Adjuvant palbociclib + ET does not improve outcomes vs ET alone in early breast cancer

Adjuvant palbociclib in combination with endocrine therapy (ET) does not improve invasive disease-free survival (iDFS) or secondary endpoints vs ET alone in patients with hormone receptor–positive, HER2-negative early breast cancer, final results of the phase III PALLAS trial have shown.

The intention-to-treat population of the study included 5,761 patients. Of these, 2,884 patients (stage IIB or III disease, 82.2 percent; T2 stage, 55.6 percent; N1 stage, 49.6 percent; G1 or G2 tumour, 66.8 percent; [neo]adjuvant chemotherapy at baseline, 82.7 percent; postmenopausal, 54.2 percent) were randomized to receive 2 years of palbociclib (125 mg orally QD, days 1–21 of a 28-day cycle) plus adjuvant ET, while 2,877 patients (stage IIB or III disease, 82.0 percent; T2 stage, 56.9 percent; N1 stage, 49.0 percent; G1 or G2 tumour, 68.5 percent; [neo]adjuvant chemotherapy at baseline, 82.4 percent; postmenopausal, 53.3 percent) were randomized to receive adjuvant ET alone for at least 5 years. [J Clin Oncol 2021, doi:10.1200/JCO.21.02554]

After a median follow-up of 31 months, iDFS (primary endpoint) events occurred in 8.8 percent of patients in the palbociclib plus ET group vs 9.1 percent of those in the ET alone group. At 4 years, iDFS rates were similar between the two groups, at 84.2 percent vs 84.5 percent (hazard ratio [HR], 0.96; 95 percent confidence interval [CI], 0,81 to 1.14; p=0.65).

“Treatment effect heterogeneity analysis to detect a relationship between a higher baseline risk and the HR effect size showed no significant palbociclib effect trend from low- to high-risk patients with regard to iDFS,” the investigators noted.

Results of secondary outcomes were also similar between the palbociclib plus ET group and ET alone group. At 4 years, rates of invasive breast cancer–free survival, distant recurrence–free survival and locoregional recurrence–free survival were 85.4 percent vs 86.0 percent, 86.2 percent vs 87.8 percent and 96.8 percent vs 95.4 percent, respectively, while overall survival rates were 93.8 percent vs 95.2 percent.

“There were no new safety signals for palbociclib in this trial,” the investigators reported.

Overall, 99.5 percent of patients in the palbociclib plus ET group vs 89.7 percent of those in the ET alone group experienced at least one adverse event (AE), while serious AEs occurred in 13.0 percent vs 7.9 percent of the patients.

“This final protocol-defined analysis of the PALLAS trial, with 5,796 recruited patients, a 31-month median follow-up and events exceeding the predefined number, did not show significant improvements in survival endpoints for the addition of palbociclib to adjuvant ET,” the investigators noted.

“These definitive findings, already indicated by an interim analysis, are surprising given the established efficacy of palbociclib and other cyclin-dependent kinase 4/6 [CDK4/6] inhibitors in advanced breast cancer,” they continued, adding that the combination of a CDK4/6 inhibitor with ET has become standard of care in patients with hormone receptor–positive metastatic breast cancer.

“The lack of adjuvant palbociclib efficacy does not preclude further integration of CDK4/6 inhibitors into the breast cancer treatment algorithm,” they suggested.

Research is ongoing to evaluate new combination regimens in various breast cancer subtypes, and to better understand unique tissue and/or serum biomarkers that may predict individual benefit or resistance for each approved CDK4/6 inhibitor to guide optimal patient selection and treatment combinations. [Expert Rev Anticancer Ther 2021;21:1237-1251; Crit Rev Oncol Hematol 2021;157:103191; Cancer Discov 2018;8:1390-1403; Cancer Discov 2021;11:916-932]