In summary, for patients with stage IIA disease enrolled in the PALLAS trial, the addition of palbociclib to adjuvant ET did not prolong iDFS compared to ET alone. In addition, at 42 months of follow up, there continues to be no benefit detected to the addition of palbociclib in the Stage IIB/III or overall study cohorts. Other planned secondary time-to-event endpoints also did not show a benefit, and notably, there was no benefit observed in those with lower grade disease or in those who did not receive chemotherapy. While no statistically significant benefits to palbociclib were seen, the numbers of patients in each subset were small in this preplanned cohort.

These results from the PALLAS trial continue to contrast with the positive results of the MONARCH-E [4] and NATALEE [8] adjuvant trials. In the MONARCH-E trial, at a median follow up of 42 months, the addition of abemaciclib to adjuvant endocrine therapy continued to show an improvement in IDFS (85.8% abemaciclib + ET vs. 79.4% for ET alone, HR 0.664; 95% CI 0.578−0.762) [4]. In the NATALEE Trial, at a median follow up of 44.2 months, the addition of ribociclib to adjuvant endocrine therapy also demonstrated a sustained IDFS benefit (88.5% for ribociclib + ET vs. 83.6% for ET alone, HR0.715; 95% CI 0.609–0.840) [9] supporting the recent FDA approval of ribociclib in the adjuvant setting [5]. In both studies, the iDFS benefits also remain statistically significant within stage II and III subgroups. The reasons underlying the differences in outcomes is not clear, though could be related to important differences in CDK target potency between agents or differences in the underlying risk profiles of the study patient populations that extend beyond anatomic stage alone. While adherence has been cited as a possible issue, all three trials had substantial discontinuation rates, and a sensitivity analysis of the PALLAS results based on adherence did not support this hypothesis [10]. It is notable that PALLAS included lower risk, node negative, stage IIA patients without additional high-risk features, distinct from the other trials, and importantly, eligibility for PALLAS was based solely on pathologic stage, using the AJCC version 7 without requiring additional high-risk features such as high Ki-67 or a high-risk genomic test. In this AJCC version, stage IIA includes both patients with N1 (1–3 positive axillary lymph nodes) and patients with T2N0 disease. While MONARCH-E did not enroll any patients with N0 disease, NATALEE did enroll N0 patients, but they were required to have either tumor size > 5 cm, or tumor size 2–5 cm with either Grade 2 (and high genomic risk or Ki67 ≥ 20%) or Grade 3. It is possible that CDK4/6 inhibitors as a class require high proliferative activity to prevent early relapse. But it is notable that at 4 year follow up, the N0 patient population in the NATALEE trial, despite additional high-risk features, did not show a statistically significant benefit from the addition of ribociclib to standard ET (iDFS HR 0.666, 95% CI 0.397–1.118). While this group was included in the current FDA approval of ribociclib, it will be important to determine if a statistically significant iDFS benefit emerges with longer follow up and more events, to ultimately determine the extent of benefit to a lower risk group, albeit not quite as low risk as that in the PALLAS trial. Moreover, additional follow up in both the MONARCH-E and NATALEE trials is necessary to determine whether benefits of abemaciclib and ribociclib in the adjuvant setting extend to reducing late recurrence or improving overall survival. It is worth noting that overall survival benefits with CDK4/6 inhibitors have been difficult to demonstrate in the first-line metastatic setting, with only ribociclib conferring overall survival benefit [5] despite progression-free survival (PFS) benefits for all three cell cycle inhibitors.

Despite a lack of benefit from palbociclib, the PALLAS trial provides an important benchmark for outcomes in ER+ breast cancer in an international study population with modern therapy, showing excellent outcomes in both treatment arms among those patients with stage IIA disease. Notably, the risk of recurrence within the ET control arms differed between PALLAS, MONARCH-E [4], NATALEE [9] and PENELOPE [11] at the same follow-up time. These differences likely reflect important differences in inclusion criteria for stage and other risk factors between the trials that may have further impacted trial results.

Excellent outcomes for patients receiving standard adjuvant therapy begs the question of whether the era of large adjuvant trials based on the clinical stage alone is now past. The results of PALLAS and other large adjuvant trials in ER+ early breast cancer show that while there may be incremental improvements in outcomes, there is also a substantial fraction of patients being exposed to additional therapy who may never relapse. This situation calls for new trial designs and biomarkers that can enrich enrollment for only those patients who will truly benefit from more therapy.

Such an approach requires the ability to identify those patients who are still at risk to enable escalation strategies for those who truly need it. Diagnostic tumor blocks along with serial blood samples were collected on all 5,796 PALLAS participants. This robust biospecimen bank, combined with clinical follow-up and serial bio sample collection over ten years, has enormous potential for additional knowledge generation. Additional investigations include planned correlative analyses of RNA-based gene expression profiles, germline DNA and circulating biomarkers (including ctDNA). Such analyses will enable further investigation of the PALLAS population to evaluate whether there are subpopulations of patients who might benefit from palbociclib and to further our understanding of the biology and natural history of ER+ early breast cancer. Ongoing analyses by the TRANS-PALLAS investigators seek to identify tumors with poor prognosis (using genomic predictors), tumors that respond better to ET (through the SET index and pharmacogenetic markers), and assessment of longitudinal serial blood samples to understand the link between detection of ctDNA and recurrent disease. These studies will help unravel the complex mechanisms of tumor dormancy and reactivation in ER+ disease and have the potential to identify critical biomarkers of poor prognosis and/or imminent relapse that can be utilized in future biomarker enrichment trial designs. Such approaches hold promise in enabling the identification of meaningful therapeutic targets and optimal strategies for surveillance and interception to prevent recurrence in ER+ early breast cancer.

In conclusion, this pre-specified analysis of the PALLAS trial focusing on patients with lower risk stage IIA disease compared to those with higher stage disease failed to demonstrate a benefit to 2 years of adjuvant palbociclib, regardless of stage. Notably, there were substantial differences in outcome for stage IIA versus IIB/III patients at 4 years of follow-up, demonstrating the excellent outcomes for patients with early-stage disease who receive modern adjuvant endocrine therapy, providing a critical benchmark for future studies. Building on these data, the TRANS-PALLAS tumor and serial blood samples will provide further insights of ER+ breast cancer biology.