In a Phase 3 Paloma-III study of Pfizer’s CDK4/6 inhibitor (Ibrance – palbociclib) and an estrogen receptor antagonist (Faslodex – fulvestrant), patients receiving the combination had significantly prolonged progression-free survival than women with breast cancer who received Faslodex, alone.
The study randomized 521 pre/perimenopausal and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer whose disease had progressed during or after endocrine therapy to receive Faslodex in combination with Ibrance or placebo. An interim analysis showed that PFS was 9.2 months in patients given Ibrance plus Fasodex, versus 3.8 months for those who received Faslodex plus placebo.
In February, Ibrance was granted accelerated approval by FDA when combined with an aromatase inhibitor (Femara – letrozole) in patients with HR+ (hormone receptor positive) / HER-2 negative breast cancer. Ibrance has now shown activity in combination with anti-estrogen therapy in patients with metastatic breast cancer both in the front-line and after progression following endocrine therapy.
What is the mechanism of action of Ibrance?
Ibrance (palbociclib) is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation resulting in reduced E2F expression and signaling and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling and tumor growth compared to each drug alone.
Virtually all mitogenic signals to the cell are processed through CDK4/6 – it is truly the central molecule that governs pRb phosphorylation status up through the R-point transition.
What is anti-estrogen therapy?
Anti-estrogen therapy involves blocking the production, binding, or signaling of estrogen in cancer cells. Estrogen is a mitogenic growth factor – disrupting the production or effective signaling of estrogen deprives cells of signals to divide.