Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)

Abstract

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting

“…However, the duration of therapy varied; ribociclib was given for 3 years in NATALEE, 42 abemaciclib for 2 years in monarchE, 43 palbociclib for 2 years in PALLAS, and 1 year in PENELOPE-B, Table 2 . 44 , 45 …”

“…No specific subgroup seemed to benefit from the addition of palbociclib to ET. 44 At an earlier interim analysis, the independent data monitoring committee recommended discontinuing palbociclib in patients still receiving it. The AEs within the palbociclib arm were a major issue, with two-thirds of patients developing grade-3 or 4 AEs.…”

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic

“…In 2021, Erica L Mayer and colleagues, 9 reported an interim analysis in The Lancet Oncology of the ongoing, global, phase 3 PALLAS trial, with the updated preplanned final analysis published in December, 2021. 10 Between Sept 1, 2015, and Nov 30, 2018, 5761 patients with early-stage breast cancer were randomly assigned (1:1) at 406 cancer centres in 21 countries to receive either 2 years of the CDK4/6 inhibitor palbociclib in addition to standard adjuvant endocrine therapy (n=2884) or adjuvant endocrine therapy alone (n=2877). 10 2841 patients received palbociclib plus endocrine therapy and 2901 patients received endocrine therapy only; 36 individuals were excluded.…”

“… 10 Between Sept 1, 2015, and Nov 30, 2018, 5761 patients with early-stage breast cancer were randomly assigned (1:1) at 406 cancer centres in 21 countries to receive either 2 years of the CDK4/6 inhibitor palbociclib in addition to standard adjuvant endocrine therapy (n=2884) or adjuvant endocrine therapy alone (n=2877). 10 2841 patients received palbociclib plus endocrine therapy and 2901 patients received endocrine therapy only; 36 individuals were excluded. The safety analysis of the PALLAS trial showed no new signals of adverse events for palbociclib, with grade 3–4 neutropenia being the most prevalent (in 1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone).…”

“…As of Dec 1, 2019, of the 5761 patients who were randomly assigned and included in the intention-to-treat population, 10 5125 (89·0%) remained on study (2552 [88·5%] of 2884 allocated to palbociclib plus endocrine therapy, of whom 847 [33·2%] were still receiving palbociclib, and 2573 [89·4%] of 2877 allocated to endocrine therapy alone). From Dec 1, 2019, to Nov 20, 2020, 721 (14·1%) of 5125 patients were tested for COVID-19 (test type not mandated, 362 [14·2%] of 2552 in the palbociclib group and 359 [14·0%] of 2573 in the endocrine therapy only group).…”