Take your PI3K.

Top Line: Where are we with PI3K-inhibitors for breast cancer?
The Study: SOLAR-1 randomized women with advanced ER(+), HER2(-) breast cancer to fulvestrant +/- the PI3K-inhibitor, alpelisib. Why a PI3K-inhibitor? Well, as many as 40% of women with ER(+), HER2(-) breast cancer harbor PIK3CA-activating mutations (yes, K before 3...it’s confusing). So here patients were selected up-front based on said receptor status and were then split into two cohorts based on whether they had this PI3KCA-mutation. Unfortunately, the PIK3CA-wild type group had no benefit with the addition of alpelisib. However, the PIK3CA-mutated group saw a significant improvement in response rate (13 → 27%) and median progression free survival (6 → 11 months). The most common side effects seen with alpelisib were hyperglycemia (grade 3+ in two-thirds), rash, and diarrhea. And here’s where things get complicated. As recently pointed out by Vinay Prasad, a fair number of cancer drugs make it to market without facing what would be considered “the standard.” In this particular scenario, most advanced ER/PR+, HER2- patients nowadays get first-line endocrine therapy + CDK4/6-inhibition. So, how would alpelisib compare to the -ciclib’s? We’re not sure. However, we should note that PIK3CA-mutations are a common mechanism of CDK4/6-inhibitor resistance—meaning these drugs could have important complementary roles.
Bottom Line: Patients with advanced ER(+), HER2(-) breast cancer harboring PIK3CA-mutations have improved progression free survival with the addition of a PI3K-inhibitor to endocrine therapy. | Andre, N Engl J Med 2019


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