Abstract P4-13-03: Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy
Authors: Verma S , DeMichele AM , Loi S , Ro J , Colleoni M , Iwata H , Harbeck N , Stearns V , Cristofanilli M , Huang Bartlett C , Schnell P , Zhang K , Thiele A , Turner NC , Rugo HS 
Published: May 2016

Abstract
Background: Endocrine therapy (ET) resistance remains a major clinical problem for patients (pts) with hormone receptor (HR+) breast cancer (BC). In PALOMA-3, palbociclib (P) combined with fulvestrant (F) demonstrated significant prolongation of progression-free survival (PFS) vs F plus placebo (PLB) in pre/peri and postmenopausal women with HR+/HER2– metastatic BC (MBC) whose disease progressed on prior ET (median PFS 9.2 vs 3.8 m; HR=0.422, P=0.0001).
Methods: In this double-blind phase 3 study, 521 pts with HR+/HER2– MBC were randomized 2:1 to receive P (125 mg/d orally for 3 weeks followed by 1 week off) and F (500 mg given per standard of care) or PLB plus F. Pre- and perimenopausal women also received goserelin. One previous line of chemotherapy (CT) for MBC was allowed. Safety assessments occurred at baseline and D1 of each cycle; blood counts occurred every 2 wks for the first 2 cycles and on D1 of subsequent cycles. As pts may have experienced multiple episodes of neutropenia during treatment, we analyzed all episodes in aggregate based on laboratory data per CTCAE4.0.
Results: The results reported here are from the data cutoff of Dec 2014, with a median follow-up of 5.6 m. Overall rate of any grade (G) and G3/4 AEs was 98/70% of pts in P+F vs 89/18% in PLB+F. The most commonly reported AEs in P+F (≥20%) were hematologic toxicities, fatigue, nausea, and headache. Per lab data, G3/G4 neutropenia occurred in 52.2/8.2%, G3/G4 leukopenia in 39.5/1.2%, G3/G4 anemia in 20.8/2.9% and G3/G4 thrombocytopenia in 2.1/1.2% of pts on P+F. Neutropenia occurred early, with a median onset time for first episode of ≥G3 neutropenia of 15 d (13–197) and median time from first dose to the lowest absolute neutrophil count (ANC) of 29 d (13–334). The median duration of ≥G3 episode was 7 d (1–35), suggesting that most pts can resume treatment after a 1-week cycle delay. A comparable proportion of any grade neutropenia was observed in pts with or without prior CT (prior CT 88.4% vs no prior CT 85.4%). There was no difference in the rate of G3/G4 neutropenia in the older pts (&gt;65 yrs, 51% vs ≤65 yrs, 57%) in P+F arm. Concurrent G≥3 infections occurred in 1% of pts with G≥3 neutropenia (2/192 pts). Febrile neutropenia occurred in 0.6% of pts in both arms. 21% of pts had dose reductions and 45% had dose interruption due to neutropenia. Dose intensity was maintained at 89.7% for P. Serious adverse events (SAEs) were reported in 9.6% of pts on P+F and in 14% of pts on PLB+F. The most common SAEs on P+F were pulmonary embolism (0.9%) and pyrexia (0.9%). Safety analyses with longer follow-up (data cut off, March 2015) are ongoing and will be presented.
Conclusions: Findings suggest P+F has a favorable safety profile characterized mainly by asymptomatic hematologic toxicity. Overall SAE rates were low and comparable between the 2 arms. Palbociclib-related neutropenia differs from that seen with CT, consistent with proposed mechanism of action, in that it is not commonly associated with fever, and can be effectively managed by a dose interruption or cycle delay.
Funding: Pfizer, Inc.
Citation Format: Verma S, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Stearns V, Cristofanilli M, Huang Bartlett C, Schnell P, Zhang K, Thiele A, Turner NC, Rugo HS. Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-03.