Three agents were already on the market – palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) – with a fourth, alpelisib (Piqray), approved this May. This could change the space even more for premenopausal women with PIK3CA-mutant advanced breast cancer that progressed on or after an endocrine-based regimen, according to Christopher R. Chitambar, MD, FACP.
“It turns out that about 40% of patients with ER- or HR-positive breast cancer have these mutations that drive cancer proliferation,” Chitambar, professor at the Medical College of Wisconsin, said in an interview with OncLive, a sister publication of Oncology Nursing News.
How CDK4/6 Inhibitors Work
CDK4/6 inhibitors work by blocking the cell cycle, Chitambar said, with the PALOMA-1 trial showing the first signs of promise with palbociclib. The study showed that combining the agent with an anti-estrogen therapy created a synergy that caused tumors that were previously resistant to anti-estrogen therapy respond.
“In effect, we were bypassing drug resistance or anti-estrogen blockade,” Chitambar said. “That was very exciting. This was rapidly translated to the PALOMA-2 and PALOMA-3 clinical trials. The combinations were of nonsteroidal (aromatase inhibitors), such as anastrozole or letrozole, plus palbociclib.”
The PALOMA trials showed superiority and prolonged disease-free survival (DFS), “no matter which way you looked at it,” said Chitambar.
The MONALEESA trials also showed DFS prolongation with a CDK4/6 inhibitor – in this case ribociclib – plus an anti-estrogen agent.
“The same is true of abemaciclib. These studies differ somewhat in the timing, specifically in terms of whether they’re first- or second-line therapies, but all of the results show a similar benefit,” Chitambar said.
Then, alpelisib was approved for the treatment of postmenopausal women and with HR-positive, HER2-negative, PIK3CA-mutant advanced or metastatic breast cancer, thanks to findings from the SOLAR-1 trial. Data showed a 35% reduction in the risk of progression or death for those enrolled on the alpelisib arm.
Dosing and Toxicity Profiles
While CDK4/6 inhibitors are similar to some extent, there are different adverse events and dosing schedules between them that oncology nurses should be on the lookout for.
“For example, palbociclib and ribociclib are more myelosuppressive, and therefore have to be given 3 weeks on (and) 1 week off, whereas abemaciclib can be given continuously,” Chitambar explained. “There you run into other gastrointestinal toxicities, such as diarrhea and fatigue; it’s a different profile.”
Researchers and clinicians are also still on the fence with the best way to sequence these agents. The MONALEESA-7 trial examined this in premenopausal women, with more trials coming down the pipeline.
“The combinations are going to be quite interesting,” Chitambar said. “Much of our success in the treatment of patients with metastatic disease has come by mixing and matching.”
A version of this article originally appeared on OncLive as, “Bypassing Endocrine Resistance in Advanced HR+ Breast Cancer