PHARE trial results comparing 6 to 12 months of trastuzumab as adjuvant therapy for early breast cancer

An academic randomised, non-inferiority trial from the French National Cancer Institute (INCa) presented at ESMO 2012 compared a shorter trastuzumab exposure of 6 months versus the standard treatment of 12 months in terms of disease-free survival according to a non-inferiority schema. The presented results of this study were inconclusive for this non-inferiority hypothesis, but nevertheless showed a trend in favor of the 12 months regimen. Further subgroupanalyses are currently underway in effort to identify subgroups of patients for whom 6 months of trastuzumab could suffice. Data of this analysis will be presented at the 2012 San Antonio Breast Cancer Symposium (SABCS).

Since 2005, one year of trastuzumab has been providing survival benefit to patients with early breast cancer and HER2 overexpression. However, the optimal duration of this trastuzumab therapy has been debatable due to concerns on cardiac toxicity. Furthermore, results from the FinHer trial showed that 9 weeks of trastuzumab provided a similar magnitude of benefit than the 1-year treatment. This formed the rationale to set up an academic randomised non-inferiority trial comparing a shorter trastuzumab exposure of 6 months versus the standard duration of 12 months.

Over 150 cancer care centers from all over France participated in the PHARE trial and in total 3,382 patients with with HER2-positive early breast cancer who received at least 4 cycles of (neo)-adjuvant chemotherapy were included in the study. Patients in the study were randomised (1:1) between 1 year or 6 months of trastuzumab. The randomisation was stratified for concomitant or sequential trastuzumab administration with chemotherapy, oestrogen receptors status and study center. The primary objective of the PHARE trial was to show non-inferiority for 6 months of trastuzumab in terms of disease-free survival, while secondary objectives included overall survival and cardiac toxicity.

The hazard ratio (HR) for disease-free survival (DFS) in the study was 1.28 (95% CI: 1.05-1.56; p=0.29). As the lower bound of the 95% CI crosses the prespecified non-inferiority margin of 1.15, the non-inferiority of 6 months of trastuzumab compared to 12 months could not be demonstrated. “However, despite this inconclusive result in terms of non-inferiority, the HR of 1.28 suggests a trend favouring 12 months,” said Prof. Xavier Pivot of the Université de Franche Comté, France. The current presentation of the PHARE data was based on an analysis with a median follow-up of 3.5 years. Given the convergent trend for the DFS curves observed in the Kaplan-Meier plot, longer follow-up is warranted. Furthermore, a significant difference in the rate of cardiac events was observed in favor of the 6 months treatment.

Further exploration of the data, especially in selected subgroups is ongoing and these results will be presented during the upcoming San Antonio Breast Cancer Symposium in December.

Reference

Pivot X, Romieu G, Bonnefoi H et al. PHARE trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. Presented at ESMO 2012, Abstract LBA5.