The addition of palbociclib to adjuvant estrogen therapy (ET) for women with Stage IIA breast cancer did not improve outcomes compared to ET alone at a median follow-up of 50 months, according to a preplanned analysis of the PALLAS trial. Palbociclib did not improve invasive disease-free survival-the primary endpoint-invasive breast cancer-free survival, distant relapse-free survival, locoregional relapse-free survival, or overall survival.
"Overall outcomes were excellent in both arms, which is an important benchmark for ER-positive disease with modern therapy," said Angela DeMichele, MD, MSCE, the Alan and Jill Miller Professor in Breast Cancer Excellence and Co-Leader of the Breast Cancer Program at the Abramson Cancer Center at the University of Pennsylvania, at the October 2022 session of the ASCO Plenary Series (Abstract 390216). She noted that more than 92 percent of patients in both arms were free of invasive disease at 4 years.
CDK4/6 inhibitors like palbociclib have become standard of care for advanced hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer in combination with ET, with one approved for high-risk patients in the adjuvant setting. The PALLAS trial investigated the addition of palbociclib to adjuvant ET in patients with Stage II-III breast cancer. Stage IIA patients were specifically enrolled to evaluate the potential benefit of using palbociclib with adjuvant ET patients diagnosed at lower risk who may have more indolent disease.
In the prospective, randomized, Phase III PALLAS trial, 5,796 patients at 406 centers in 21 countries worldwide with HR+/HER2- early breast cancer were randomly assigned to receive adjuvant ET for at least 5 years with or without 2 years of palbociclib. They received palbociclib 125 mg orally once daily on days 1-21 of a 28-day cycle and ET of provider's choice.
The current analysis included 1,010 patients, median age 54 years, with Stage IIA disease. In this group, 410 patients (40.6%) were pre/perimenopausal, 506 patients (50.1%) had T2/N0 disease, 272 patients (26.9%) had Grade 3 disease, and 561 patients (55.5%) received chemotherapy.
Invasive disease-free survival events occurred in 31 patients who received palbociclib plus ET and in 45 patients who received ET alone, resulting in a statistically nonsignificant difference in invasive disease-free survival at 4 years (92.9% vs. 92.1%). Nonsignificant differences were also observed for invasive breast cancer-free, distant recurrence-free, and locoregional cancer-free survival. No significant differences in invasive disease-free survival were observed in subgroups, including age group, receipt of chemotherapy, tumor grade, and clinical risk (T1/N1 vs. T2/N0), DeMichele said.
In addition, she reported outcomes were similar between the arms in the Stage IIB/III cohort, with an invasive disease-free survival rate at 4 years of 85.3 percent in the palbociclib arm versus 83.6 percent in the endocrine therapy-alone arm. Future analyses of PALLAS will incorporate genomic risk and other molecular patterns, and an additional follow-up (10-year minimum) is underway to assess the impact of palbociclib exposure on late recurrence in HR+ disease.
"At median follow-up of 50 months, no significant difference in 4-year invasive disease-free survival was observed between treatment arms," DeMichele stated. "The result of the PALLAS trial begs the question of whether the era of large patient adjuvant trials based upon clinicopathologic stage is now past. The data we have shown today suggests that in such trials we are overtreating a substantial fraction of patients who may never relapse. This calls for new trial designs and biomarkers to enroll only those patients who would benefit from more therapy."
ASCO Discussant Fabrice Andre, MD, PhD, Professor of Medicine at University Paris Saclay, commented: "The key message from Dr. DeMichele is there is no signal for efficacy for palbociclib in patients with Stage IIA breast cancer. Failure of PALLAS has provided some suggestions to further improve trials in the adjuvant setting."
He suggested trials should explore the efficacy of the drug in preoperative or adjuvant ctDNA-driven Phase II trials before moving to Phase III trials; characterize the mechanism of action before moving to the adjuvant setting; monitor compliance, dose reduction, and discontinuation more closely; and find the right duration, "a major issue in general in drug development in patients with early-stage cancers," Andre concluded.
Mark L. Fuerst is a contributing writer.