Adding the investigational drug pictilisib (previously GDC-0941) to the endocrine therapeutic fulvestrant increased progression-free survival for women with aromatase inhibitor-resistant, advanced or metastatic breast cancer positive for both estrogen receptor (ER) and progesterone receptor (PR), according to data from the randomized, phase II FERGI clinical trial presented at the 2014 San Antonio Breast Cancer Symposium.
“When we analyzed data for all women with ER-positive disease, the improvement in progression-free survival was not statistically significant,” said Ian E. Krop, MD, PhD, director of clinical research for the Breast Oncology Program at the Dana-Farber Cancer Institute in Boston, Massachusetts. “However, when we considered only those women who had breast cancer positive for both ER and PR, adding pictilisib resulted in a significant doubling of progression-free survival, from 3.7 months to 7.4 months, in an exploratory analysis, and we are planning on investigating whether the benefit of pictilisib for women with ER/PR-positive breast cancer holds true in an additional cohort of patients within this study.”
After 17 months of follow-up, analysis of the overall study population of women with ER-positive breast cancer showed that those randomized to pictilisib and fulvestrant were 26% less likely to have disease progression compared with women randomized to placebo and fulvestrant. This improvement in progression-free survival was not statistically significant (P=.09). Post hoc analysis of progression-free survival among those women with ER- and PR-positive disease found that those randomized to pictilisib and fulvestrant were 56% less likely to have disease progression compared with women randomized to placebo and fulvestrant, a statistically significant improvement (P=.002).
“There are compelling preclinical data, and some clinical data, to suggest that activation of the PI3K signaling pathway drives resistance to endocrine treatment for ER-positive breast cancer,” said Krop. “This provided the rationale for testing whether adding the PI3K inhibitor pictilisib to fulvestrant would improve progression-free survival for women with ER-positive, advanced or metastatic breast cancer that had become resistant to endocrine treatments called aromatase inhibitors.
“One surprise from our data was that having breast cancer with a mutation in the PIK3CA gene, a central component of the PI3K signaling pathway, was not predictive of benefit from pictilisib,” continued Krop. “It may be that PIK3CA mutation is not the only way to activate PI3K signaling.”
For this study, Krop and colleagues enrolled 168 postmenopausal patients with ER-positive, HER2-negative, advanced or metastatic breast cancer who had relapsed or progressed following or during treatment with an aromatase inhibitor. Patients were randomized to fulvestrant with pictilisib or fulvestrant with placebo.
No unexpected toxicity was reported. The side effects of pictilisib and fulvestrant were similar to those observed in clinical trials testing pictilisib as a single treatment.
FERGI stands for fulvestrant in ER-positive breast cancer with GDC-0941 and GDC-0980 inhibitors.
This study was supported by funds from Genentech. Krop receives research funding from Genentech.