Commentary for monarchE and PENELOPE-B was provided by C. Kent Osborne, MD, and Ruth M. O’Regan, MD, respectively. Dr. Osborne is Professor of Medicine, Hematology, and Oncology and the Dudley and Tina Sharp Chair for Cancer Research at Baylor College of Medicine, as well as Founding Director of the Dan L. Duncan Comprehensive Cancer Center. Dr. O’Regan is Professor and Division Chief of Hematology and Medical Oncology at the University of Wisconsin and Chief Scientific Officer of the Big Ten Cancer Research Consortium.
During a press briefing, Dr. Osborne called the results of monarchE “very encouraging,” especially in subgroups with high tumor proliferation, who had a risk reduction of 31% with abemaciclib.
C. Kent Osborne, MD
Ruth M. O’Regan, MD
“However, caution in these data is needed, given the still rather short follow-up. Estrogen receptor–positive disease is known for its persistent recurrence rate, even past 10 years,” he said. “Given this class of inhibitors is largely cytostatic rather than cytocidal, meaning it blocks cell proliferation rather than killing the cells, an important question remains: Will the invasive disease–free survival curves come together when the drug is stopped?”
“With these caveats in mind, this is still an important trial that could be practice-changing in this very high–risk patient population if the results continue to be positive and show improved overall survival with longer follow-up,” Dr. Osborne concluded.
Dr. O’Regan explored some of these questions as well: “The interesting thing is that in PENELOPE-B, there was a benefit of 4.3% at 2 years, dropping to 3.5% at 3 years, but with the curves coming together at 4 years. The elephant in the room is that the delta favoring abemaciclib in monarchE is 3% at 2 years, whereas it’s 4.3% with palbociclib, before the curves come together.”
“This begs the question of whether we may just be treating patients with occult metastatic disease, because these curves mirror what we might see in the first-line metastatic setting. Longer follow-up of monarchE is crucial to make sure the positive results remain positive,” Dr. O’Regan said.
Why the Differences Between the Two Drugs?
Other potential explanations for the differences may pertain to the different definitions of high risk and the eligibility requirements, the short duration of palbociclib treatment, and the possibility that abemaciclib “may just be a more effective CDK4/6 inhibitor,” stated Dr. O’Regan. “However, this is not supported by first-line metastatic trials, which have remarkably similar hazard ratios.”
It is also possible that biologically high-risk, luminal B–type tumors, presumably the predominant subtype in monarchE, may benefit more, she continued. Lacking a pathologic complete response, tumors in PENELOPE-B tended to be luminal-A, but biomarker data from the metastatic setting do not support a greater benefit in the luminal-B phenotype. This requires further analysis, she noted.
Dr. O’Regan emphasized the need for longer follow-up of monarchE, since the impact on late recurrences is unclear. “If the results hold up, we have to assume it’s about differences in the CDK4/6 inhibitor, the definition of high risk, or adherence, although this last issue is not really supported by PENELOPE-B,” she said.
The results of the NATALEE trial, which is evaluating 3 years of adjuvant ribociclib, will be very informative, she added.
DISCLOSURE: Dr. Osborne has received book royalties from Wolters Kluwer, serves on the advisory board and has minor stock holdings in GeneTex, and serves on the data monitoring committees of Lilly and Tolmar. Dr. O’Regan has served as an advisor to Pfizer, Lilly, Novartis, Puma, Biotheranostics, Seattle Genetics, and Cyclabel.
The primary outcome analysis of the phase III monarchE trial, an update of previous data, continued to show significant benefit for abemaciclib in the adjuvant setting, reducing the risk for invasive disease recurrence by 28.7%. Meanwhile, the first results of the phase III PENELOPE-B trial of...