As reported in the Journal of Clinical Oncology by Michael Gnant, MD, of the Comprehensive Cancer Center, Medical University of Vienna, and colleagues, the final analysis of the phase III PALLAS trial has shown no invasive disease–free survival benefit with the addition of adjuvant palbociclib to endocrine therapy in patients with hormone receptor–positive, HER2-negative early breast cancer.1
Michael Gnant, MD
As noted by the investigators, the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor palbociclib is approved for advanced breast cancer. However, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer in the adjuvant setting has not been confirmed.
In the open-label trial, 5,761 patients from sites in 21 countries were randomly assigned between September 2015 and November 2018 to receive standard adjuvant endocrine therapy (tamoxifen and aromatase inhibitor, with or without ovarian function suppression) for at least 5 years with (n = 2,884) or without (n = 2,877) 2 years of palbociclib at 125 mg once daily on days 1 to 21 of 28-day cycles. Randomization stratification factors included stage (I–IIA vs IIB–III), previous adjuvant or neoadjuvant chemotherapy (yes vs no), and age (≤ 50 vs > 50 years). The primary endpoint was invasive disease–free survival.
For the palbociclib vs control groups, 99.4% vs 99.3% were women; the median age was 52 in both; stage of disease was I–IIA and IIB-III in 18% and 82% in both; 17% vs 18% had not and 83% vs 82% had received prior neoadjuvant or adjuvant chemotherapy; 54% vs 53% were postmenopausal and 45% vs 46% were premenopausal; and region was Europe, United States, and other for 45%, 44%, and 11% in both.
Invasive Disease–Free Survival
Median follow-up at the final protocol-defined analysis was 31 months (interquartile range = 24.5–37.3 months). Invasive disease–free survival events occurred in 253 patients (8.8%) in the palbociclib group vs 263 (9.1%) in the control group, with a 4-year invasive disease–free survival rate of 84.2% vs 84.5% (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.81–1.14, P = .65).
Among all patients, the first invasive disease–free survival event was distant metastasis in 356 (6.2%) and second primary invasive cancer of non-breast origin in 67 (1.2%); local or regional recurrences, contralateral invasive breast cancers, and deaths without prior cancer recurrence were first events in less than 1% of patients. A total of 176 patients (3.1%) died during the observation period, including 100 (3.5%) in the palbociclib group and 76 (2.6%) in the control group.
In stratification subgroups, hazard ratios for the palbociclib group vs control group were 0.70 (95% CI = 0.41–1.18) for stage I–IIA and 0.98 (95% CI = 0.82–1.18) for stage II–III disease; 0.69 (95% CI = 0.41–1.15) for no prior and 0.99 (95% CI = 0.83–1.20) for prior neoadjuvant/adjuvant chemotherapy; and 1.05 (95% CI = 0.81–1.37) for age ≤ 50 and 0.90 (95% CI = 0.71–1.13) for age > 50 years.
In other subgroup analyses, hazard ratios were 1.10 (95% CI = 0.68–1.78) for T0, T1, Tis, or TX; 0.87 (95% CI = 0.69–1.10) for T2; and 1.07 (95% CI = 0.80–1.45) for T3–4 disease; 0.63 (95% CI = 0.37–1.08), 1.09 (95% CI = 0.81–1.48), 0.91 (95% CI = 0.66–1.25), and 0.89 (95% CI = 0.64–1.24) for N0, N1, N2, and N3 disease; and 0.89 (95% CI = 0.70–1.12) and 0.98 (95% CI = 0.74–1.29) for grade 1 or 2 and grade 3 disease.
No significant differences were found in the 4-year rates of invasive breast cancer–free survival (85.4% vs 86.0%, HR = 0.99, 95% CI = 0.82–1.19), distant recurrence–free survival (86.2% vs 87.8%, HR = 1.05, 95% CI = 0.87–1.28), locoregional recurrence–free survival (96.8% vs 95.4%, HR = 0.84, 95% CI = 0.57–1.23), or overall survival (93.8% vs 95.2%, HR = 1.32, 95% CI = 0.98–1.78).
Adverse events of any grade occurred in 99.5% of patients in the palbociclib group and 89.7% of the control group, with the most common in the palbociclib group being neutropenia (83.5% vs 5.0%), leukopenia (55.1% vs 7.5%), and fatigue (41.0% vs 19.3%); other adverse events more common in the palbociclib group were upper respiratory tract infection (29.5% vs 16.6%), anemia (23.5% vs 5.5%), thrombocytopenia (21.8% vs 1.7%), and alopecia (18.0% vs 5.1%). Grade ≥ 3 adverse events occurred in 73.8% vs 15.5%, with the most common in the palbociclib group being neutropenia (62.0% vs < 1%) and leukopenia (30.4% vs < 1%). Serious adverse events occurred in 13.0% vs 7.9% of patients. No treatment-related deaths were reported.
The investigators concluded: “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…. These definitive findings from the PALLAS trial, already indicated by an interim analysis, are surprising given the established efficacy of palbociclib and other CDK4/6 [inhibitors] in advanced breast cancer.”
DISCLOSURE: The study was funded by Pfizer. Dr. Gnant has received honoraria from Amgen, Novartis, AstraZeneca, and Lilly; has served as a consultant or advisor to Daiichi Sankyo, Veracyte, Tolmar, LifeBrain, and Lilly; and reported an immediate family member works for Sandoz. For full disclosures of the other study authors, visit ascopubs.org.
Over the past 7 years, the introduction of combined endocrine therapy with cyclin-dependent kinase (CDK) 4/6 inhibitors resulted in a dramatic improvement in outcomes for patients with metastatic, hormone receptor–positive, HER2-negative breast cancer. Early attempts to modulate the cell cycle with ...