Higher Doses of Fulvestrant Prolonged Survival in Patients With Advanced Breast Cancer

This abstract will be presented at a press conference hosted by Peter Ravdin, M.D., Ph.D., director of the Breast Health Clinic at the CTRC, on Wednesday, Dec. 5 at 7:30 a.m. CT in Room 217 A-C of the Henry B. Gonzales Convention Center. Reporters who cannot attend in person can call in using the following information:• U.S./Canada (toll free): 1 (800) 446-2782• International (toll call): 1 (847) 413-3235

Newswise — SAN ANTONIO — Increasing the dose of fulvestrant from 250 mg to 500 mg improved median overall survival in women with locally advanced or metastatic estrogen receptor-positive breast cancer, according to updated data from the CONFIRM trial presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held here Dec. 4-8.

The Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial is a randomized, double-blind, parallel-group, multicenter, phase III trial of postmenopausal women with estrogen receptor (ER)-positive advanced breast cancer that recurred or progressed following endocrine therapy.

“Of note, the improvement in survival with the higher dose of fulvestrant was achieved without increasing treatment toxicity. Indeed, the dose of 500 mg had the same toxicity profile as the 250-mg dose,” said Angelo Di Leo, M.D., Ph.D., head of the department of medical oncology at the Hospital of Prato, Istituto Toscano Tumori in Prato, Italy.

Between February 2005 and August 2007, researchers randomly assigned 736 women from 128 centers in 17 countries to 250 mg or 500 mg of fulvestrant and followed them until 75 percent of the patients died. At the time of analysis, 554 patients had died, 63 were lost to follow-up and 16 withdrew consent.

Among the entire study population, the 500-mg dose was associated with a clinically relevant 4.1-month difference in median overall survival compared with the lower dose: 26.4 months in the 500-mg group and 22.3 months in the 250-mg group. Researchers also saw a 19 percent reduction in risk for death in the 500-mg group compared with the 250-mg group. Serious adverse events occurred in 8.9 percent of patients who had received the 500-mg dose and in 6.7 percent of patients in the 250-mg group.

“For those postmenopausal women with recurrent or progressing ER-positive locally advanced or metastatic breast cancer for whom fulvestrant is the appropriate treatment choice, the standard of care is a 250-mg dose,” said Di Leo. “Our results indicate that this should be modified to a 500-mg dose.”

According to Di Leo, the next research step will be to study 500 mg of fulvestrant in combination with biological agents, such as PI3K inhibitors or anti-HER2 agents that can reverse resistance to endocrine therapy.

“This approach could further increase the activity of fulvestrant given at the 500-mg dose,” he said.

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The mission of the 2012 CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR’s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit www.sabcs.org.

Abstract:Publication Number: S1-4

Title: Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg

Angelo Di Leo1, Guy Jerusalem2, Lubos Petruzelka3, Roberto Torres4, Igor N Bondarenko5, Rustem Khasanov6, Didier Verhoeven7, José L Pedrini8, Iva Smirnova9, Mikhail R Lichinitser10, Kelly Pendergrass11, Sally Garnett12, Yuri Rukazenkov12 and Miguel Martin13. 1Hospital of Prato, Prato, Italy; 2Centre Hospitalier Universitaire Sart Tilman, Liège, Belgium; 3First Faculty of Medicine of Charles University, Prague, Czech Republic; 4Instituto Nacional del Cáncer, Santiago, Chile; 5Dnipropetrovsk Municipal Clinical Hospital, Dnipropetrovsk, Ukraine; 6Republican Clinical Oncological Center, Kazan, Russian Federation; 7AZ Klina, Brasschaat, Belgium; 8Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil; 9Medical Radiological Science Center, Obninsk, Russian Federation; 10Russian Cancer Research Centre, Moscow, Russian Federation; 11Kansas City Cancer Center, Kansas City; 12AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom and 13Hospital Universitario Gregorio Maranon, Madrid, Spain.

Body: Background The COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial (NCT00099437) compared fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer who had recurred or progressed following prior endocrine therapy. Fulvestrant 500 mg was associated with a statistically significant increase in progression-free survival compared with fulvestrant 250 mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600). At the time of the primary analysis approximately 50% of patients had died. Median overall survival was 25.1 months and 22.8 months for fulvestrant 500 mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.69, 1.03; p=0.091). A follow-up analysis of overall survival was subsequently planned for when 75% of patients had died and the results are presented here.

Methods: CONFIRM was a randomized, double-blind, parallel-group, multicenter, Phase III study. Patients were randomized 1:1 to either fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28 days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days). After the primary analysis, patients on fulvestrant 250 mg were permitted to switch to 500 mg and all patients were followed up for overall survival, regardless of treatment discontinuation, unless consent was withdrawn. Overall survival was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) were also reported.

Results: In total, 736 women (median age 61.0 years) were randomized between February 2005 and August 2007 from 128 centers in 17 countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374). At time of follow-up analysis, 63 (9.0%) patients were lost to follow-up, 16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients crossed over from fulvestrant 250 mg to 500 mg. Median overall survival was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p=0.016). During the treatment period, a total of 32 (8.9%) patients had at least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in the fulvestrant 250 mg groups, and SAEs that were causally related to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients, respectively. SAEs with an outcome of death were reported for 5 (1.4%) and 6 (1.6%) patients, respectively, during the treatment period. Overall, there were no clinically important differences in the profiles of SAEs between the treatment groups and no clustering of SAEs could be detected in either treatment group.

Conclusions: Overall survival data from CONFIRM demonstrate that, in patients with locally advanced or metastatic ER positive breast cancer, fulvestrant 500 mg is associated with a clinically relevant 4.1 month difference in median overall survival and 19% reduction in risk of death compared with fulvestrant 250 mg. There were no new safety concerns associated with the use of fulvestrant 500 mg.