The addition of palbociclib to adjuvant endocrine therapy (ET) failed to improve invasive disease-free survival over ET alone in patients with estrogen receptor–positive, HER2-negative early breast cancer.
The addition of palbociclib (Ibrance) to adjuvant endocrine therapy (ET) failed to improve invasive disease-free survival (iDFS) over ET alone in patients with estrogen receptor–positive, HER2-negative early breast cancer, according to data from a preplanned analysis of the stage IIA cohort of the phase 3 PALLAS trial (NCT02513394) presented during the 2022 October ASCO Plenary Series.1
At a median follow-up of 50 months, no significant difference in 4-year iDFS rates was observed between the palbociclib/ET (n = 503) and ET-alone (n = 507) arms, at 92.9% and 92.1%, respectively (HR, 0.75; 95% CI, 0.48-1.19; log-rank P = .23). No differential benefit was observed by histologic grade, receipt of chemotherapy, age, or anatomic clinical risk.
Moreover, key secondary end points such as iDFS excluding second cancers of non-breast origin (iBCFS), distant recurrence-free survival (DRFS), locoregional recurrence-free survival (LRFS), and overall survival (OS) were also not significantly improved with the addition of palbociclib to ET vs ET alone, nor was benefit observed in those with lower-grade disease or those who did not receive chemotherapy.
“These data provide an important benchmark for outcomes in ER-positive breast cancer in an international study population with modern therapy,” Angela DeMichele, MD, MSCE, co-leader of the Breast Cancer Research Program at Abramson Cancer Center of the University of Pennsylvania, said in a presentation of the data. “While these patients did well as a group, t these data also highlight the need to identify those who are still at risk, be it with circulating tumor DNA or another minimal residual disease biomarker, to be able to escalate therapy [in] those who truly need it. Thus, an important outcome of the PALLAS trial may be helping us to understand the diverse prognosis of ER-positive disease.”
CDK4/6 inhibitors counteract the loss of cell cycle control in hormone receptor–positive, HER2-negative breast cancer, noted DeMichele, who is also a physician leader in the Breast Cancer Clinical Research Unit and co-director of the 2-PREVENT Breast Cancer Translational Center of Excellence at the University of Pennsylvania. It has been shown that pairing CDK4/6 inhibitors with ET is tolerable and can improve progression-free survival and OS in patients with metastatic disease.
Many large, adjuvant clinical trials examining these agents are ongoing. One such trial resulted in the October 2021 FDA approval of abemaciclib (Verzenio) plus ET for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive, early breast cancer who are at high risk of recurrence and who have a Ki-67 score of 20% or higher.2
The global, open-label, randomized, phase 3 PALLAS trial enrolled patients with stage I to II, hormone receptor–positive, HER2-negative breast cancer who had completed all definitive therapy aside from ET, and were within 12 months of diagnosis and within 6 months of initiating adjuvant ET. To participate, patients were required to submit a paraffin-embedded tumor block.
The planned sample size for the trial was 5600 patients, with stage IIA enrollment capped at 1000 patients. “This was done to assure that this important group of patients was included in the trial, but to avoid overrepresentation of this group, due to their high prevalence in the early breast cancer population,” DeMichele explained.
Study participants were randomly assigned 1:1 to receive standard ET with the addition of palbociclib at a starting dose of 125 mg daily as part of a 3-week-so-on/1-week-off schedule or ET alone. The choice of ET was made by the treating physician and the patient and could include any standard regimen with a planned treatment duration of at least 5 years.
Key stratification factors included disease stage (IIA vs IIB/III), receipt of chemotherapy (yes vs no), age (≤50 years vs >50 years), and geographic region (North America vs Europe vs other). “Notably, Ki-67 assessment was not mandated,” DeMichele added.
iDFS served as the primary end point of the trial, and this was assessed using STEEP criteria. Secondary end points comprised iBCFS, DRFS, LRFS, OS, and safety. Translational and other end points included biomarkers and adherence, as well as patient-reported outcomes and quality of life data.
“Sample size and number of events was selected to ensure that the overall cohort would reach the primary analysis in a timely fashion, and that the point estimates for the stage IIA cohort would be stable,” DeMichele noted.
Between September 2015 and November 2018, a total of 5796 patients were recruited to the PALLAS trial. In September 2017, the stage IIA cohort was closed to screening; this was done before the full trial enrollment was complete, according to DeMichele. “At the time of the second interim analysis, the independent data monitoring committee recommended stopping palbociclib in patients still receiving it due to the unlikely possibility of benefit,” she added.
The final analysis of the overall trial occurred at 31 months of follow-up, with 516 events. “The preplanned analysis of the stage IIA cohort was triggered when an 8% iDFS event rate was reached in the ET-alone arm, corresponding to 45 events,” DeMichele explained. “This subsequently resulted in a new follow-up data cutoff of 43.1 months for the full trial and 50.0 months for the stage IIA cohort.”
In the stage IIA cohort, the median age of those who received palbociclib/ET was 55 years (range, 29-84) vs 53 years (range, 30-85) in those who were given ET alone; most patients were female (99.4% vs 99.6%, respectively) and approximately half (54.2% vs 53.3%) were postmenopausal. Moreover, 28.8% of those in the investigative arm and 25.0% of those in the control arm had high-grade (grade 3) tumors.
Overall, characteristics of the stage IIA population was noted to be comparable to those of the stage IIB/III population, except with regard to prior chemotherapy. “As expected, the stage IIA patients received chemotherapy less frequently than the stage IIB/III patients,” DeMichele noted. “[However,] those in the stage IIA cohort still received chemotherapy more than 50% of the time; the treatment arms were well balanced with regard to this factor.”
Additional data showed that within the stage IIA cohort, the iBCFS rates at 4 years in the palbociclib/ET arm was 94.8% vs 94.2% in the ET-alone arm (HR, 0.80; 95% CI, 0.47-1.36). The 4-year DRFS rates in the investigative and control arms were 95.3% and 95.2%, respectively (HR, 0.92; 95% CI, 0.52-1.65). The LRFS rates at 4 years in the palbociclib/ET and ET-alone arms were 98.1% and 98.2%, respectively (HR, 0.84; 95% CI, 0.35-2.00). The 4-year OS rate with palbociclib/ET was 97.7% vs 98.1% with ET alone (HR, 1.28; 95% CI, 0.57-2.86).
At a median follow-up of 43 months, no benefit to adding 2 years of adjuvant palbociclib was observed, irrespective of disease stage. In the stage IIB/III cohort, the iDFS rates reported in the palbociclib/ET and ET-alone arms were 85.3% and 83.6%, respectively (HR, 0.91; 95% CI, 0.77-1.07; log-rank, P = .24).
“These findings also highlight the difference in prognosis by stage—with the stage IIA group having substantially better outcomes, regardless of treatment,” DeMichele noted.
DeMichele added that the extensive biomarker collection in the trial offers the ability to understand how biological heterogeneity matters in terms of determining which tumors have poor prognosis or which tumors will respond to treatment.
“This robust biobank combined with clinical follow-up and serial biosample collection over 10 years has enormous potential for additional knowledge generation,” DeMichele said. “We anticipate future calls for research proposals to expand the availability of this resource to other investigators in the near future.”
The PALLAS data raise the question of whether the era of large adjuvant trials based on clinical stage alone has passed, according to DeMichele. She added that the data suggest that in such trials, a substantial fraction of patient who may never relapse are likely being overtreated.
“This situation calls for new trial designs and biomarkers than can enable us to enroll only those patients who will truly benefit from more therapy, DeMichele concluded.