Abstract PS10-17: Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL)
Authors: Pérez-García José Manuel , Llombart-Cussac Antonio , Bellet Meritxell , Dalenc Florence , Gil Miguel J. Gil , Borrego Manuel Ruiz , Gavilá Joaquín , Sampayo-Cordero Miguel , Aguirre Elena , Schmid Peter , Marmé Frederik , Di Cosimo Serena , Gligorov Joseph , Schneeweiss Andreas , Albanell Joan , Zamora Pilar , Wheatley Duncan , Martínez-De Dueñas Eduardo , Carañana Vicente , Amillano Kepa , Malfettone Andrea , Cortés Javier 
Published: February 2021

Background: P led to a meaningful improvement in clinical outcomes when used in combination with endocrine therapy for first- or later-line regimen in HR[+]/HER2[-] MBC. Grade 3-4 neutropenia was the most common adverse event (AE) in the P-containing regimens. Although venous thromboembolic events (VTE) have been rarely reported in registrational trials, a systematic review and meta-analysis of randomized controlled trials demonstrated a higher rate of these AEs. Moreover, rare but severe cases of interstitial lung disease (ILD)/pneumonitis have been observed during post-approval use of P. Here, we present a comprehensive toxicity profile of pts included in the PARSIFAL study, with particular emphasis given to AEs of special interest of the overall safety population. Methods: A total of 486 pts with HR[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse &gt;12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with de novo metastatic disease) were randomly assigned 1:1 to receive P (oral 125 mg/day [d]; 3 weeks on/1 week off) plus either F (intramuscular injection 500 mg/d; d 0, 14, 28, and then every 28 ds) or L (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (de novo/recurrent). Safety assessments included blood analysis and collection of vital signs at screening, d1 of each cycle, and end of treatment/withdrawal. Severity was graded as per the NCI Common Terminology Criteria for Adverse Events v.4.03. Results: The incidence rate of any grade, grade 3-4, and serious AEs was 99.6%, 80.9%, and 29.9%, respectively, in the FP arm, and 99.2%, 78.5%, and 21.1% in the LP arm. Discontinuations due to AEs were 5.4% in the FP arm and 2.1% in the LP arm. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both arms. Febrile neutropenia was reported in 1.2% (3 pts) and 0.4% (1 patient) in the FP and LP arms, respectively. The rate of VTE of any grade was 5.8% (14 pts) in the FP arm and 4.5% (11 pts) in the LP arm (p = 0.531). Among 18 pts who had grade ≥ 3 pulmonary embolism (PE), the incidence reported in the FP and LP arms was 5% (12 pts) vs 2.5% (6 pts), respectively, and many of them (n=16, 88.9%) were unrelated PE. Asymptomatic grade 3 PE was reported in 10 pts of the entire study population on every 3-mo CT scan. Further, in 5 pts PE was detected in the context of progressive disease. Median time from the first dose of study drugs to occurrence of PE was 4.1 mo (range 1.4-32.0 mo) in the FP arm and 7 mo (range 1.8-19.3 mo) in the LP arm. Analysis of baseline characteristics in the whole population revealed that older pts had a significantly increased risk for developing PE (69.5 years [range 47-84 years]; p &lt; 0.01). ECOG performance status, menopausal status, metastatic disease, visceral involvement, number of disease sites, and prior therapies including antithrombotic agents did not significantly increase the risk for developing PE. Grade 3 ILD/pneumonitis was rarely observed in the FP and LP arms (0.8% vs 1.2%, respectively) with no grade 4 AE. Conclusions: First-line treatment with FP and LP for HR[+]/HER2[-] MBC in the PARSIFAL study confirmed the favorable safety profile, with neutropenia representing the most common AE. Although rare, ILD/pneumonitis can be a side effect of P-based regimens. VTE and PE incidence rates were low and consistent with age-specific analyses from PALOMA trials and breast cancer population. Early detection of these AEs may assist in optimizing their management.

Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Meritxell Bellet, Florence Dalenc, Miguel J. Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Serena Di Cosimo, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés. Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-17.