Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Palbociclib in Combination With Endocrine Therapy vs Capecitabine in HR-Positive, HER2-Negative, Aromatase Inhibitor–Resistant Metastatic Breast Cancer
TAKE-HOME MESSAGE
-
In this multicenter, open-label, randomized phase III trial, the authors compared palbociclib plus endocrine therapy (ET) with capecitabine in patients with hormone receptor–positive metastatic breast cancer with progression on an aromatase inhibitor. Estrogen receptor–1 (ESR1) mutation was identified in 29% of patients included in the trial. Progression-free survival (PFS) was not statistically increased for palbociclib plus fulvestrant versus capecitabine in either the overall study population or the ESR1 wild-type population. Secondary endpoints showed similar efficacy for palbociclib plus ET versus capecitabine in the overall population.
- Ultimately, this study failed to meet its primary endpoint of improved PFS for palbociclib plus ET compared with capecitabine, regardless of ESR1 mutational status or in patients with wild-type ESR1. However, palbociclib plus ET was significantly more tolerable than capecitabine in this patient population.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Palbociclib plus endocrine therapy (ET) is the standard treatment for hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial.
PATIENTS AND METHODS
PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitors (AIs)-resistant MBC were included in two consecutive cohorts. In cohort 1 (C1), patients were randomised 1:1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about oestrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2 (C2), in which patients were randomised 1:1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in C2 and in wild-type ESR1 patients (C1+C2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA.
RESULTS
From March-2014 to July-2018, 296 and 305 patients were included in C1 and C2, respectively. Palbociclib plus ET was not superior to capecitabine in both C2 (median PFS: 7.5 vs. 10.0 months; adjusted hazard ratio [aHR]: 1.13; 95% confidence Interval [CI]: 0.85-1.50) and wild-type ESR1 patients (median PFS: 8.0 vs. 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant, and capecitabine were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85).
CONCLUSIONS
There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.
Additional Info
Disclosure statements are available on the authors' profiles:
Palbociclib in Combination With Endocrine Therapy Versus Capecitabine in Hormonal Receptor-Positive, Human Epidermal Growth Factor 2-Negative, Aromatase Inhibitor-Resistant Metastatic Breast Cancer: A Phase III Randomised Controlled Trial – PEARL
Ann. Oncol 2020 Dec 29;[EPub Ahead of Print], M Martin, C Zielinski, M Ruiz-Borrego, E Carrasco, N Turner, EM Ciruelos, M Muñoz, B Bermejo, M Margeli, A Anton, Z Kahan, T Csöszi, MI Casas, L Murillo, S Morales, E Alba, E Gal-Yam, A Guerrero-Zotano, L Calvo, J Haba-Rodriguez, M Ramos, I Alvarez, A Garcia-Palomo, CH Bartlett, M Koehler, R Caballero, M Corsaro, X Huang, JA Garcia-Sáenz, JI Chacón, C Swift, C Thallinger, M Gil-GilFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Oncology
As CDK4/6 inhibitors have dramatically changed the treatment paradigm for ER-positive/HER2-negative patients with MBC, it is important to note that all the studies that led to approval of these treatments included comparison with single-agent endocrine therapy and not chemotherapy. A commonly utilized chemotherapy agent is capecitabine, especially early on in the treatment course. The phase III PEARL trial was a direct comparison of capecitabine versus palbociclib in combination with endocrine therapy. The study was initially designed to test the combination of palbociclib and exemestane versus capecitabine, but was modified in 2016 given the accumulating data regarding ESR1 mutations as a major mechanism of resistance to AIs. It became apparent that fulvestrant may be a more optimal endocrine therapy partner for these patients. The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either endocrine partner in those with ESR1 wild-type tumors. The palbo-containing regimens were, however, generally better tolerated, with lower numbers of treatment discontinuations and serious adverse events. Given that the goal of therapy in treating metastatic disease is to maintain quality of life, this advantage cannot be understated. As we continue to develop new therapies for patients with metastatic disease, we must not “lose the forest for the trees” and keep in mind the drivers of therapy selection.