Palbociclib fails to benefit breast cancer subgroup, yielding lessons for future research
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Adjuvant palbociclib combined with endocrine therapy failed to extend invasive DFS compared with endocrine therapy alone among patients with stage IIA hormone receptor-positive, HER2-negative breast cancer, according to study results.
The findings, presented during an ASCO Plenary Series session, also showed the addition of the cyclin-dependent kinase (CDK)4/6 inhibitor did not improve other outcomes, including OS, among this patient population, nor did it benefit those with lower-grade disease or those who did not receive chemotherapy.
“While these patients did well as a group, these data also highlight the need to identify those patients who are still at risk, be it with [circulating tumor] DNA or another minimal residual disease biomarker, to be able to escalate therapy to those who truly need it,” Angela DeMichele, MD, MSCE, of Abramson Cancer Center at University of Pennsylvania, said during a presentation.
Background
The randomized phase 3 PALLAS trial enrolled 5,796 patients with hormone receptor-positive, HER2-negative early breast cancer, including 1,010 with stage IIA disease, at 406 centers worldwide. Researchers randomly assigned patients to adjuvant endocrine therapy for no less than 5 years with or without palbociclib (Ibrance, Pfizer) dosed at 125 mg daily in a 3-weeks-on, 1-week-off schedule for 2 years.
Invasive DFS served as the primary endpoint. Secondary endpoints included distant and locoregional recurrence-free survival, OS and safety.
DeMichele presented results from the preplanned analysis of the stage IIA cohort, with median follow-up 50 months. The palbociclib and endocrine therapy-alone groups in this cohort had similar baseline characteristics, including median age (55 years vs. 53 years) and percentages of postmenopausal patients (54.2% vs. 53.3%) and those who received prior chemotherapy (56.1% vs. 55%).
Results
Researchers observed no significant difference in 4-year invasive DFS between patients in the palbociclib and endocrine therapy-alone groups (92.9% vs. 92.1%; HR = 0.75; 95% CI, 0.48-1.19). Subgroup analyses showed no differential benefit with palbociclib based on histologic grade, receipt of chemotherapy, age and anatomic clinical risk. The groups had similarly high rates of invasive breast cancer-free survival, distant RFS, locoregional RFS and OS.
The stage IIB/stage III cohort also did not appear to benefit from the addition of 2 years of adjuvant palbociclib to endocrine therapy vs. endocrine therapy alone. With median follow-up of 43 months, results showed 4-year invasive DFS rates of 85.3% vs. 83.6% (HR = 0.91; 95% CI, 0.77-1.07).
Next steps
The work of the PALLAS trial, with its large sample size and biomarker collection, is now focused on several translational and clinical projects, DeMichele said. Meanwhile, the current findings must be taken with a grain of salt, recognizing that more follow-up is needed, she said.
“To definitively move the needle in preventing recurrent breast cancer, understanding tumor dormancy and reactivation is a critical step to ultimately determining which biomarkers of [minimal residual disease] can identify a window in which interception of recurrence is possible, what to target with additional therapies, and when it’s the right time to add or change therapy to prevent recurrence,” DeMichele said.
The results highlight the need to enter into a new era of patient stratification that incorporates artificial intelligence-based biomarkers, clinical data and tumor biology, according to discussant Fabrice André, MD, PhD, research director at Gustave Roussy Cancer Campus in France.
André cited four lessons that can be derived from the PALLAS trial.
“We need to [further] explore the efficacy of the drugs in the preoperative setting or, now more and more, in the adjuvant ctDNA-driven phase 2 trials before moving to phase 3,” he said. “We must characterize the mechanism of action of the drugs before moving [into the adjuvant setting]. We need to better monitor compliance of the drug, and we need to find the right duration in the adjuvant setting.”
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DeMichele A, et al. Adjuvant palbociclib for ER+ breast cancer (PALLAS trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): A preplanned analysis of the stage IIA cohort. Presented at: ASCO Plenary Series; Oct. 18, 2022.
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