PHARE Trial Fails to Establish Noninferiority of 6 vs 12 Months of Adjuvant Trastuzumab in Early HER2-positive Breast Cancer
The phase III open-label PHARE trial, conducted in 156 centers in France, examined whether 6 months of adjuvant trastuzumab (Herceptin) was noninferior to 12 months of treatment in women with early HER2-positive breast cancer. As reported by Xavier Pivot, MD, of University Hospital Jean-Minjoz, France, and colleagues in Lancet Oncology, the trial did not establish the noninferiority of the shorter treatment course. Although the longer course was associated with significantly more cardiac events, the results suggest that the 12-month course of trastuzumab should remain standard treatment.
Study Details
In this noninferiority trial, 3,380 patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, undergone breast-axillary surgery, and received up to 6 months of trastuzumab were randomly assigned to continue trastuzumab for another 6 months (n = 1,690) or to discontinue trastuzumab at 6 months (n=1,690). The primary endpoint was disease-free survival with a prespecified noninferiority hazard ratio (HR) margin of 1.15.
Patients in the 12-month and 6-month groups were well matched for age, nodal status, tumor size, estrogen receptor (ER) and progesterone receptor status, tumor location, type of chemotherapy (taxane- and anthracycline-containing regimen in 74% and 73%, respectively), and timing of chemotherapy and trastuzumab (concomitant in 57% and 56%, respectively).
Median follow-up was 37.9 months in patients treated with concomitant trastuzumab and chemotherapy and 47.5 months in those receiving sequential treatment. The mean duration of trastuzumab treatment was 11.8 months in the 12-month group and 6.3 months in the 6-month group.
Disease-free Survival Outcomes
After an overall median follow-up of 42.5 months, disease-free survival events (local, regional, or distant recurrence; contralateral breast cancer; second primary cancer; or death) occurred in 175 patients in the 12-month group (10.4%) and 219 patients in the 6-month group (13.0%). Two-year disease-free survival was 93.8% in the 12-month group and 91.1% in the 6-month group; since the estimated hazard ratio of 1.28 (95% confidence interval [CI] = 1.05–1.56, P = .29 for noninferiority) did not meet the prespecified margin of 1.15, it could not be concluded that the 6-month regimen was noninferior. Fewer patients in the 12-month group had distant recurrences as first disease-free survival events (6.4% vs 8.3%, HR = 1.33, 95% CI = 1.04–1.71). The incidence of other types of disease-free survival event was similar in the two groups. Additional follow-up is needed for mature overall survival data.
Disease-free survival was also analyzed by the stratification factors of ER status and sequential or concurrent timing of chemotherapy and trastuzumab treatment. Among patients with ER-negative tumors, disease-free survival was significantly reduced in patients in the 6-month group receiving sequential chemotherapy and trastuzumab compared with patients in the 12-month group receiving sequential treatment (HR = 1.57, 95% CI = 1.08–2.28). There were no significant differences between other 6-month and 12-month subgroups according to ER status and timing of treatment.
Cardiac Events
Of the total of 128 cardiac events observed, 119 (93%) occurred while patients were receiving trastuzumab. Overall, cardiac events were significantly more common in the 12-month group than in the 6-month group (5.7% vs 1.9%, P < .0001). Significantly more patients in the 12-month group had a left-ventricular ejection fraction value < 50% (6.3% vs 4.7%, P = .04), but there were no significant differences between the 12-month and 6-month groups with regard to proportions of patients with left-ventricular ejection fraction value < 50% (independent of baseline value) and a decrease > 10% (4.8% vs 3.6%, P = .07) or proportions with a decrease > 15% from baseline with a value > 50% (7.4% vs 7.0%, P = .64).
The investigators concluded, “This analysis of the PHARE trial, after a median follow-up of 42 months, did not show that 6 months of treatment with adjuvant trastuzumab is noninferior to 12 months of such treatment for women with HER2-positive early breast cancer. Thus, despite the increased risk of cardiac events with longer treatment duration, 12 months of trastuzumab should remain the standard adjuvant treatment for such patients.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
