Preliminary Data from Ongoing Adjuvant Aromatase Inhibitor Trials I

Vol. 7, 4397s-4401s, December 2001 (Suppl.) Clinical Cancer Research 4397s

Paul E. Goss z Introduction Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada The growth of hormone receptor-positive breast cancer can be altered clinically by several classes of agents that antagonize the effects of estrogen (1). The SERMs, 3 exemplified by tamox- Abstract ifen, constitute one such class of drugs. Pure antiestrogens such With recent results showing letrozole and anastrozole as fulvestrant (Faslodex) also exert a potent antiestrogenic effect to be superior to tamoxifen as initial therapy for advanced and show efficacy in tamoxifen-resistant cell lines in preclinical disease, the aromatase inhibitors are poised to establish their models. Thus, unlike tamoxifen, which exerts both an agonist place in the adjuvant therapy of postmenopausal receptor- and an antagonist effect, fulvestrant is a pure antagonist and acts positive breast cancer. A review of the rationale, design, and by down-regulating ER content (2). preliminary results of the ongoing adjuvant trials that in- Aromatase (estrogen synthetase) inhibitors antagonize the clude aromatase inhibitors will be presented, along with the action of estrogen by reducing its levels both in the circulation ongoing or planned substudies. Two strategies employing and in normal and malignant breast tissue (3). They were ini- aromatase inhibitors after tamoxifen are being evaluated. tially tested in postmenopausal women with breast cancer progression after tamoxifen treatment. A superior outcome with The MA.17 international intergroup trial is randomizing these drugs compared to either megestrol acetate or aminoglu- postmenopausal patients who are disease-free after 5 years tethimide resulted in their becoming the established second-line of adjuvant tamoxifen to an additional 5 years of ietrozole or treatment for ER-positive metastatic breast cancer (4-13). More placebo. In a similar design, the National Surgical Adjuvant recently, three of the selective third-generation inhibitors, anas- Breast and Bowel Project (NSABP) B33 trial is randomizing trozole, letrozole, and exemestane, have been compared to ta- this patient population to 2 years of exemestane or placebo moxifen in the same setting (14-17). On the basis of both after the standard 5 years of adjuvant tamoxifen. The sec- improved efficacy and superior side effect profiles, anastrozole ond approach under study is the use of both aromatase and letrozole have now been approved for use as first-line inhibitor and tamoxifen in sequence within the first 5 post- treatment for women at first relapse of their disease. These data operative years. The International Cancer Collaboration are reviewed in detail elsewhere in this journal issue (18, 19). Group (ICCG) trial is comparing 2 years of exemestane Although useful in the treatment of advanced disease, the after 3 years of tamoxifen to a standard 5-year course of real benefits of tamoxifen have been seen in its ability to reduce tamoxifen. Similarly, the ARNO trial is comparing 5 years mortality by as much as one-third for up to 15 years after of tamoxifen versus 2 years of tamoxifen followed by 3 years primary surgery in women given 5 years of adjuvant treatment. 4 of anastrozole. In a four-arm study Breast International This makes tamoxifen one of the most successful anticancer Group/Femara-Tamoxifen (BIG/FEMTA) conducted by the therapeutics ever developed in terms of "number of years of life BIG, one arm contains letrozole given for 3 years after 2 saved." The recently demonstrated superiority of the aromatase years of tamoxifen. Several trials are investigating the role of inhibitors over tamoxifen in the advanced disease setting is, anastrozole, letrozole, or exemestane as a 5-year adjuvant therefore, a significant finding. Consequently, they are currently therapy to replace the standard 5 years of tamoxifen. Only being tested in the adjuvant setting in women with early-stage the Arimidex and Tamoxifen, Alone or in Combination breast cancer, and the results promise to alter the current treat- (ATAC) trial is testing a 5-year combination of tamoxifen ment paradigm of the disease. The trials that are ongoing and plus an aromatase inhibitor in this setting. Companion stud- their companion studies are briefly described. ies of effects on end-organs other than the breast are ongoing in a number of these trials. Aromatase inhibitors are Rationale and Design of Ongoing Adjuvant Trials poised to alter the treatment paradigm of breast cancer and Biological and Pharmacological Concepts: Disease "Re- hopefully improve outcome for a substantial number of sistance" Mechanisms. After initially responding to tamox- patients. ifen, metastatic breast cancer inevitably begins to progress de-

3 SERM, selective ER modulator; ER, estrogen receptor; BMD, bone 1 Presented at the First International Conference on Recent Advances mineral density; NSABP, National Surgical Adjuvant Breast and Bowel and Future Directions in Endocrine Therapy for Breast Cancer, June Project; NCIC, National Cancer Institute of Canada; CTG, Clinical 21-23, 2001, Cambridge, MA. Trials Group; ATAC, Arimidex and Tamoxifen, Alone or in Combina- z To whom requests for reprints should be addressed, at Princess Mar- tion (trial). garet Hospital, 610 University Avenue, Toronto, ON M5G 2M9, Can- 4 R. Peto, Oxford ECTG meta-analysis. Presented at Seventh Interna- ada. Phone: (416) 946-4501, extension 5103; Fax: (416) 946-2983; tional Conference on Adjuvant Therapy of Primary Breast Cancer, E-mail: [email protected]. February 21-24, 2001, St. Gallen, Switzerland. Unpublished data.

1 ll~.vno~nn,i~ l~.Qfrno~n Fig. 1 Five examples of potential mechanisms of stimulating 5.?E2 tumor cell growth: 1, exogenous estrogens; 2, ER mutation giving rise to estrogen hypersensitivity; 3, tumor cell estrogen syn- thesis by tumor aromatase; 4, 4. Estrogen circulating extratumoral (pe- ripheral) estrogens; and 5, es- Biosynthes~ trogenic tamoxifen metabolites. Tamoxifen could block 1 and 4, and aromatase inhibitors could address 2, 3, and 4. The relative importance of these pathways as mechanisms of tumor resistance either to tamoxifen or to the aromatase inhibitors could determine whether tamoxifen m or the inhibitors should be given first or whether they II- ,, should be given in combination.

spite ongoing therapy. On occasion, withdrawal of tamoxifen in may overcome the development of resistance by several of the this circumstance results in further clinical remission-a phe- mechanisms outlined above (Fig. 1). However, stimulation of a nomenon termed tamoxifen resistance or "dependence" (20, 21 ). "hypersensitive" receptor by exogenous estrogens or the agonist Further credence has been lent to this concept by the observation effects of tamoxifen and/or its metabolites would remain theo- in the NSABP B 14 trial and in a Scottish adjuvant trial (22, 23) retical mechanisms of resistance to this "total estrogen block- that patient outcome is worse if tamoxifen therapy is continued ade" strategy with combination therapy (Fig. 1). beyond 5 years of treatment. This has resulted in 5 years of Pharmacological Considerations. Pharmacological in- tamoxifen becoming the standard duration of treatment in the teraction between endocrine therapies may interfere with effi- adjuvant setting. cacy and disease outcome. Timing may be critical in switching Several theories have been offered as to the mechanism of from one treatment to another. For example, cells that have tamoxifen resistance. First, mutation of the ER has been dem- developed one or more of the resistance mechanisms outlined onstrated in MCF-7 cells, resulting in estrogen hypersensitivity above may be eradicated by subsequent therapy, provided the when passaged in estrogen-deprived media (20). This poten- switch is made promptly and the appropriate therapeutic doses tially results in tamoxifen exerting an estrogen agonistic effect. given. Potential problems exist with both of these requirements. It has been postulated that this may be enhanced by increasing First, drug interaction with tamoxifen results in a reduction in metabolism of tamoxifen to metabolites with weak estrogen the plasma levels of letrozole and anastrozole to 62.4% (26) and agonist action. In addition, hypersensitivity to residual estrogen 73% (27), respectively. It has been proposed that these small may result (Fig. 1). In vivo experiments have also shown that differences would unlikely be of importance, although they MCF-7 cells in nude mice initially regress in response to ta- might be in the presence of a hypersensitive receptor capable of moxifen but are later stimulated by its weak estrogen agonist being stimulated by very low picomolar concentrations of es- properties (24). Secondly, estrogen-deprived MCF-7 cells de- trogen. In addition, tamoxifen and its metabolites have very long velop up-regulation of aromatase, which may in turn result in half-lives and tissue binding (28), and by definition any switch increased autocrine stimulation by estrogen (20). In principle, from tamoxifen to an aromatase inhibitor would involve a tamoxifen might have the same effect. Thus, theoretically, ces- degree of combination therapy for a significant period. This sation of tamoxifen in a patient with disease progression, fol- could have therapeutic implications. lowed by the initiation of an aromatase inhibitor, might simul- Design of Ongoing Adjuvant Trials. A number of the taneously withdraw tamoxifen's estrogen agonist effect and trials are comparing an arm containing an aromatase inhibitor deplete both locally produced and circulating estrogen, to which given for 5 years against a standard 5 years of tamoxifen as the disease may be exquisitely sensitive (20, 21). immediate postoperative adjuvant therapy. The investigational Alternatively, breast cancer may be treated initially by an arm of these trials, which similarly are all given for 5 years, aromatase inhibitor, and tamoxifen or other endocrine therapy include the following configurations: an aromatase inhibitor, reserved for second-line treatment. Use of an aromatase inhib- tamoxifen followed by an inhibitor, an inhibitor followed by itor as first-line therapy is supported by the recent demonstration tamoxifen, and the combination of an inhibitor with tamoxifen. of superior outcomes both in first-line therapy and in the neo- A second set of trials are being conducted in which patients adjuvant setting (25). Finally, combination therapy with an completing 5 years of adjuvant therapy are enrolled on study to inhibitor and tamoxifen is a therapeutic option that in principle either 5 or 2 years of inhibitor or placebo. A brief update of

these trials as of June 2001 is given below. The primary end NSABP B33. This trial has only recently opened to pa- points of these trials include disease-free and overall survival, tient accrual in May 2001 and is evaluating the outcome of and although secondary end points differ, they include the patients randomized to 2 years of exemestane or placebo after 5 incidence of new contralateral primary tumors. In all of the years of adjuvant tamoxifen. The planned sample size of the trials, the once-daily dose of tamoxifen is 20 mg and of letrozole study is 3000 women. Bone, lipid, quality-of-life, and other is 2.5 mg. substudies are planned. Tamoxifen versus Exemestane: Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial. An additional head- Letrozole-containing Trials to-head comparison of tamoxifen versus exemestane is planned. BIG/FEMTA (Breast International Group/Femara- The study has recently opened and plans are to enroll 4400 Tamoxifen). This study has 4 arms, each running for 5 years: patients. The substudies planned include endometrial changes, tamoxifen; letrozole; tamoxifen for 2-3 years followed by letro- lipids, quality-of-life, and tolerability. zole for 2-3 years; and letrozole for 2-3 years followed by tamoxifen for 2-3 years. The trial started in 1999 and has enrolled 3672 patients of a planned sample size of 5310. The Anastrozole-containing Trials two monotherapy arms of the trial have been fully accrued for The ATAC Trial. This is the largest adjuvant trial ever some time, but it is unclear whether these results will be pre- conducted in breast cancer patients. A total of 9366 patients sented independently before the final analysis of all four arms. were accrued between 1996 and 1999. Patients are now in This is the only trial being conducted that examines the se- follow-up, and the first report of the results is expected at the quence of inhibitor given prior to tamoxifen. No companion 24th Annual San Antonio Breast Cancer Symposium, December trials have been conducted as yet, but both bone and lipid 10-13, 2001. Companion studies include bone metabolism as metabolism substudies are under consideration. assessed by BMD, lipid metabolism, an endometrial evaluation (J)MA.17. This study is an intergroup study being led by study, pharmacokinetic interactions between tamoxifen and the NCIC CTG and includes members of the North American anastrozole, and a quality-of-life (FACT-ES) study. Intergroup including Cancer and Acute Leukemia Group B Preliminary data from the pharmacokinetic study were (CALGB), Eastern Cooperative Oncology Group (ECOG), presented at the 23rd Annual San Antonio Breast Cancer Sym- North Central Cancer Treatment Group (NCCTG), Southwest posium in December 2000 (27). The study evaluated drug con- Oncology Group (SWOG), European Organization for Research centrations (Cmin) of anastrozole, tamoxifen, and desmethylta- and Treatment of Cancer (EORTC), International Breast Cancer moxifen in patients who had been on study medication for >3 Study Group (IBCSG), and United Kingdom participants. The months. Drug levels of anastrozole were 27% lower in the trial was initiated in 1998 and has enrolled 3017 patients with a presence of tamoxifen than in patients on anastrozole alone. planned accrual of 4800. The median age of the participants to Estradiol suppression in the anastrozole-alone arm versus the date is 63 years; 56% have had prior chemotherapy, and 46% combination was, however, identical. The authors concluded had node-negative disease at their initial presentation. Hot that the modest suppression of anastrozole levels by tamoxifen flushes, sweating, and arthralgias are the most common side is, therefore, clinically irrelevant. This is discussed further be- effects in patients on study. The main study contains two low. At the same meeting, the initial results from the substudy quality-of-life tools, the SF-36 and the MENQOL (meno- evaluating the endometrium were presented. Of 285 women pausal-specific quality of life). Additionally, several substud- studied with transvaginal ultrasound and hysteroscopy, 23% of ies are under way. These include bone (n = 49/200) and lipid women developed endometrial thickening of >5-mm thickness, (n = 169/300) metabolism trials. The bone substudy is address- and 8% had preexisting fibroids, polyps, and ovarian cysts (29). ing whether women without osteopenia (BMD T score less than The ARNO Trial. This study is being conducted by the -2.0), taking daily calcium (500 rag) and vitamin D (400 IU), ABCSG (Austrian Breast Cancer Study Group) in collaboration develop accelerated bone loss above those taking the supple- with the GABG (German Adjuvant Breast Cancer Group). In ments and placebo. End points of the bone substudy include this trial, patients are randomized either to tamoxifen for 5 years bone biomarkers (serum bone alkaline phosphatase, serum C- or to 2 years of tamoxifen followed by 3 years of anastrozole. To telopeptide and urine N-telopeptide) and BMD; cholesterol, date, 2300 patients of a planned sample size of 2500 have been triglycerides, LDL, HDL, and Lp(a) are the measurable end enrolled. This trial was opened to accrual in October of 1996 points of the lipid substudy. and has accrued slowly primarily because the randomization occurs at the time of initial diagnosis rather than during clinical follow-up, as has been done in several of the other sequence Exemestane-containing Trials trials. No companion trials are ongoing. "EXACT" Trial. This study conducted by the ICCG (International Cancer Collaboration Group) compares 5 years of tamoxifen to 2-3 years of tamoxifen followed by 2-3 years of Discussion exemestane. The trial was activated in March 1999, and of 4400 The paradigm that tamoxifen with or without chemother- patients, 4135 have been enrolled to date. Bone metabolism is apy is the adjuvant treatment of choice for all breast cancer being evaluated by BMD in a companion trial and quality of life patients is likely to change in the next few years. The data that using the FACT-ES (functional assessment of chronic therapy- will be forthcoming from the trials described above in the next endocrine symptoms) tool is being evaluated. Endometrial as- decade, starting with the first report from the ATAC trial, will sessment by transvaginal ultrasound is also ongoing. be unprecedented both in terms of the extent of the data and the

speed with which these results will become available to oncolo- start in 2001. This trial will randomize postmenopausal women gists. The efficacy of the aromatase inhibitors as a class of drugs between tamoxifen, anastrozole, and placebo. in adjuvant therapy will be defined, and their appropriate se- The application of the aromatase inhibitors to the treatment quence or combination with tamoxifen determined. Importantly, of breast cancer has proved to be an important step for women the ultimate clinical utility will depend not only on the efficacy with breast cancer, and it is hoped that the adjuvant results will against breast cancer but also on their tolerability and long-term further improve their outcome. effects on end-organs other than the breast. The provocation of vasomotor and urogenital symptoms will be important particu- Open Discussion larly for long-term use. Serious toxicities such as the endome- Dr. Angela Brodie: We have some data on using tamox- trial cancer and venous thromboembolism seen with tamoxifen, ifen and then switching to letrozole back and forth before although not expected, will require evaluation. As mentioned, resistance develops. Thus far, it doesn't really make any differ- the effect on bone and lipid metabolism and neurocognitive ence which you start with, going from letrozole to tamoxifen function will also be critical. Although the assumption that these and back again or vice versa. But they're not as good as just drugs may cause bone resorption and elevation in cholesterol is giving letrozole alone. widely held, it is important to recognize that the role of physi- Dr. Per Lonning: I think one of the problems with these ological estrogens in postmenopausal women is not understood, combinations of the SERM and aromatase inhibitor is that the and this assumption may be incorrect. Moreover, important previous clinical trials didn't work. We know there was a drug differences in this regard may become evident among different interaction between aminoglutethimide and tamoxifen. On the aromatase agents. Pharmacological interactions between tamox- other hand, the paper by Decensi (J. Clin. Oncol., 17: 2633- ifen and inhibitors lower the plasma concentration of the inhib- 2638, 1999) 2 years ago showed that for all types of surrogate itor and may be relevant in the setting of estrogen hypersensi- parameters, you got exactly the same effects with 5 mg of daily tivity. This could be particularly true if full therapeutic levels are tamoxifen as with 20 mg. So it's not like that drug interaction needed for a cytocidal effect at the time of the switch from one played a key role in suppressing tamoxifen levels. That raises therapy to another. In addition, letrozole has a more impressive some concerns to me, whether this concept would work. track record in both the preclinical and the metastatic setting Dr. Goss: I don't think we can extrapolate from the met- than anastrozole. Its more complete suppression of estradiol and astatic setting to the adjuvant setting. Also, I don't know if its better penetration into cells may yield important clinical anyone else in the room thinks that we've truly satisfied our- differences. Exemestane as a steroid may have a positive effect selves that combination endocrine therapy isn't going to work. on bone and lipid metabolism through androgenic action of the I don't think the combination of tamoxifen and aminoglutethim- parent compound and its 4-hydroxy exemestane metabolite. ide is comparable to what we're doing now with third-genera- Many unanswered questions will remain at the conclusion tion aromatase inhibitors. of the current set of trials. For example, the optimal 10-year Dr. Aman Buzdar: With anastrozole, that drug sat on the adjuvant treatment will be unclear if the inhibitors are superior shelf for a long time because in a small animal toxicology study the drug cleared very quickly and they thought that it would to tamoxifen as initial therapy but also add a benefit after 5 years have to be given several times a day. Maybe there are a number of tamoxifen. The optimal duration of treatment with the aro- of other differences that we don't know of; I think these animal matase inhibitors may also not be defined, because more than 5 data are very interesting, but clinical data will be the most years might be superior to a 5-year exposure. If combination relevant. therapy in the ATAC trial is superior to monotherapy, it will open up the possibility of future combination therapy trials with newer SERMs or antiestrogens such as fulvestrant. 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Paul E. Goss

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