Two years of adjuvant palbociclib added to endocrine therapy failed to improve invasive disease-free survival or any other efficacy endpoint in patients with stage II-III HR-positive, HER2-negative 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 CDK4/6i [inhibitors] in advanced breast cancer,” according to lead author Michael Gnant, MD, professor in the department of surgery, Medical University of Vienna, and colleagues.
The results from the PALLAS trial were presented Dec. 7 at the San Antonio Breast Cancer Symposium and simultaneously published in the Journal of Clinical Oncology.
At a median follow-up of 31 months and at the final protocol-defined analysis, invasive disease-free survival events occurred in 253 (8.8%) of 2,884 patients who received the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy and in 263 (9.1%) of 2,877 patients who received endocrine therapy alone. At 4 years, invasive disease-free survival rates were similar in the palbociclib group (84.2%) and standard treatment group (84.5%).
Caught by surprise
Studies have shown that combining CDK4/6 inhibitors and endocrine therapy prolongs progression-free survival (PFS) and overall survival in metastatic HR-positive, HER2-negative breast cancer, with good tolerability.
“CDK4/6 inhibitors have markedly changed outcomes in the metastatic setting and are now standard of care,” said Dr. Gnant, who presented the recent findings at SABCS. “It seem[ed] only logical to try to transfer these benefits to the curative setting of early breast cancer.”
But in 2020, palbociclib manufacturer Pfizer issued a press release noting that the PALLAS trial was unlikely to show a statistically significant improvement in the primary endpoint of invasive disease-free survival.
The results “caught many of us by surprise,” Kathy D. Miller, MD, codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis, wrote in response to this announcement.
The trial was based on strong science and incredibly positive results in the metastatic setting but did not meet its primary endpoint when incorporated into the adjuvant setting, Dr. Miller noted in a Medscape blog. “That is certainly not the result we had hoped for, and it’s not the result many of us were expecting.”
Dr. Miller emphasized that “more than anything else, this trial reminds us of the absolute necessity of putting our ideas to the test and doing appropriately powered, appropriately controlled, and well-conducted randomized trials.”
The PALLAS trial enrolled 5,796 patients from 406 centers in 21 countries worldwide over a 3-year period, with 5,761 included in the intention-to-treat population.
Participants 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.
Dr. Gnant and colleagues found that the primary endpoint – invasive disease-free survival – did not differ significantly different between the two treatment groups (hazard ratio, 0.96; P = .65). Secondary endpoints in the palbociclib versus no-palbociclib groups were also similar: 4-year survival rates for invasive breast cancer-free survival were 85.4% versus 86%, distant recurrence-free survival was 86.2% versus 87.8%, locoregional recurrence-free survival was 96.8% versus 95.4%, and overall survival was 93.8% versus 95.2%.
The main side effect of palbociclib was neutropenia, but there were no new safety signals, Dr. Gnant explained. He noted, however, that the rates of palbociclib discontinuation were monitored closely and were substantial. At 1 year, 30% of patients discontinued palbociclib and by 24 months, 45% had stopped.