Kate Johnson

June 01, 2015

CHICAGO — Hope for reversing breast cancer endocrine resistance was the main reaction to results of PALOMA 3, the first phase 3 study of palbociclib ( Ibrance, Pfizer), announced in a late-breaking presentation at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) here.

Palbociclib is the first CDK4/6 inhibitor for breast cancer, and was granted an accelerated approval in the US based on phase 2 data earlier this year.

The phase 3 trial — conducted in estrogen-receptor (ER)-positive/HER2 negative breast cancer patients previously treated with hormone therapy — was stopped prematurely earlier this year after an interim analysis showed that the drug more than doubled the duration of disease control and delayed progression by more than 5 months.

"CDK4/6 inhibitors represent an important therapeutic advance in ER positive metastatic breast cancer," noted Joseph A. Sparano, MD, the discussant for the study, from Montefiore Medical Center in New York.

"It is exciting to have a novel, active, and well tolerated biologic enter the treatment space," Erica Mayer, MD, assistant professor of medicine at Harvard Medical School, told Medscape Oncology. "PALOMA 3 demonstrates efficacy in pre-treated hormone receptor positive breast cancer, suggesting the ability of CDK4/6 inhibition to overcome the challenge of endocrine resistance."

"For women with advanced breast cancer, it's remarkable to be able to stall disease progression and stave off the need for chemotherapy for months with a simple pill," added ASCO expert Don Dizon, MD, from Massachusetts General Hospital in Boston.

PALOMA 3 randomized 521 endocrine-resistant, advanced breast cancer patients in a 2:1 ratio to palbociclib (n = 341) at a dose of 125 mg/d orally for 3 weeks followed by 1 week off or placebo (n = 174), with all subjects also receiving standard endocrine therapy with fulvestrant (Faslodex, AstraZeneca).

The trial included menopausal women, but also pre- and perimenopausal women who received goserelin for ovarian suppression.

The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival, safety, biomarkers, and patient-reported outcomes.

A planned interim analysis performed after 195 PFS events showed a significant benefit in the palbociclib arm (hazard ratio, 0.422), with a median PFS of 9.2 months compared with 3.8 months for the fulvestrant only arm, reported lead study author Nicholas C. Turner, a consultant medical oncologist at The Royal Marsden and a team leader at The Institute of Cancer Research in London, United Kingdom.

The palbocicllib-fulvestrant combination was well tolerated, although hematological adverse events were frequent on palbociclib, including neutropenia (79%), leukopenia (46%), anemia (26%), and thrombocytopenia (19%), compared with 3%, 4%, 10%, and 0%, respectively, in the placebo arm. However, the incidence of febrile neutropenia was "very rare," at 0.6% in both arms.

The benefits of the combination therapy were seen in both pre- and postmenopausal women.

"This relatively easy-to-take new drug can substantially delay the point when women need to start chemotherapy, making this an exciting new approach," said Dr Turner.

"This study is very important because it is the first phase III study to demonstrate efficacy in any setting for these agents…and represents the first phase III data supporting the use of this group of novel therapies in combination with endocrine therapy for women with hormone sensitive advanced breast cancer," Conleth Murphy, MB, BCh, BAO, a medical oncologist at Bon Secours Hospital, in Cork, Ireland, told Medscape Medical News.

Dr Murphy recently published a review on CDK4/6 inhibition in breast cancer (Oncologist. 2015 May;20(5):483-490).

Early signs of palbociclib's efficacy were already evident in the phase 2 study, which led to the accelerated approval for use with the endocrine agent letrozole in postmenopausal women with ER-positive, HER2-negative disease.

"But we have all been awaiting phase III data," Dr Murphy said. "I would say this confirms the efficacy of this agent."

Furthermore, the current study indicates a role for palbociclib in reversing endocrine resistance, he added.

For me the study setting of women receiving second line endocrine therapy fits the clinical scenario where I would see palbociclib naturally fitting: not all patients may require such combination treatment in the first line setting as some patients may have very indolent disease which could be well controlled on single agent endocrine therapy for years."

Finally, PALOMA 3 confirms the utility of palbociclib in premenopausal as well as postmenopausal women, "opening up the options for young women with advanced hormone sensitive breast cancer," he said. "It is very reassuring to see that the common finding of neutropenia with palbociclib does not translate into clinically relevant febrile neutropenia, with this event being exceptionally uncommon in both study arms."

This study received funding from Pfizer.

Dr Turner and coauthors report relationships wither several pharmaceutical companies, and several coauthors were Pfizer employees.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA502. Presented June 1, 2015.

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