Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor‐Positive/HER2‐Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo‐Controlled, Phase III Study (PALOMA‐3)

Background. Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)‐positive/human epidermal growth factor receptor 2 (HER2)‐negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Materials and Methods. Patients with endocrine‐resistant, HR‐positive/HER2‐negative MBC ( n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. Results. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow‐up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below‐median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3–4 neutropenia with palbociclib. Dose modifications for grade 3–4 neutropenia had no adverse effect on progression‐free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1–2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Conclusion. Palbociclib plus fulvestrant treatment was well‐tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov , NCT01942135 . Implications for Practice: Treatment with palbociclib in combination with fulvestrant was generally safe and well‐tolerated in patients with hormone receptor (HR)‐positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib‐related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR‐positive/human epidermal growth factor receptor 2‐negative metastatic breast cancer.