As key cell cycle regulators, cyclin-dependent kinases 4 and 6 (CDK4/6) interact with cyclin D, to hyperphosphorylate retinoblastoma (Rb), releasing transcription factors that allow cell proliferation. During cancer, dysregulation of the cell cycle occurs through loss of Rb function, or amplification of cyclin D or CDK. Palbociclib (Ibrance™), a reversible, small molecule inhibitor of CDK4/6 blocks Rb phosphorylation, thus preventing cell cycle progression.

In November 2016, palbociclib received marketing authorisation by the European Medicines Agency (EMA) for the treatment of hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative locally advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor (AI), or with fulvestrant in women who progress during or following endocrine therapy (ET).

In the US, Palbociclib is authorised in combination with fulvestrant based on the multicentre, phase III PALOMA-3 trial, in which 521 HR-positive, HER2-negative women were randomised 2:1 to palbociclib plus fulvestrant (n=347) or placebo plus fulvestrant (n=174). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included overall survival (OS), confirmed objective response rate (ORR), duration of response (DOR), patient reported outcomes (PROs) and safety. Palbociclib plus fulvestrant increased median PFS from 4.6 months to 9.5 months compared to placebo plus fulvestrant (HR 0.46, 95% CI 0.36-0.59; two-sided, p < 0.0001) in the intention to treat population. OS data were not mature with only 29% of 197 events needed for analysis. DOR increased from 7.6 months to 9.3 months with palbociclib plus fulvestrant versus fulvestrant alone. Global quality of life (QoL) results were in favour of palbociclib (66.1 versus 63.0). Serious adverse events (SAEs) occurred in 44 (13%) of 345 palbociclib plus fulvestrant recipients and 30 (17%) of 172 placebo plus fulvestrant recipients. Grade 3 or 4 neutropenia and leukopenia were reported in 65% and 28% of palbociclib plus fulvestrant recipients, and 1% and 4% of placebo plus fulvestrant recipients respectively.

Palbociclib is a first-in-class CDK4/6 inhibitor for use in combination with fulvestrant as second-line treatment for HR-positive, HER2-negative advanced or MBC with disease progression during or following ET. While palbociclib increased median PFS by 4.9 months, this endpoint is not currently supported by OS data or clinically important differences in QoL. Physician and patient preference contribute to palbociclib's place in therapy due to the lack of OS data and head-to-head comparisons of first-line versus subsequent-line use. While the Rb protein is the only reliable indicator for palbociclib activity, further indicators and biomarkers may be of benefit for future use.