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Phase III Double-Blind Trial of Arzoxifene Compared With Tamoxifen for Locally Advanced or Metastatic Breast Cancer

VijayaLaxmi Deshmane, S. Krishnamurthy, Allen S. Melemed, Patrick Peterson, Aman U. Buzdar

From the Kidwai Memorial Institute of Oncology, Karnataka, Bangalore, India; Eli Lilly and Co, Indianapolis, IN; and The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to VijayaLaxmi Deshmane, Masters of Surgery, Department of Surgical Oncology, Kidwai Memorial Institute of Oncology, Hosur Rd, Bangalore 560029 India; e-mail: vldeshmane{at}hotmail.com

	ABSTRACT

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Purpose To compare the efficacy of arzoxifene with tamoxifen for the treatment of locally advanced or metastatic breast cancer.

Patients and Methods Women with estrogen- or progesterone-receptor–positive breast cancer who had not received prior systemic therapy, or who had relapsed more than 12 months after stopping adjuvant hormonal therapy, were randomly assigned to receive 20 mg arzoxifene or 20 mg tamoxifen daily. Each treatment arm was to have 240 patients enrolled. The primary end point was progression-free survival. Secondary end points included other measures of tumor response, overall survival, and safety.

Results Enrollment was stopped when a planned interim analysis of the first 200 patients suggested arzoxifene to be significantly inferior to tamoxifen. The median progression-free survival for the 352 patients who had been randomly assigned when enrollment was stopped was 4.0 months (95% CI, 3.4 to 5.6 months) for the arzoxifene group and 7.5 months (95% CI, 5.9 to 8.8 months) for the tamoxifen group. On-study progression-free survival (P = .011) and time to treatment failure (P = .029) also favored tamoxifen. Overall tumor response rate and median response duration were comparable between the groups. Adverse events were similar between the treatments, except for nausea (more frequent with arzoxifene) and vaginal discharge (more frequent with tamoxifen).

Conclusion Tamoxifen produced significantly longer progression-free survival and time to treatment failure compared with arzoxifene in the treatment of locally advanced and metastatic breast cancer. There were no significant differences between tumor response rate, clinical benefit rate, or median response duration.

	INTRODUCTION

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Tamoxifen has been the drug of choice for the treatment of both early and advanced stages of breast cancer, but it can have significant adverse effects including hot flashes,¹ venous thromboembolism,^2,3 ocular toxicities,⁴ and endometrial cancer.^5-11 Arzoxifene is a selective estrogen-receptor (ER) modulator (SERM) developed to have potent ER antagonistic activity in the breast and endometrium while maintaining favorable estrogen agonist activity on bone and lipids. Arzoxifene and its desmethyl metabolite bind to the ER with high affinity, inhibit estrogen-dependent growth of MCF-7 cells, and do not stimulate the endometrium in ovariectomized rats.^12-14 Two randomized, double-blind, phase II studies, prospectively designed to compare and select the better of two doses of arzoxifene (20 or 50 mg daily), demonstrated efficacy with respect to response rate and time to disease progression in women with locally advanced or metastatic breast cancer.^15,16 Because no significant differences in efficacy or safety between the 20- and 50-mg arzoxifene doses were observed, the 20-mg dose of arzoxifene was chosen for further study in phase III trials.^15,16

The efficacy observed for arzoxifene in phase II studies was generally similar to or greater than those historically reported for tamoxifen for treatment of recurrent or metastatic breast cancer.^15,16 However, the response to tamoxifen was quite variable across these prior studies and difficult to compare indirectly with results for arzoxifene. The primary objective of the present study was to compare progression-free survival time between arzoxifene 20 mg daily with tamoxifen 20 mg daily in the treatment of women with locally advanced or metastatic breast cancer who had not received any prior systemic therapy for this disease, or relapsed more than 12 months after stopping adjuvant hormonal therapy.

	PATIENTS AND METHODS

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Patient Characteristics
Women included in the study were at least 18 years of age and had a pathologically or cytologically documented diagnosis of locally advanced or metastatic, bidimensionally measurable breast cancer. At the time of initial diagnosis, the patient's tumor must have been ER and/or progesterone-receptor (PR) positive. Patients who were older than 50 at the time of initial diagnosis could be enrolled if their ER and PR status was unknown. Receptor status was obtained regardless of age for patients presenting with locally advanced or metastatic breast cancer. Patients were enrolled at the investigators' discretion if they were not candidates for primary chemotherapy and subsequent surgery, or if their breast cancer was outside of the radiation port or they had a measurable recurrence within the field. Prior neoadjuvant or adjuvant chemotherapy had to be completed at least 6 months, and prior adjuvant hormonal therapy had to be completed at least 12 months before diagnosis of locally advanced or metastatic breast cancer. Other entry criteria included Zubrod Performance Scale status of 0 or 1; estimated life expectancy of at least 24 weeks; childbearing potential absent or attenuated during and for 3 months following the trial, or serum pregnancy test negative within 7 days before study enrollment.

Exclusion criteria included prior hormonal, immuno-, or chemotherapy for metastatic breast cancer; radiation therapy in the preceding 2 weeks (patients must have recovered from any acute adverse effects of prior radiotherapy before enrollment); prior raloxifene therapy; current therapy with estrogen, progesterone, oral contraceptives, bile acid binding resins, corticosteroids, megestrol, gonadotropin-releasing hormone agonists, coumadin, and/or other concomitant anticancer therapy; rapidly progressive disease; disease for which chemotherapy would be more appropriate; known CNS metastases; bone as the only site of metastatic disease; second primary malignancy that could affect protocol compliance or interpretation of results; and serious concomitant systemic disorder or predisposition to thromboembolic disorder.

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The protocol and consent process were approved by all relevant ethics review boards, and all patients gave written informed consent before study enrollment.

Study Design
This randomized, phase III, double-blind study was conducted in 18 countries at 71 centers. Patients were assigned to receive either 20 mg arzoxifene or 20 mg tamoxifen by mouth daily, each with a matching placebo. Random assignment was balanced between the two treatments based on prior hormonal therapy, ER and PR status, disease stage, and use of bisphosphonates at study entry according to the minimization algorithm of Pocock and Simon.¹⁷ Treatment was to continue, at a constant dosage, until disease progression or patient-, investigator-, or sponsor-initiated discontinuation. Study phases and visits are shown in Figure A1 (online only).

The primary objective of this study was to compare progression-free survival time between arzoxifene and tamoxifen. Secondary objectives included measures of tumor response (tumor response rate; duration of response; time to disease progression; stable disease 6 months), time to treatment failure, overall survival, on-study progression-free survival, the occurrence of vaginal bleeding or discharge, and general safety profile.

Efficacy Measures and Criteria
Time to progression (TTP) for all patients, and duration of response for responders, were measured from the time of random assignment to the time of documented disease progression or death resulting from any cause. Treatment failure was defined as death resulting from any cause, documented progression of disease, or study-drug discontinuation for any reason. Progression-free survival time was measured from the date of random assignment to the first date of documented disease progression or death resulting from any cause. Progression-free survival time was excluded at the date of the last follow-up visit for patients who were still alive and who had experienced progression. On-study progression-free survival time was measured from the date of random assignment until the first date, during treatment with study therapy, of documented disease progression or death resulting from any cause. On-study progression-free survival time was excluded at the patient summary date (acknowledging discontinuation of study drug) for those patients who were still alive and who had not experienced progression.

Standard WHO criteria for tumor response were followed.¹⁸ Clinical benefit rate was defined as the sum of patients with complete response (CR), partial response (PR), or stable disease (SD) lasting at least 6 months during the study. Overall survival time was defined as the time from the date of random assignment to date of death resulting from any cause. Tumor response was assessed every 2 months in the absence of symptoms and/or signs suggestive of disease progression. Radiologically determined PR or CR was confirmed at least 4 weeks after that determination.

Safety Evaluations
The occurrences of all adverse events were recorded at each visit, and investigators assessed whether each event was possibly related to study drug. Serious adverse events were defined as those that resulted in prolonged inpatient hospitalization, immediate risk of dying, severe or permanent disability, cancer other than the one being studied, or congenital anomaly. Toxicity grades were assigned to adverse events at each physician visit using the National Cancer Institute Common Toxicity Criteria (CTC) grading system (version 1.0).¹⁹ Patients with postmenopausal vaginal bleeding or other significant pelvic symptoms were to be evaluated further per a recommended uterine algorithm involving transvaginal ultrasound, endometrial biopsy, or additional evaluations as judged appropriate by the investigator.

Statistical Methods
The study's sample size was chosen to test the hypothesis that arzoxifene is superior to tamoxifen with respect to progression-free survival time. Based on a projected progression-free survival hazard ratio of arzoxifene to tamoxifen of 0.75 or lower comparing the two treatments, at least 480 patients were to be enrolled under the original study design. If this projection was correct, this sample size provided an 80% probability of resulting in a statistically significant (P < .05) conclusion of superiority of arzoxifene.

An interim analysis of data and review by an independent data monitoring board (DMB) was planned after the first 200 patients were enrolled and treated for 6 months. The purpose of this interim review was to assess any clinically significant safety concerns and to determine whether there was evidence that arzoxifene was clinically or statistically inferior to tamoxifen with respect to tumor response rates. For the interim analysis, tumor response rate (CR + PR and CR + PR + SD 6 months) was used as the primary basis for comparison because it was deemed a more reliable indicator of efficacy at 6 months compared with progression-free survival. Statistical inferiority of arzoxifene was based on a two-tailed 95% CI for the difference in tumor response rate calculated using an unadjusted normal approximation. The DMB also considered estimates of additional efficacy parameters and a conditional statistical power calculation²⁰ to estimate the probability of arzoxifene's demonstrating superiority to tamoxifen at the final analysis in their interim assessment of whether to continue the trial to completion.

The estimation and analysis of hazard ratio (HR; arzoxifene to tamoxifen) for the primary assessment of progression-free survival was performed over the database of intent-to-treat (ITT) patients, consisting of all randomized patients at the time of analysis for whom efficacy data were available (n = 352). The Cox proportional hazards model was used to provide estimates of the natural logarithm of HR and its SE.²¹ Treatment hazard ratios from Cox models were adjusted for three randomization cofactors: ER+ or PR+ (Yes/No), prior hormonal therapy (Yes/No), and disease stage (locally advanced/metastatic). A two-tailed 95% CI for HR was constructed based on an unadjusted normal approximation of the estimated log HR. Time-to-event measures were analyzed using Kaplan-Meier estimation²² and Cox proportional hazard regression²¹ models. Estimation and analysis of response rates were performed over the database of protocol-qualified patients, defined as those who qualified for the study, had received at least 1 month of study therapy, and had assessable tumor measurements at baseline and for at least one postbaseline study visit (n = 368).

Safety analyses were performed for all randomly assigned patients who received at least one dose of study drug (n = 368). Laboratory and nonlaboratory toxicities defined by CTC grade were compared between treatments using Wald ² test of therapy group parameter in logistic regression of CTC grade on therapy group. Statistical analyses were performed with SAS version 8.0 (SAS Institute, Cary, NC).

	RESULTS

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Patients
At the planned interim analysis on the first 200 patients enrolled, the estimated response rates were less for patients assigned to arzoxifene compared with those assigned to tamoxifen. Although the difference did not reach the prespecified criteria to conclude statistical inferiority of arzoxifene, all time-to-event outcomes favored tamoxifen over arzoxifene, and the conditional statistical power calculation suggested at most a 6% likelihood that arzoxifene would demonstrate superiority to tamoxifen if the trial continued to completion. Key patient and tumor characteristics, including prior therapies and tumor receptor status, were well balanced between the treatment groups at the interim analysis. Based on these interim findings, the DMB recommended that the trial be stopped based on evidence that arzoxifene was likely clinically and statistically inferior to tamoxifen with respect to efficacy, and this recommendation was accepted by the sponsor. At the time of this decision, an additional 168 patients had been enrolled and randomly assigned to treatment for a total of 368. This report reflects the final analysis of safety data from the 368 randomly assigned patients, and results of the final efficacy analyses for the 352 patients for whom final efficacy data were available.

Of 184 patients randomly assigned into each treatment arm, 177 in the arzoxifene arm and 175 in the tamoxifen arm were included in the primary analysis of progression-free survival. Sixteen randomly assigned patients were not included in the final efficacy analysis because efficacy data were not available for these patients at the final visit cutoff date. Patient disposition is indicated in Figure A2 (online only). Baseline characteristics for all 368 randomly assigned patients are presented in Table 1. Most patients had ER-positive tumors (89%) and had not received prior tamoxifen therapy (88%). As planned, the treatment groups were balanced with respect to the stratification factors: prior tamoxifen therapy, ER and PR status, disease stage, and use of bisphosphonates at entry.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival by treatment arm.

There were no grade 3 or grade 4 laboratory toxicities and no discontinuations caused by laboratory toxicity in either treatment group. At least one grade 3 or grade 4 nonlaboratory toxicity was experienced by five patients in the arzoxifene group (hot flashes and myalgias; nausea, vomiting, and dyspnea; vomiting; dyspnea; and irregular menses) and four patients in the tamoxifen group (thrombosis/embolism [n = 2]; hot flashes; and sweating).

Overall, nausea and hot flashes were the most frequently reported adverse events regardless of relatedness to study drug (Table 4). The incidences of individual adverse events thought to be related to study drug were similar for the two treatment groups, except for nausea (reported more frequently in the arzoxifene group) and vaginal discharge (reported more frequently in the tamoxifen group; Table 4). There were two cases of venous thromboembolism reported as serious adverse events during the study, both in the tamoxifen group. One venous thromboembolism was reported in the arzoxifene group as a nonserious adverse event, but did cause the patient to discontinue the study.

	DISCUSSION

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This study comparing arzoxifene with tamoxifen for breast cancer treatment was stopped when a planned interim analysis suggested a minimal likelihood of arzoxifene demonstrating superiority to tamoxifen if the trial was completed. Final data analyses reported here are consistent with the interim analysis. Arzoxifene was statistically significantly inferior to tamoxifen with regard to progression-free survival and other time-to-event parameters, although tumor response was comparable between the treatments. These findings do not support the further development of arzoxifene as a superior treatment to tamoxifen in women with locally advanced or metastatic breast cancer.

The effect demonstrated by arzoxifene in this study was lower than anticipated on the basis of previous studies. Compared with the TTP of 4 months in the current study, the TTP for patients assigned to arzoxifene 20 mg/d who were deemed tamoxifen sensitive in the phase II studies were 10.7 months in the European study¹⁵ and 8.3 months in the US study.¹⁶ The response rate (CR + PR) in the current study (23.6%) also was less than those observed in the phase II studies (40.5% and 30.4% among tamoxifen-sensitive patients in the European and US trials, respectively). Although there were some modest differences in patient and tumor characteristics among the two phase II studies and the current phase III study, no differences appear sufficiently large to account for the lower-than-anticipated time-to-event parameters noted in the present study. The arzoxifene dose used in this study demonstrated efficacy at least equal to a higher dose in two prior phase II studies, although we cannot completely exclude the possibility that a higher dose may have shown a better tumor response in this population. The majority (> 80%) of patients enrolled had ER-positive tumors and had no prior exposure to tamoxifen, and were thus potentially responsive to hormonal therapy.

The results of the current study are similar to two other studies comparing the effect of newer SERMs with tamoxifen for the treatment of advanced breast cancer. As with arzoxifene, droloxifene and idoxifene are both SERMs with higher affinity for the ER than tamoxifen, and were expected to be at least equal to and possibly better than tamoxifen for the treatment of advanced breast cancer.^23,24 However, neither droloxifene nor idoxifene were shown to be superior to tamoxifen with respect to time to progression or response rate in patients with locally advanced or metastatic breast cancer who had not been previously treated for metastatic disease.^25,26 Droloxifene was statistically inferior to tamoxifen with respect to time to progression in these women,²⁵ consistent with the current data for arzoxifene. The explanation for these results is not clear, but some hypotheses have implicated the longer half-life of tamoxifen or effects of the active tamoxifen metabolite (4-OH-tamoxifen) that could contribute to greater antitumor efficacy.^25,26

Raloxifene is a SERM currently approved for osteoporosis prevention and treatment in postmenopausal women. Raloxifene and tamoxifen were shown to reduce the risk of invasive breast cancer by a similar degree in postmenopausal women at increased risk for developing breast cancer.²⁷ Arzoxifene demonstrated improved potency and efficacy compared with raloxifene in preventing bone loss in ovariectomized rats,^28,29 and was superior to raloxifene in a rat mammary tumor prevention model.¹³ These findings suggest potential value of arzoxifene in osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women.¹⁴ Two phase III trials are ongoing to test this hypothesis: an osteoporosis prevention study³⁰ and a long-term outcomes study of the effect of arzoxifene on vertebral fracture and invasive breast cancer in postmenopausal women.³¹

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Allen S. Melemed, Eli Lilly and Co; Patrick Peterson, Eli Lilly and Co Leadership: Allen S. Melemed, Eli Lilly and Co Consultant: N/A Stock: Allen S. Melemed, Eli Lilly and Co; Patrick Peterson, Eli Lilly and Co Honoraria: N/A Research Funds: Aman U. Buzdar, Eli Lilly and Co Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: VijayaLaxmi Deshmane, Patrick Peterson

Administrative support: S. Krishnamurthy

Provision of study materials or patients: VijayaLaxmi Deshmane, S. Krishnamurthy, Aman U. Buzdar

Collection and assembly of data: VijayaLaxmi Deshmane, S. Krishnamurthy, Patrick Peterson, Aman U. Buzdar

Data analysis and interpretation: VijayaLaxmi Deshmane, S. Krishnamurthy, Allen S. Melemed, Patrick Peterson, Aman U. Buzdar

Manuscript writing: Allen S. Melemed, Patrick Peterson

Final approval of manuscript: VijayaLaxmi Deshmane, S. Krishnamurthy, Allen S. Melemed, Patrick Peterson, Aman U. Buzdar

	Appendix

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The following served as Primary Investigators (presented in alphabetical order by country and investigator): Argentina: Mario F. Bruno, Daniel J. Campos, Luis E. Fein, Leonardo Koliren, Roberto Orti, Christina M. Nasurdi, Ofelia Rodrigues Nievas, Elizabeth Mickiewiecz; Australia: Ehtesham A. Abdi, Russell Basser, S. Begbie, Ivon W. Burns, Boris W. Chern, Jacqui H. Chirgwin, Phil R. Clingan, John Collins, Joanna Dewar, John Forbes, Colin Furnival, Grantly Gill, M. Green, Guy Van Hazel, Fred Kirsten, Craig R. Underhill; Brazil: Agnaldo Anelli, Gilson Delgado, Auro Giglio, Roberto Hegg, Valeria R. Lopes, Manoel Odorico Moraes, Andre Murad, Célia Tosello Oliveira, Jose G. Segalla, Luiz Carlos Teixeira; Canada: Ronald E. Maccormick, Lawrence Panasci, Yasmin Rahim, Daniel Rayson, Jehan Siddiqui, M. Trudeau; Chile: Jose Miguel Reyes, Sergio Kleinman; Czech Republic: L. Petruzelka, Milan Kuta, Jindrich Finek, Pavel Vodvarka; Egypt: Mostafa M El Serafy; Germany: G. Bastert, Kay Goerke, J. P. Hanker, Bernhard Heinrich, Manfred Hoffman, Wolfram Jaeger, W. Jonat; O. Klein, Alexander Knuth, G. Morack, Olaf Ortmann, G. Von Minckwitz; India: M. Babaiah, Rajan Badwe, Jayantha Balawardane, Vijayalakshmi Deshmane, D. R. Raghunadhrao, B. Rajan, S. G. Ramanan, Biswajit Sanyal, Pankaj M. Shah, Atul Sharma, A. K. Vaid; Italy: G. L. Cetto, Pier Franco Conte, Lucio Crino, Gioacchino Robustelli Della Cuna, V. Fosser, Paolo Marchetti, A. Martoni; Mexico: Jesus Cardenas, Maria Teresa Ramirez, Guadalupe Cervantes Sanchez; Netherlands: Zeba Aziz, R. S. De Jong, J. Douma, A. H. Honkoop, L. G. M. Kerkhofs, J. G. M. Klijn, H. P. Sleeboom, P. H. B. Willemse; Pakistan: Asim Amin, Prof. Shaharyar, Tariq Siddiqui, M. Zaidi; Poland: Tadeusz Pienkowski, Anna Pluzanska, Cezary Szczylik; Singapore: Kei Siong Khoo, Siew Eng Lim; Slovakia: Lubomir Bohunicky, Stanislav Spanik; Spain: Antonia Marquez Aragonés, H. Cortes Funes De Castro, Antonio Llombart, A. Lluch, J. J. Lopez-Lopez, Montserrat Muñoz Mateu, Amadeu Pelegrí, Teresa Ramón Y Cajal, Jose Baselga Torres; Sweden: Maria Albertsson, Nils-Olof Bengtsson, Jonas Bergh, Tommy Fornander, Thomas Hatschek, Bo Nordenskjöld; Taiwan, Province Of China: Hsien-Kun Chang, Ruey-Ho Kao, Chit-Kheng Kok, Wing-Yiu Lui; United Kingdom: Anthony Branson, John P. Crown, Stephen R. D. Johnston, Janine Mansi, N. S. Stuart; United States: Wallace Akerly, G. Thomas Budd, Gary V. Burton, Aman U. Buzdar, Angela Demichele, Jeffrey B. Hargis, E. G. Levine, Hyman Muss, Beth Overmoyer, Kishan J. Pandya, Robert E. Smith, Donald K. Strickland, Haluk Tezcan, Shou-Ching Tang, Denise Yardley; Venezuela: Nelson Guedez.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Study phases and visits.

View larger version (43K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Patient disposition.

	ACKNOWLEDGMENTS

 
We thank David A. Cox, PhD, of Eli Lilly and Company for comments and suggestions during the preparation of this report; Safia Wasi, PhD, for medical writing support; and all of the investigators and patients who made this study possible.

	NOTES

 
Supported by Eli Lilly and Company, Indianapolis, IN.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted October 30, 2006; accepted August 7, 2007.

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