Final results from a large phase 3 trial confirm no benefit to adding palbociclib (Ibrance) to endocrine therapy in early hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
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 to 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, Austria, and colleagues.
The results from the PALLAS trial were presented December 7 at the 2021 San Antonio Breast Cancer Symposium (SABCS) 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 2884 patients who received the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy and in 263 (9.1%) of 2877 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 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 last year, 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, co-director 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, 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."
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 5796 patients from 406 centers in 21 countries worldwide over a 3-year period, with 5761 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.
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% vs 86%; distant recurrence-free survival was 86.2% vs 87.8%; locoregional recurrence-free survival was 96.8% vs 95.4%; and overall survival was 93.8% vs 95.2%.
The main side effect of palbociclib was neutropenia, but there were no new safety signals, 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.
Not the Final Word?
An interim analysis of the phase III monarchE trial did not align with the PALLAS trial.
The monarchE trial found that adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for 2 years significantly reduced the risk of early recurrence compared with endocrine therapy alone in the same patient populations — those with early HR-positive, HER2-negative breast cancer. The researchers reported the combination was associated with a 25% relative risk reduction invasive disease-free survival (HR, 0.75; P =.0096).
The research was presented at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.
Miller speculated how about how these two drugs that look so similar in the metastatic setting have given such different results in the adjuvant setting. One potential reason is pure chance.
"Any study, no matter how many zeros in the P value, could be simply the play of chance," she told Medscape Medical News. "And that is true for negative and positive studies."
The fault could also lie in the study design. "Remember, these are agents that we think of as reversing endocrine resistance and extending the benefit of hormone therapy," she pointed out. "And yet we looked at very early results. Perhaps the study design was just wrong for palbociclib."
Yet another possibility: The relative potency of those two CDK4/6 inhibitors could differ. "In a metastatic setting, that did not seem to affect effectiveness, but it clearly affected the toxicity profile. Perhaps in the adjuvant setting, those differences really do drive differences in efficacy," she said.
Gnant also speculated that differences in the treatment schedules for the two drugs, as abemaciclib is taken continuously without a break, could potentially explain the different efficacies in the early breast cancer setting.
He called for long-term follow up, saying it's essential for comprehensively examining outcomes in HR-positive luminal breast cancers.
"Ongoing analyses in the Trans-PALLAS translational and clinical science program, with almost 6000 tumor blocks and tens of thousands of blood samples, will improve understanding of CD4/6 inhibition as well as contemporary management of HR-positive, HER2-negative breast cancer," Gnant said.
The trial was funded by Pfizer, who provided study drug and financial support. In addition, the academic organizations ABCSG and AFT supported the trial by providing human resources.
Gnant reported employment at Sandoz; honoraria from Amgen, Novartis, AstraZeneca, Lilly; and consulting or advisory roles at Daiichi Sankyo, Veracyte, Tolmar¸ LifeBrain, Lilly. Disclosures for the other study authors can be found with the original article.
San Antonio Breast Cancer Symposium 2021: Abstract GS1-07. Presented December 7, 2021.
J Clin Oncol. Published online December 7, 2021. Abstract
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Cite this: 'Surprising’ Lack of Benefit to Adding Palbociclib to Endocrine Therapy in Early HR+/HER2- Breast Cancer - Medscape - Dec 10, 2021.