The phase III registration study PALOMA-31 reports that adding the investigational targeted agent palbociclib to standard hormonal therapy (fulvestrant) more than doubled the duration of disease control, delaying disease progression by roughly five months in women with previously treated, hormone receptor-positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer.
This trial was stopped early based on efficacy seen in the interim analysis.
Approximately 75% of all breast cancers are hormone receptor-positive (HR+), HER2 negative,2 and palbociclib in combination with hormonal therapy could become a very effective treatment option after initial hormonal therapy for women with HR+, HER2- advanced breast cancer.
"After initial hormonal therapy stops working in metastatic breast cancer, the next step is typically chemotherapy, which can be effective, but the side effects are often very difficult for women," said lead study author Nicholas C. Turner, a consultant medical oncologist at The Royal Marsden and a team leader at The Institute of Cancer Research, London, United Kingdom. "This relatively easy-to-take new drug can substantially delay the point when women need to start chemotherapy, making this an exciting new approach for women."
Palbociclib is a novel, first-in-class oral drug that blocks cyclin dependent kinases (CDKs) 4 and 6. Prior research has shown that CDK4 and CDK6 are among the key proteins that fuel the growth of hormone receptor-positive breast tumors. Strong preclinical evidence supports combining CDK4 and CDK6 inhibitors with hormonal therapy. Fulvestrant is one of the most active hormone therapies for patients with HR+/ HER2- advanced breast cancer.
Women with HR+/HER2- breast cancer were randomly assigned to palbociclib with fulvestrant or placebo with fulvestrant. All patients had metastatic disease that had worsened or relapsed after initial hormonal therapy, and 21% were premenopausal. According to the authors, PALOMA-3 is one of the first registration targeted therapy–hormone therapy combination studies in advanced breast cancer to include younger, premenopausal women.
At the time of this interim analysis, the average time to disease progression was 9.2 months in the palbociclib arm compared to 3.8 months in the placebo arm. Comparable benefits were seen in pre- and postmenopausal women.
Longer follow-up is needed to determine the effect of palbociclib on overall survival. Quality of life data were collected and will be reported at a later date.
The palbociclib combination was generally well tolerated, with only 2.6% of patients having to stop treatment due to side effects, the most common being blood count abnormalities. Despite frequent occurrences of low white blood cell counts, the rates of a serious complication known as febrile neutropenia were very low (0.6%), the same in both treatment groups.
Another study known as PALOMA-2 is exploring the efficacy of palbociclib as a therapy for advanced breast cancer not previously treated with hormonal therapy. Dr. Turner noted that researchers are also looking at the possibility of using this therapy in women with early-stage hormone receptor-positive breast cancer.
Earlier this year, the FDA granted palbociclib accelerated approval for use in combination with letrozole for women with advanced (metastatic) estrogen receptor positive (ER+), HER2- breast cancer who have not yet received hormonal therapy for their metastatic disease. The approval was granted based on results of a prior phase II study, PALOMA-1.
This study received funding from Pfizer.
1PALbociclib: Ongoing trials in the Management of breast cAncer
2http://www.webmd.com/breast-cancer/breast-cancer-types-er-positive-her2-positive. Accessed May 20, 2015