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Adding adjuvant palbociclib to standard endocrine therapy did not improve outcomes in patients with stage II to III hormone receptor–positive, HER2-negative early breast cancer.
Adding adjuvant palbociclib (Ibrance) to standard endocrine therapy (ET) did not improve outcomes, compared with ET alone, in patients with stage II to III hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative early breast cancer, according to a final analysis from the phase 3 PALLAS trial (NCT02513394) presented at the 2021 San Antonio Breast Cancer Symposium (SABCS).1,2
Although the combination of CDK4/6 inhibitors with ET have demonstrated prolonged progression-free (PFS) and overall survival (OS) in the metastatic setting of this patient population, “The benefits previously observed … with palbociclib did not translate into the earlier curative adjuvant setting,” explained Michael Gnant, MD, FACS, FEBShon, professor in the Department of Surgery, Medical University of Vienna, Austria, during a presentation at SABCS.
The final protocol-defined analysis of the global, prospective, open-label, randomized phase 3 PALLAS (PALbociclib CoLlaborative Adjuvant Study) trial — which were simultaneously published in the Journal of Clinical Oncology — included 5761 patients in the intent to treat (ITT) population.
At a median follow-up of 31 months, invasive disease-free survival (iDFS) events occurred in 252 patients (8.8%) in the palbociclib combination arm and 263 patients (9.1%) of the ET-only arm. Similarly, 4-year iDFS rates were 84.2% vs 84.5%, respectively (hazard ratio, 0.96; 95% CI, 0.81-1.14; P = .65).
In addition, there was no difference observed in the subgroup analysis (anatomic staging, T-stage, N-stage, grading, neo/adjuvant chemotherapy, age group, or clinical risk). Moreover, in the palbociclib combination group compared with those who received ET alone, 4-year rates of invasive breast cancer–free survival (BCFS; 85.4% vs 86.0%, respectively; HR, 0.99; 95% CI, 0.82-1.19) and distant recurrence-free survival (DRFS; 86.2% vs 87.8%; HR, 1.05; 95% CI, 0.87-1.28) were similar.
No no new safety signals were found among those treated with palbociclib. Any grade adverse event (AE) occurred in 99.5% of the palbociclib arm (grade 3, 67.5%; grade 4, 5.7%) and 89.7% of the ET-only arm (grade 3, 14.4%; grade 4, 0.8%). Serious AEs were observed in 13.0% of the palbociclib arm (n = 369), compared with 7.9% in those who received ET alone (n = 229). Of the 176 deaths recorded in the trial, Gnant noted that none were related to study treatment.
“The treatment was, in general, well tolerated in the early-disease setting,” he added. “Neutropenia, however, was an issue in the trial.”
Gnant added that because this was a pivotal trial in the curative setting, dose reduction and stoppages were “much stricter than we use nowadays in clinical practice. As a result, the rates of early discontinuation of palbociclib based on competing risk analysis were substantial.” For example, rates of early discontinuation of palbociclib at 6, 12, 18, and 24 months were 17.9%, 30.2%, 38.3%, and 44.9%, respectively.
“This relatively high proportion of patients who did not receive palbociclib the full 2 years was interpreted by some as a potential reason for the disappointing result. At the second interim analysis, we can today put this myth to rest.”
In the planned second interim analysis, at a median follow-up of 23.7 months (range, 16.9-29.2), 170 patients in the palbociclib arm and 181 patients in the ET-only arm experienced iDFS events, with 3-year iDFS rates of 88.2% (95% CI, 85.2%-90.6%) and 88.5% (95% CI, 85.8%-90.7%), respectively (hazard ratio, 0.93; 95% CI, 0.76-1.15; P = .51).3
“On the basis of these findings, this regimen cannot be recommended in the adjuvant setting,” the study authors concluded in the study, published in January.
In the trial, investigators randomized patients to receive either 2 years of 125 mg oral palbociclib once daily on days 1 through 21 of a 28-day cycle in combination with adjuvant ET (n = 2884), or adjuvant ET alone for at least 5 years (n = 2877). ET could be amoxicillin or an aromatase inhibitor with the addition of an LHRH agonist.
Eligibility criteria included stage II to III HR-positive, HER2-negative breast cancer; completion of prior surgery, with or without chemotherapy, and radiation therapy; be 12 months within diagnosis, and within 6 months of starting adjuvant ET; and a formalin fixed paraffin embedded tumor block submitted and received at biorepository.
iDFS served as the primary end point of the trial. Secondary end points included iBCFS, DRFS, locoregional cancer-free survival, and OS.
In total, 5796 patients were enrolled at 406 centers across 21 countries over 3 years.
Patients were stratified by stage, prior receipt of chemotherapy, age, and geographic region. Most patients in the ITT had higher stage disease (82%), previously received chemotherapy (83%), and were considered high-risk (59%). Median age was 52 years (range, 45-61).
Gnant concluded, noting that long-term follow-up is essential to comprehensively examine outcomes in HR-positive luminal breast cancers, which is ongoing in the PALLAS trial. Moreover, there is an ongoing analysis in the Trans-PALLAS program, evaluating thousands of tumor blocks and blood samples, to improve the understanding of CDK4/6 inhibition and the contemporary management of HR-positive, HER2-negative breast cancer.