MedicalResearch.com Interview with:
Rita Mehta, MD, HS Clinical Professor,
Chao Family Comprehensive Cancer Center
University of California School of Medicine, Irvine
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Most patients with HR-positive breast cancer become resistant to hormonal therapies like aromatase inhibitor-anastrozole over time, and downregulating estrogen receptor was identified as a mechanism for overcoming or delaying resistance to hormonal therapy in advanced HR-positive breast cancer. The prospective, randomized phase III S0226 trial, first reported by us in NEJM 2012, showed that the selective estrogen receptor degrader fulvestrant in combination with anastrozole significantly improved progression-free survival in 707 women with HR-positive metastatic breast cancer in first-line setting.
Treatment with the selective estrogen receptor degrader (SERD) fulvestrant achieved a clinically significant and meaningful improvement in overall survival in patients with hormone receptor (HR)-positive advanced breast cancer in first-line therapy, according to the final analysis of overall survival results from the S0226 study reported by us (Mehta et al. NEJM 2019)
- Results showed that median overall survival improved by 7.8 months with anastrozole plus fulvestrant (median overall survival = 49.8 months) compared to anastrozole (median overall survival = 42.0 months).
- The improvement was even greater in patients with endocrine naive disease, with an absolute improvement in median overall survival of 11.9 months.
- No new safety signals were observed with longer follow-up.
MedicalResearch.com: What should readers take away from your report?
Response: The new analysis assessed overall survival, a key secondary endpoint of S0226, after a median follow-up of 7 years in 694 patients with HR-positive metastatic breast cancer. The enrolled patients had initial diagnosis of breast cancer with concurrent metastasis at presentation and had no prior systemic therapy or had relapsed after prior diagnosis of early breast cancer and may have received adjuvant tamoxifen. About 60% patients were endocrine naïve. They were randomly assigned to receive fulvestrant (500 mg d1 and 250 mg d14 and D28 and then every 28 days) + anastrozole 1 mg/day or anastrozole 1 mg/ day alone. We carried out the overall survival analysis when >70% of 694 patients in the study had died.
Results showed that median overall survival improved by 7.8 months with fulvestrant+ anastrozole (median overall survival = 49.8 months), compared to anastrozole (median overall survival = 42.0 months, HR 0.82, 95% confidence interval 0.69-0.98, p=0.03 by stratified log-rank test).
The improvement was even greater in endocrine therapy-naïve patients, with an absolute improvement in median overall survival of 11.9 months. Median overall survival improved significantly by 15 months in patients with initial diagnosis more than 10 years prior. Patient with visceral disease also showed benefit as did patients with non-visceral or bone only metastasis. No new safety signals were observed with longer follow-up.
Here, we present long term overall survival results from a phase III study for addition of fulvestrant in a preplanned analysis of the S0226 trial. Importantly, this report confirms that the relative gain in survival is similar to the relative gain in progression-free survival in the whole population, and is not only clinically significant but also clinically meaningful. Moreover, this prolongation of life is of a large magnitude in patients with no prior endocrine therapy and in patients with prior diagnosis of more than 10 years before the relapse-regardless of prior tamoxifen use
This is very important for patients, as it shows that the improvement in overall survival observed in previous report has a positive impact on long term overall survival, an ultimate goal of treatment, therefore improving the chance for a long-term life in spite of advanced disease. The demonstration of a positive impact on overall survival without significant additional long term toxicity apart from the discomfort of an extra intramuscular shot also provides additional confidence to clinicians and patients as to the benefits of this combination as an appropriate and effective treatment approach.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Given that the study was powered for overall survival, and despite the longer survival in the control arm (projected 36 months, observed 42 months), the experimental arm even performed better than projected (projected 48 months, observed 49.8 months). Moreover, the results strongly suggest that the progression-free survival benefit translates into an overall survival benefit with the same relative benefit, despite cross-over to fulvestrant in 45% of patients on anastrozole alone arm.
Collecting mature overall survival data at longer follow-up from the randomized trial that investigated the combination of endocrine therapy is crucial to have a clearer understanding on the benefit of addition of fulvestrant. The overall survival data that we had at median follow up of 36 months are now supported by the longer updated results at median follow up of 7 years, which strongly suggest that this treatment should be considered in women with advanced HR-positive disease. Barring visceral crisis, patients with visceral metastasis also benefitted in addition to patients with bone and soft tissue metastasis. who may benefit from dual endocrine therapy alone.
The significant impact of fulvestrant on disease-free and overall survival in metastatic disease lead to the trials using fulvestrant in early breast cancer in adjuvant and neo-adjuvant setting, where our goal is to improve the cure rate. On that front, one large randomized adjuvant trial of fulvestrant in early-stage breast cancer and one in the neoadjuvant setting—Spanish trial and ALTERNATE—are ongoing.
Disclsoures: The study was supported by NIH grants to SWOG and drug support by Astrazeneca.
Rita S. Mehta, M.D., William E. Barlow, Ph.D., Kathy S. Albain, M.D., Ted A. Vandenberg, M.D., Shaker R. Dakhil, M.D., Nagendra R. Tirumali, M.D., Danika L. Lew, M.A., Daniel F. Hayes, M.D., Julie R. Gralow, M.D., Hannah H. Linden, M.D., Robert B. Livingston, M.D., and Gabriel N. Hortobagyi, M.D.
March 28, 2019
N Engl J Med 2019; 380:1226-1234
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