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Palbociclib plus hormone therapy slows progression of HR-positive breast cancer
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CHICAGO – The addition of the investigational agent palbociclib to fulvestrant more than doubled the duration of disease control for women with hormone receptor-positive, HER-2–negative advanced breast cancer who had progressed on prior endocrine therapy, according to findings from the PALOMA-3 study presented at the ASCO Annual Meeting.
The trial was stopped early based on the efficacy of the combination identified in the interim analysis of the data.
“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,” Nicholas C. Turner, MD, PhD, a consultant medical oncologist at the Royal Marsden and a team leader at the Institute of Cancer Research in London, said in a press release. “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.”
Resistance to endocrine treatment commonly occurs in women with hormone receptor (HR)-positive breast cancer, according to study background. Palbociclib (Ibrance, Pfizer) is a first-in-class oral agent that blocks cyclin dependent kinases (CDKs) 4 and 6, proteins that fuel the growth of HR-positive tumors. Further, the addition of palbociclib to the standard hormone therapy drug fulvestrant (Faslodex, AstraZeneca) showed promise in preclinical studies.
Turner and colleagues conducted this double-blind, phase 3 study to assess the safety and efficacy of the palbociclib–fulvestrant combination.
The analysis included 521 patients with HR-positive/HER-2–negative advanced metastatic breast cancer who had relapsed on or experienced disease progression with prior endocrine therapy. Seventy-nine percent of the women were post-menopausal, 60% had visceral disease and 79% were sensitive to prior endocrine therapy. A total of 33% of the patients had prior chemotherapy.
Researchers randomly assigned patients 2:1 to 500 mg fulvestrant with 125 mg daily palbociclib every 3 weeks with 1 week off (n = 347; median age, 57 years) or placebo (n = 174; median age, 56 years).
Pre- and peri-menopausal women also received goserelin (Zoladex, AstraZeneca).
PFS served as the study’s primary endpoint and secondary endpoints included OS, response assessment, patient-reported outcomes, safety and tolerability.
Researchers conducted an interim analysis after 195 PFS events had occurred. At that time, the median PFS was 9.2 months in the combination group vs. 3.8 months in the placebo group (HR = 0.42; 95% CI, 0.32-0.56), which indicated that the primary endpoint of the study had been met.
Researchers observed a consistent benefit of the combination therapy among pre- and postmenopausal women.
A greater proportion of patients in the combination arm experienced neutropenia (78.8% vs. 3.5%), leucopenia (45.5% vs. 4.1%) and fatigue (38% vs. 26.7%). Febrile neutropenia occurred in 0.6% of the patients in each arm. Two percent of patients in the combination arm discontinued treatment compared with 1.7% of patients in the control group.
Because the trial was stopped, longer follow-up is needed to determine the effect of palbociclib on OS, according to the researchers. Quality-of-life data will be reported at a later date.
A sister study known as PALOMA-2 also is evaluating palbociclib as therapy for women with advanced breast cancer who had not previously received hormone therapy. The combination also may be evaluated in women with early-stage HR-positive breast cancer, Turner said.
In February, the FDA granted accelerated approval for palbociclib for use in combination with letrozole (Femara, Novartis) for women with advanced metastatic ER-positive, HER-2–negative breast cancer who have not yet received hormone therapy.
“What we’re identifying in HR-positive breast cancer is that CDK4 and 6 are the key genes that allow HR-positive breast cancer to proliferate,” Turner said at a press conference. “Previous studies have shown palbociclib is active in endocrine sensitive breast cancer but this study confirms that as breast cancers become resistant to endocrine therapy CDK 4 and 6 is still a target and palbociclib is still active.” – by Anthony SanFilippo
Reference:
Turner NC, et al. Abstract LBA502. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: The study was funded by Pfizer. Turner reports honoraria from AstraZeneca, BioMarin, Clovis Oncology, Novartis, Pfizer, Roche and Servier and research funding from AstraZeneca, Pfizer and Roche/Genentech. Please see the full study for a list of all other researchers’ relevant financial disclosures.