Findings from a phase II trial show that combining the experimental PI3 kinase inhibitor pictilisib with fulvestrant improves progression-free survival and may help overcome resistance to aromatase inhibitors in a subgroup of patients with advanced estrogen receptor–positive and progesterone receptor–positive breast cancer.

Adding the experimental PI3K inhibitor pictilisib (Genentech) to the anti-estrogen fulvestrant (Faslodex; AstraZeneca) did not significantly delay progression of estrogen receptor (ER)–positive advanced breast cancers that were resistant to aromatase inhibitors. However, the combination unexpectedly doubled progression-free survival (PFS) in a subgroup of women whose tumors were both ER-positive and progesterone receptor (PR)–positive, researchers reported December 10 at the San Antonio Breast Cancer Symposium in Texas.

“The PI3 kinase pathway has been the focus of a great deal of attention over the past 10 years, particularly in ER-positive breast cancer,” said the study's co-investigator Eric Winer, MD, director of the Breast Oncology Program at Dana-Farber Cancer Institute in Boston, MA.

Winer noted that 40% to 45% of patients with ER-positive breast cancer have a PIK3CA mutation, which leads to signaling through the pathway. “This signaling has been implicated as a resistance mechanism to anti-estrogen therapy both in vitro and in the clinical setting,” he said.

The randomized phase II study, dubbed FERGI, was the first to test whether combining hormonal therapy with a PI3K inhibitor could help overcome that resistance. The trial included 168 postmenopausal women with advanced ER-positive breast tumors with and without PIK3CA mutations.

For the cohort as a whole, adding pictilisib to fulvestrant resulted in a median PFS of 6.6 months compared to 5.1 months for fulvestrant alone—a difference that was not statistically significant. Researchers also found that having a PIK3CA mutation did not improve outcome. “That was a surprise,” said Winer.

However, an unplanned analysis of patients with both ER- and PR-positive disease, which accounted for about 70% of study participants, showed a significant improvement in median PFS: 7.4 months with the combination versus 3.7 months with fulvestrant alone. “This is the group of patients that are thought to have the most hormonally sensitive disease because PR helps to facilitate signaling through the ER pathway,” said Winer.

The findings suggest that a PIK3CA mutation may not be the only way to activate PI3K signaling, he said.

Within the FERGI study, investigators are now examining whether the benefit of pictilisib plus fulvestrant holds true for 60 women with PIK3CA-mutant ER- and PR-positive breast cancer. Data from this additional cohort is expected in 2015.

The study provides more evidence that targeting the PI3K pathway “continues to be important in hormone receptor–positive breast cancer,” said Jennifer Litton, MD, director of the Breast Medical Oncology Education Program at The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the study.

Winer agreed, but noted that pan-PI3K inhibitors such as pictilisib may not be as effective as alpha-selective PI3K inhibitors that are now in late-phase clinical testing. “Many of us are quite optimistic about those studies,” said Winer.