Dual-drug vs single-agent aromatase inhibitor therapy

ABSTRACT: Fulvestrant-anastrozole combination did not demonstrate advantage despite a better dose loading schedule and compelling preclinical data.

SAN ANTONIO-Adding fulvestrant (Faslodex) to anastrozole (Arimidex) therapy had "not a hint of an effect" for first relapse in hormone-receptor-positive breast cancer, according to Jonas Bergh, MD, an investigator in the FACT trial. The open-label, phase III study looked at the loading dose of fulvestrant combined with anastrozole compared with anastrozole alone in 514 patients.

Fulvestrant is usually given at a dose of 250 mg/mo, which results in a pharmacokinetic steady state after three to six months, said Dr. Bergh, who is from the Karolinska Hospital and Institute in Stockholm. The more aggressive loading schedule used in this study-500 mg on day zero, 250 mg on days 14 and 28, and 250 mg once a month thereafter plus 1 mg anastrazole daily-offered a pharmacokinetic steady state at 28 days.

©SABCS/Todd Buchanan 2009

"We had two major prerequisites that made us optimistic," he said. "We had a better loading schedule, which should have given us better pharmacokinetic concentration right away at the start of therapy, and we had two nice preclinical studies demonstrating a clear benefit of combined use" (J Clin Oncol 26:1664-1670, 2008; Cancer Res 68:3516-3522, 2008).

Patients were randomized to fulvestrant plus anastrazole at the study dosage or to anastrozole alone (1 mg daily). The median patient age was 65 years in the combination arm and 63 years in the anastrozole arm (SABCS 2009 abstract 23).

With regard to previous adjuvant endocrine therapy, "30% in the combined arm and 35% in the anastrazole arm received no prior adjuvant endocrine therapy," Dr. Bergh said. "That was quite a big surprise to me. Twelve percent and 14%, respectively, had a relapse within two years of completion of tamoxifen. Twenty-eight percent and 25%, respectively, had relapse more than two years after completion of tamoxifen. Twenty-seven percent in the combined arm and 24% in the anastrozole-alone arm relapsed on tamoxifen therapy. Only five individuals who had previous aromatase inhibitor therapy were included."

Fact What is fulvestrant? Fulvestrant is a selective estrogen-receptor downregulator and antiestrogen that induces receptor polyubiquitination and subsequent degradation via the 26S proteasome (

Cancer Biol Ther

online, March 11, 2010).

He added that "these patients should have been endrocine-responsive because three-fourths of the patients were both estrogen-receptor positive and progesterone-receptor positive. Only five individuals were ER negative and PgR positive."

The primary endpoint for the study was time to progression (TTP); secondary endpoints included objective response rate (ORR) and clinical benefit rate (CBR).

The median TTP was 10.2 months for the anastrozole-only arm and 10.8 months for the combination arm (P = .91). Dr. Bergh reported that disease progression was demonstrated in 77.5% of the combination arm and 78.1% of the single-agent arm. The investigator-assessed ORR on patients with measurable disease for the combination arm was 31.8% vs 33.6% for the anastrozole arm. The CBR rate for the fulvestrant plus anastrozole arm was 55% vs 51% for the single-agent arm.

There were more instances of liver metastases in the combination arm than in the single-agent arm, Dr. Bergh said. More patients in the combination arm experienced hot flashes.

In terms of overall survival, 102 patients died in each arm. There were three cases of cardiac failure in the combination arm, but the instances of cardiac failure were not statistically significant. However, the median survival time at 38 months was good, especially for metastatic breast cancer patients, he said. n

Vantage Point

Fulvestrant worth second look among other AIs

©Patrick Cunningham, City of Hope

In the adjuvant setting, one-third of women stop taking their oral aromatase inhibitors because of joint discomfort or other adverse effects, said Dr. Mortimer, vice chair and professor of medical oncology and therapeutics research at City of Hope in Duarte, Calif. "I think we've moved fulvestrant down the line in favor of oral agents, but compliance and side effects really do favor fulvestrant," she said. "Fulvestrant is actually a very nice drug. When you give fulvestrant once a month as a shot, you certainly have ensured compliance. Also, fulvestrant doesn't have a lot of side effects aside from a very large injection."

Results from the two trials presented at SABCS 2009 will hopefully encourage oncologists to take another look at the therapeutic value of fulvestrant in women with advanced disease, added Dr. Mortimer, who is also administrative director of phase I programs and associate director of affiliate programs.

Of the two trials, Dr. Mortimer said that she did find one more compelling.

"The FACT study results were not a surprise. In women who are postmenopausal, there has never been a study that has consistently shown that two endocrine therapies added together are superior to giving those agents sequentially," she said.

"I think the stronger message is the CONFIRM study," she said. "I think the CONFIRM trial raises the question that maybe we need to use higher doses of fulvestrant."