast. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 749–97. Kuerer HM, Buzdar AU, Singletary E. Biologic basis and evolving role of aromatase inhibitors in the management of invasive carcinoma of the breast. J Surg Oncol 2001;77:139–47. Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer 2003;98:229–38. Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer 2005;104:236–9. Steger GG, Gips M, Simon SD, et al. Fulvestrant (‘Faslodex’): clinical experience from the compassionate use programme. Cancer Treat Rev 2005;31(Suppl. 2):S10–6. Atkins L, Fallowfield L. Intentional and non-intentional nonadherence to medication amongst breast cancer patients. Eur J Cancer 2006;42:2271–6. Robertson JFR. Incidence of polypharmacy in patients with breast cancer. Breast 2005;14(Suppl. 1):S39. Fallowfield L, Atkins L, Catt S, et al. Patients’ preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol 2006;17:205–10. ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–2. Thurlimann B, Keshaviah A, Coates A, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–57. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007;369:559–70. Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in
ARTICLE IN PRESS S. Chia, W. Gradishar / The Breast 17 (2008) S16–S21 postmenopausal women—a prospective combined analysis of two multicenter trials. Cancer 2003;98:229–38. 22. Robertson JFR, Agrawal A, Hannon RA, Cheung KL, Eastell R. Bone turnover markers in postmenopausal breast cancer patients treated with fulvestrant. Breast 2007;16:S53. 23. Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5,(10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res 2001;61:6739–46. 24. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20:3386–95.
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25. Howell A, Robertson JFR, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396–403. 26. Robertson JF. Fulvestrant (Faslodex) how to make a good drug better. Oncologist 2007;12:774–84. 27. Martin L-A, Farmer I, Johnston SRD, et al. Enhanced estrogen receptor (ER) a, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 2003;278:30458–68. 28. Jelovac D, Macedo L, Goloubeva OG, Handratta V, Brodie AM. Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res 2005;65:5439–44.
Original article
Fulvestrant: Expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer Stephen Chiaa,, William Gradisharb a
Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada b Northwestern University Feinberg School of Medicine, USA
Abstract With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptorpositive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (FaslodexTM) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment. r 2008 Published by Elsevier Ltd. Keywords: Fulvestrant; Endocrine therapy; Advanced breast cancer; Early breast cancer
Introduction In 2005, adjuvant endocrine treatment guidelines for postmenopausal breast cancer were changed. For the first time, it was proposed that adjuvant endocrine therapy for postmenopausal women with early hormone receptorpositive breast cancer should include a third-generation aromatase inhibitor (AI).1–5 Consequently, an increasing number of patients in clinical practice today will be treated with an AI as the preferred treatment option. However, despite the superior efficacy profile of the AIs compared with tamoxifen, some patients with early disease will eventually experience a recurrence of their breast cancer and progress to advanced disease and all those with preCorresponding author. Tel.: +1 604 877 6098; fax: +1 604 877 0585.
E-mail address: [email protected] (S. Chia). 0960-9776/$ - see front matter r 2008 Published by Elsevier Ltd. doi:10.1016/j.breast.2007.12.004
existing advanced disease will experience further progression events. Therefore, there is a need to evaluate appropriate endocrine treatment options following AI failure. Until recently, clinical trial research in advanced disease focused on treatment following tamoxifen failure, with the AIs and fulvestrant all shown to be effective treatment options in this setting. As clinical practice changes and AIs replace tamoxifen as the treatment of choice in postmenopausal women, a shift in clinical trial design is also needed. Several endocrine therapy options with varying modes of action are now available, and it is often standard practice that following the failure of one endocrine option another is introduced. Resistance to subsequent endocrine therapies is thought to be reduced if an endocrine treatment from a different class or with a differing mode of action is used. Fulvestrant (FaslodexTM) is an oestrogen receptor (ER)
ARTICLE IN PRESS S. Chia, W. Gradishar / The Breast 17 (2008) S16–S21
antagonist that binds to and downregulates the ER in a mechanism that is distinct from that of the AIs or tamoxifen (a selective ER modulator). Fulvestrant is at least as effective as anastrozole in postmenopausal women with advanced breast cancer who had progressed while on anti-oestrogen therapy (predominantly tamoxifen), while Phase II data have indicated it also has efficacy against breast cancers that progressed during therapy with an AI.6,7 Recently, fulvestrant was compared with exemestane in the Evaluation of Faslodex and Exemestane Clinical Trial (EFECT), which investigated these two agents in postmenopausal women who had progressed or recurred following non-steroidal AI treatment (anastrozole or letrozole).8 The EFECT trial EFECT is a randomised, double-blind, double-dummy, multicentre study, and the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and exemestane following the failure of a non-steroidal AI.8 Women who had hormone receptor-positive locally advanced or metastatic breast cancer and had progressed during nonsteroidal AI therapy or recurred while receiving adjuvant therapy with a non-steroidal AI were enrolled. In total, 693 patients were randomised to receive either fulvestrant (n ¼ 351) or exemestane (n ¼ 342). Patients who were randomised to fulvestrant received 2 250 mg IM injections on Day 0, 250 mg on Days 14 and 28, and 250 mg every 2873 days thereafter (plus exemestane placebo). Exemestane was administered at a dose of 25 mg orally per day (plus fulvestrant placebo). Approximately 60% of patients had received X2 prior endocrine therapies and approximately 60% had visceral involvement. Patients were followed until progression, withdrawal or death. Median time to progression, which was the primary endpoint of EFECT, was 3.7 months in both the fulvestrant and exemestane groups (Table 1) (hazard ratio (HR) 0.963; 95% confidence intervals (CI) 0.819, 1.133; p ¼ 0.6531). A prospective analysis in patients who were evaluable for response revealed 7.4% achieved an objective response (OR) in the fulvestrant group compared with 6.7% in the exemestane group (OR 1.120; 95% CI 0.578, 2.186; p ¼ 0.7364), and 32.2% of fulvestrant patients gained clinical benefit (CB; defined as an OR or stable disease X6 months) compared with 31.5% of patients receiving exemestane (OR 1.035; 95% CI 0.720, 1.487; p ¼ 0.8534) (Table 1). In those who responded to endocrine treatment, duration of response was 13.5 months with fulvestrant versus 9.8 months with exemestane (Table 1). In patients experiencing CB, median duration of CB with fulvestrant compared with exemestane was 9.3 months versus 8.3 months, respectively (Table 1; Fig. 1). In a retrospective subgroup analysis of second-line AI-sensitive patients, there was a visual separation in the curves for time to progression between fulvestrant and exemestane from approximately 6 months onwards
S17
Table 1 Time to progression (TTP), objective response (OR), clinical benefit (CB) and duration of CB, for patients receiving fulvestrant and exemestane in EFECT, overall and according to visceral metastases8,9 Median TTP, months
Total population Fulvestrant Exemestane
3.7 3.7
Patients with visceral metastases Fulvestrant 3.1 Exemestane 2.8 Patients with no visceral metastases Fulvestrant 4.1 Exemestane 5.2 a
OR, n (%)
CB, n (%)
Median duration of CB, monthsa
20 (7.4) 18 (6.7)
87 (32.2) 85 (31.5)
9.3 8.3
13 (7.1) 8 (4.4)
53 (29.1) 50 (27.2)
9.9 8.1
7 (8.0) 10 (11.6)
34 (38.6) 35 (40.7)
8.0 8.6
Retrospective analysis.
Fig. 1. Duration of clinical benefit in patients receiving fulvestrant or exemestane in the EFECT trial.
(Fig. 2). Although median time to progression was similar for both groups (3.8 months versus 3.7 months, respectively; HR 0.73; 99.8% CI 0.45, 1.19), it raises the question of whether there is a potential benefit for fulvestrant over exemestane in this setting. Both agents also demonstrated good CB in the subgroup of patients who had visceral metastases (Table 1), although median duration of CB (9.9 months versus 8.1 months) in these patients was slightly longer in the fulvestrant group compared with the exemestane group.9 Patients with visceral metastases are widely acknowledged to be less responsive to hormonal therapy than non-visceral metastases, with the result that they are commonly treated with cytotoxic chemotherapy,10 and so activity of endocrine therapy in this group is encouraging and raises the profile of hormonal therapy in this cohort of patients.11 Fulvestrant and exemestane were both well tolerated in EFECT. Withdrawals due to adverse events were low in both treatment groups (2.0% fulvestrant; 2.6% exemestane), and there were no differences in the reported adverse
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steroidal AI. The results from EFECT corroborate the efficacy findings reported for fulvestrant in the posttamoxifen setting. No other endocrine agent has been shown to be more effective than fulvestrant in either of these scenarios. In addition, in both settings fulvestrant was associated with a prolonged duration of response and duration of CB, and was effective in patients with visceral metastases who are traditionally more difficult to treat with endocrine therapies. Which patients are candidates for treatment with fulvestrant?
Fig. 2. Time to progression in a subset of patients from EFECT who were AI-sensitive and receiving fulvestrant or exemestane as second-line endocrine treatment.8 [Reprinted with permission from the American Society of Clinical Oncology. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo-controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. Published online March 3, 2008 10.1200/JCO.2007.13.5822].
Table 2 Analysis of pre-specified adverse event categories in EFECT
Weight gain Increased appetite Hot flushes Joint disorders Nausea and/or vomiting Diarrhoea Androgenic effects Injection-site reactions
Fulvestrant, n (%)
Exemestane, n (%)
p-Value
4 (1.1) 2 (0.6) 47 (13.4) 93 (26.5) 88 (25.1) 46 (13.1) 15 (4.3) 56 (16.0)
3 (0.9) 1 (0.3) 54 (15.9) 99 (29.1) 84 (24.7) 46 (13.5) 12 (3.5) 46 (13.5)
40.999 40.999 0.389 0.446 0.930 0.911 0.6966 0.392
events for fulvestrant or exemestane. The most common events included joint disorders and hot flushes, which are expected with anti-oestrogen therapies, and nausea and diarrhoea (Table 2). Clinical implications of EFECT Until EFECT, our knowledge of fulvestrant in controlled clinical trials predominantly came from the posttamoxifen setting, including two large Phase III trials versus anastrozole (Trials 0020/21)12,13 and supportive data published from the fulvestrant compassionate use programme.14 With the shift in current treatment paradigms to include AIs earlier in the treatment sequence, data from EFECT are essential in increasing our understanding of the use of fulvestrant in the endocrine treatment sequence. EFECT confirmed that fulvestrant and exemestane are effective and safe treatment options for patients who have progressed or recurred following treatment with a non-
The data from Trials 0020/21 and EFECT show that fulvestrant is a valid option for all patients progressing or recurring while on tamoxifen or a non-steroidal AI. Additionally, there may be particular groups of patients who will be especially well-suited to fulvestrant treatment, not least because of its requirement for once-monthly injections, but also for its favourable tolerability profile, as shown in Phase III trials.12,13 Compliance to oral medication is generally a major challenge for clinical practice and remains an issue even in potentially life-threatening conditions such as cancer. In one study where 131 patients with stable breast cancer were interviewed, 55% admitted being non-compliant to their breast cancer medication frequently or occasionally.15 Patients may choose not to comply with medication for several reasons, including side effects, the benefits of treatment not being immediately obvious, patients not wanting a daily reminder of the disease, and a lack of psychological adaptation to needing the medication. However, Atkins and Fallowfield reported that of the patients who were non-compliant to medication, 83.3% were unintentionally non-compliant.15 This may happen for many reasons but a common factor may be the level of polypharmacy occurring in the advanced breast cancer setting. Many patients with advanced breast cancer, particularly the elderly, are prescribed multiple concomitant oral medications for comorbid conditions.16 Additional prescriptions for tablets can cause confusion and difficulty in remembering to take the correct medication— such patients may find the IM route of administration of fulvestrant attractive, as may patients who have difficulty in swallowing tablets. Although the majority of patients prefer oral medications, few patients have true injection phobias and most are happy to receive IM injections. In fact, in a recent study 25% of breast cancer patients stated that they preferred receiving their medication via this route.17 Furthermore, monthly injections mean more regular contact with healthcare professionals and so the parenteral administration route of fulvestrant may also be preferred by patients who like the support of regular clinic visits. Special consideration should also be given to patients with low bone mineral density, arthralgia or other musculoskeletal problems. The AIs have been associated with increased levels of arthralgia and fractures compared with tamoxifen.18–20 Fulvestrant was associated with
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significantly lower levels of joint disorders compared with anastrozole,21 although in EFECT the incidence was similar between fulvestrant and exemestane.8 It is possible that the residual effect of prior AI therapy may have masked any difference between treatments in the EFECT trial. In addition, bone marker data from postmenopausal women with breast cancer who were treated with fulvestrant over a 6-month treatment period indicate stability of bone turnover in patients receiving fulvestrant.22 Therefore, fulvestrant may also be a preferable option for patients with pre-existing bone or joint issues, or those who have encountered such problems during prior AI treatment. Where next for fulvestrant? Is there potential for a high-dose regimen? The approved dosing regimen for fulvestrant is a 250 mg IM injection once per month. While this dose is effective, it takes approximately 3–6 months to achieve steady-state plasma levels of fulvestrant. The loading-dose regimen used in EFECT successfully achieved steady-state plasma levels within 1 month. But is there also potential for a high-dose regimen of fulvestrant? An early study of the effects of fulvestrant versus tamoxifen or placebo on tumour ER and progesterone receptor (PgR) content revealed that fulvestrant induces ER downregulation in a dose-dependent manner.23 Fulvestrant 50 mg reduced the ER content from baseline by 39%, while fulvestrant 125 and 250 mg led to reductions of 50% and 59%, respectively. In addition, clinical data have shown a longer median time to progression in patients receiving higher doses (250 mg versus 125 mg) of fulvestrant.24,25 All these data suggest that increasing doses of fulvestrant achieve greater ER downregulation.26 The high-dose (500 mg/month) regimen for fulvestrant is being investigated in the ongoing Comparison of Faslodex in Recurrent or Metastatic breast cancer (CONFIRM) trial (Fig. 3). In CONFIRM, 720 postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have progressed on one prior endocrine therapy are being randomised to either the approved dose or the high-dose regimen of fulvestrant and followed until progression. This will be the first Phase III trial to directly compare these two dosing regimens and should determine any benefit from an increased monthly fulvestrant dose. Could additional benefits be gained by combining fulvestrant with an AI? Preclinical data suggest that fulvestrant may be particularly effective in a low-oestrogen environment such as that produced in the presence of an AI.27 In line with this, it has now been shown that fulvestrant plus letrozole is more active than either agent alone in murine tumour xeno-
Fig. 3. Ongoing clinical trials (schemas for CONFIRM, SWOG, FACT, and NEWEST).
grafts,28 and several Phase III clinical trials are underway to investigate the combination of fulvestrant with an AI. The Southwestern Oncology Group (SWOG) S0266 and Fulvestrant and Anastrozole Clinical Trial (FACT) studies are currently evaluating the efficacy of fulvestrant plus anastrozole versus anastrozole alone as first-line treatments for patients with advanced disease (Fig. 3). Who benefits most from fulvestrant? Not all tumours expressing hormone receptors will respond to endocrine therapy, and the quality and quantity of response amongst responsive patients may differ between treatments. Although the mechanisms are not fully understood, it has been observed that patients who respond to fulvestrant generally demonstrate a good duration of response and duration of CB.24 From a clinical standpoint, it would be useful if the patients most likely to respond to fulvestrant treatment could be identified upfront as these are the patients who are likely to gain maximum benefit. In addition, biological markers may be
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useful in this respect and some will be investigated in studies such as the NEWEST (Neoadjuvant Endocrine therapy for Women with Estrogen-Sensitive Tumors) trial. NEWEST is a randomised Phase II study comparing the approved fulvestrant dose (250 mg/month) and the fulvestrant high dose (500 mg/month plus 500 mg on Day 14 of Month 1) as neoadjuvant therapy for postmenopausal women with newly diagnosed, locally advanced breast cancer (Fig. 3). In addition to biological endpoint (ER, PgR and Ki67) analyses, exploratory biomarker and expression gene array analyses will be performed in order to explore their prognostic and/or predictive value in relation to response and dose of fulvestrant treatment.
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Conclusions EFECT has significantly broadened our understanding of the role of fulvestrant in the endocrine treatment sequence. Along with exemestane, fulvestrant now has confirmed activity in the treatment of advanced disease following non-steroidal AI failure. Although both agents provide valid treatment options in this setting, certain patients, for example, those with compliance issues or those with bone or joint problems, may be particularly wellsuited to fulvestrant treatment. Fulvestrant has now demonstrated efficacy in the post-tamoxifen and post-AI settings. The ability to identify those patients who are more likely to respond, using baseline clinical and/or biological markers will be invaluable for the optimal clinical use of this novel endocrine treatment. Results from ongoing trials evaluating new dosing and combination regimens, as well as assessing the utility of clinical or biological markers of response, are awaited with interest.
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Conflict of Interest Statement Honorarium received for speaking engagements and Advisory Boards by Astra-Zeneca Canada by AstraZeneca Canada for prospective clinical and tissue bank of post-menopausal women starting aromatase inhibitors in British Columbia. Acknowledgement
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