First Trial of Three Aromatase Inhibitors: Similar Efficacy, Safety

Kristin Jenkins

April 06, 2018

The first-ever direct comparison of three adjuvant aromatase inhibitors for the treatment of postmenopausal hormone receptor–positive early breast cancer shows no significant differences in clinical efficacy or safety, according to an Italian research team.

In the randomized, open-label phase 3 FATA-GIM3 trial of almost 3700 women, the 5-year disease-free survival for patients treated with anastrozole (Arimidex, Novartis), exemestane (Aromasin, Pfizer), or letrozole (Femara, Novartis) was 90.0%, 88.0% and 89.4%, respectively.

There were no unexpected serious adverse reactions or treatment-related deaths, say Francesco Perrone, MD, of the Istituto Nazionale per lo Studio e la Cura dei Tumori, in Naples, Italy, and colleagues. No differences were observed between patient subgroups, even though more than 50% of patients were overweight or obese.

The study was published online February 23 in the Lancet Oncology.

This is also the first trial to compare an up-front treatment schedule with a switch schedule using anastrozole, the study authors note. The up-front schedule consisted of 5 years of treatment with aromatase inhibitors; the switch schedule consisted of 2 years of treatment with tamoxifen followed by 3 years of treatment with aromatase inhibitors.

The study shows that both treatment schedules were clinically relevant. There was only a 1.6% difference in disease-free survival after 2 years. After 5 years, the disease-free survival was 88.5% with the switch strategy and 89.8% with the up-front regimen (hazard ratio [HR], 0.89; P = .23).

"FATA-GIM3 is the only trial to compare upfront treatment with a switch strategy using anastrozole, and the first trial to directly compare the three aromatase inhibitors; thus, contributing to the knowledge base, which is currently limited to indirect comparisons of the EBCTCG [Early Breast Cancer Trialists' Collaborative Group] meta-analysis and two head-to-head trials, one of which was limited to node-positive patients," Perrone and colleagues write.

"The number of deaths and other breast-related events was too low to allow reliable conclusions to be drawn on endpoints other than disease-free survival," the investigators add. The 5-year overall survival was 95.3% with the switch schedule and 96.8% with the up-front schedule (HR, 0.72; P = .052).

Tamoxifen vs AIs: Clear Differences

The researchers suggest that clinicians consider patient preferences, tolerability, and cost when determining the best treatment approach.

"Clinical benefits and tolerability are particularly important in the choice between aromatase inhibitors and tamoxifen," Perrone told Medscape Medical News. The safety profile is "clearly different," he added. He noted that musculoskeletal side effects are seen more frequently with aromatase inhibitors.

"We should still consider tamoxifen a good option," Perrone emphasized.

Findings from the earlier ATAC study suggested that less costly switch therapy might be more effective than up-front therapy, state the investigators, who conducted a literature search through August 30, 2017. ATAC findings also indicated that longer exposure to aromatase inhibitors could be associated with a greater risk for cardiac and musculoskeletal toxicity.

When FATA-GIM3 was designed in 2006, the up-front aromatase inhibitor treatment strategy was about to become standard practice, the study authors say.

In an accompanying comment, Luc Y. Dirix, MD, of the University of Antwerp, Belgium, called the FATA-GIM3 trial "an important confirmatory study.

"These data are the first for the switch approach with anastrozole," he confirmed. "Patients and clinicians can be confident that any aromatase inhibitor is acceptable in this treatment strategy."

FATA-GIM3 reinforces results from the EBCTGC meta-analysis, which demonstrated a small absolute benefit with up-front therapy after 5 years of follow-up, Dirix notes. Two large international trials established the clinical relevance of the up-front and switch regimens while the FATA-GIM2 trial was still underway, he points out.

The BIG1-98 trial found that tamoxifen followed by letrozole was more effective then letrozole alone. Similarly, the TEAM trial showed that tamoxifen followed by exemestane was more effective than exemestane alone.

"The duration of adjuvant endocrine therapy is now considered a more crucial factor in treatment outcomes," Dirix says.

The editorialist also says that "even if the upfront strategy is preferred, FATA-GIM3 confirms the absence of a relevant difference between the aromatase inhibitors (with only small differences in toxicities but not in efficacy), giving clinicians the freedom to exchange one aromatase inhibitor for another."

For the study, 3697 postsurgical patients with invasive hormone receptor–positive breast cancer were enrolled from 76 Italian public healthcare institutions between March 9, 2007, and July 31, 2012. Participants were randomly assigned to one of six treatment groups.

A total of 1847 participants received up-front treatment. These patients took oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 5 years. A total of 1850 patients were assigned to switch therapy. These patients received oral tamoxifen 20 mg once daily for 2 years followed by oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 3 years.

The median time on tamoxifen was 24 months. The median time on the three aromatase inhibitors was 32 to 35 months in the switch group and 54 to 56 months in the up-front group.

Toxicity was the main reason for early treatment interruption. This was seen more frequently in patients treated with tamoxifen (11%) than in those treated with aromatase inhibitors (5% in the switch group and 7% in the up-front group).

Endometrial side effects were the most frequent reason for tamoxifen interruption (4%). Three percent of patients in the switch group and 4% in the up-front group experienced grade 3-4 musculoskeletal side effects.

A total of 85 patients were diagnosed with a second nonbreast cancer. Five patients were diagnosed after breast cancer recurrence.

There were 138 deaths, including 80 participants treated using the switch schedule and 58 patients treated using the up-front schedule. Breast cancer was the most frequent cause of death in both groups: 55 participants (3%) in the switch group, and 30 (2%) in the up-front group.

The study was funded by the Italian Drug Agency. Dr Perrone has financial relationships with AstraZeneca, Eli Lilly, Roche, Bayer, Ipsen, and Bristol-Myers Squibb. A number of study coauthors also have disclosed relevant financial relationships, as listed in the original article. Dr Dirix has disclosed no relevant financial relationships.

Lancet Oncol . Published online on February 23, 2018. Abstract, Comment

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