In a preplanned analysis of the stage IIA cohort of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone. This finding suggests this agent provides no benefit in reducing the risk of early relapse in patients with lower-stage hormone receptor–positive/HER2-negative breast cancer.1
In addition, palbociclib offered no additional benefit in terms of invasive disease–free survival (the primary endpoint), invasive breast cancer–free survival, distant relapse–free survival, locoregional relapse–free survival, or overall survival, according to results presented at the October 2022 ASCO Plenary Series by Angela DeMichele, MD, MSCE. Dr. DeMichele is the Alan and Jill Miller Professor in Breast Cancer Excellence and Co-Leader of the Breast Cancer Program at Abramson Cancer Center at the University of Pennsylvania, Philadelphia.
“Overall outcomes were excellent in both arms, which is an important benchmark for estrogen receptor–positive disease treated with modern therapy.”— ANGELA DeMICHELE, MD, MSCE
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“Overall outcomes were excellent in both arms, which is an important benchmark for estrogen receptor–positive disease treated with modern therapy,” said Dr. DeMichele. She reported that more than 92% of patients in both arms were free of invasive disease at 4 years.
“Although 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 measurable residual disease biomarker, to be able to escalate therapy to those who truly need it. That’s an important lesson from PALLAS,” Dr. DeMichele stated.
Evaluating CDK4/6 Inhibitors in the Adjuvant Setting
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) in combination with endocrine therapy have become a standard of care for metastatic hormone receptor–positive/HER2-negative breast cancer, and the class of agents is being studied in the adjuvant setting. For high-risk early-stage disease, the CDK4/6 inhibitor abemaciclib has been approved, based on results from the monarchE trial.2 Palbociclib, in contrast, did not show a benefit in disease-free or overall survival in previous analyses of the PALLAS trial.3
The current prespecified analysis investigated the potential benefit of palbociclib in the cohort of 1,010 patients with stage IIA disease enrolled in the PALLAS trial. These patients were specifically enrolled in a cohort designed to be capped at 1,000 patients to evaluate the treatment in those diagnosed at lower clinical risk. This population was not included in the monarchE trial.
The global phase III PALLAS trial (AFT-05/ABCSG-42/BIG-14-03/PrE0109) enrolled 5,796 patients with stage II to III disease from sites in 21 countries. The majority had higher-stage disease (82%), prior chemotherapy (83%), and were considered clinically at high risk (59%), although the study also included a subset of patients with node-negative disease (13%).
Patients were randomly assigned to receive a planned 2 years of palbociclib at a starting dose of 125 mg once daily for 3 weeks of a 28-day cycle plus the provider’s or patient’s choice of adjuvant endocrine therapy, vs endocrine therapy alone. Median patient age within the stage IIA subgroup was 54 years; 40.6% were pre/perimenopausal; 50.1% had T2/N0 disease; 26.9% had grade 3 tumors; and 55.5% also received chemotherapy.
The current analysis of the stage IIA cohort was triggered at an 8% invasive disease–free survival event rate in the endocrine therapy–alone arm, corresponding to 45 events, at a median follow-up of 43 months for the full population and 50 months for the stage IIA cohort.
Similar Outcomes in Both Arms
Invasive disease–free survival events occurred in 31 patients who received palbociclib plus endocrine therapy and in 45 patients treated with endocrine therapy alone, resulting in a nonsignificant difference at 4 years of 92.9% vs 92.1% (hazard ratio [HR] = 0.75; confidence interval [CI] = 0.48–1.19; P = .23). Nonsignificant differences were also observed for invasive breast cancer–free, distant recurrence–free, and locoregional cancer–free survival, Dr. DeMichele reported.
“Of note, no differential benefit was seen by histologic grade, receipt of chemotherapy, age, or anatomic clinical risk (T1/N1 vs T2/N0),” she added.
Dr. DeMichele also reported that outcomes were similar between the arms in the stage IIB/III cohort. The invasive disease–free survival rate at 4 years was 85.3% with palbociclib vs 83.6% with endocrine therapy alone (HR = 0.91; 95% CI = 0.77–1.07; P = .24).
“These results enable us to conclude that with a median follow-up of 43 months for the overall study, there is no benefit to adding 2 years of adjuvant palbociclib to standard adjuvant endocrine therapy, regardless of stage group. These findings also highlight the difference in prognosis by stage, with the stage IIA group having substantially better outcomes regardless of treatment,” Dr. DeMichele observed.
Why Was PALLAS Negative and monarchE Positive?
Dr. DeMichele said that “many have pondered” why the PALLAS trial did not show benefit from the addition of palbociclib, and the monarchE trial did show benefit from the addition of abemaciclib. “Especially as the effect on progression-free survival in the meta-static setting with palbociclib, ribociclib, and abemaciclib were highly aligned, there was an expectation that the impact in the adjuvant setting would be similar as well. We have not seen that, and certainly our team has spent a lot of time trying to figure out why that is,” she said.
She offered several potential reasons: a greater proportion of higher-risk patients in monarchE and a population enriched for Ki67, which appears to be a marker of proliferation; the intermittent dosing of palbociclib which possibly enables cells to “go back into” the cell cycle; and the possibility that there are real differences among the CDK4/6 inhibitors themselves. Data from the ongoing NATALEE trial of adjuvant ribociclib are awaited.
“What’s interesting is that abemaciclib seems to have activity in the metastatic setting as a single agent and in aggressive tumors—which sort of predicts what we saw in the adjuvant setting. Whereas for palbociclib, we saw the most benefit in patients whose tumors had been initially endocrine-sensitive and then developed resistance,” Dr. DeMichele added. “This makes you wonder whether giving it right up front as you start the endocrine therapy might be too early, and it might work better in patients who develop some resistance to adjuvant endocrine therapy. Of course, we’re just postulating…, but I think there are lots of lessons to learn from this experience that we will all take into the adjuvant setting in the future.”
Considerations and Future Research
“The results of the PALLAS trial to date beg the question of whether the era of large adjuvant trials, based upon clinical stage alone, is now passed. The data we’ve shown suggest that in such trials, we are likely overtreating a substantial fraction of patients who may never relapse,” explained Dr. DeMichele. “This situation calls for new trial designs and biomarkers that can enable us to enroll only those patients who will truly benefit from more therapy.”
Future analyses of PALLAS will incorporate genomic risk and other molecular patterns from this extensive correlative program. Clinical follow-up and collection of serial biosamples will continue for at least 10 years on all patients. Investigators aim to assess the impact of palbociclib exposure on late recurrence in hormone receptor–positive disease.
“The extensive biomarker collection in this trial provides the ability to determine how biological heterogeneity matters, which tumors have poor prognosis, and which tumors may respond to therapy. Indeed, this is where the work of the PALLAS trial is now focused,” she concluded.
The PALLAS trial is being conducted collaboratively by several academic-based global research groups. PALLAS is cosponsored by the Austrian Breast & Colorectal Cancer Study Group (ABCSG) and Alliance Foundation Trials (AFT) as part of a clinical research collaboration with Pfizer (providing study drug and funding) and other study groups, including PrECOG, LLC; NSABP Foundation Inc; and the Breast International Group (BIG). This targeted collaboration between academia and industry is allowing the independent generation of clinical data while providing a unique public-private research partnership aimed at bringing more innovative cancer treatments to patients in more efficient ways.
DISCLOSURE: Dr. DeMichele has received institutional research funding from Calithera Biosciences, Genentech, Novartis, and Pfizer.
1. DeMichele A, Dueck AC, Hlauschek D, et al: Adjuvant palbociclib in ER+ breast cancer (PALLAS Trial ABCSG-42/AFT-05/PrE0109/BIG-14-13): A preplanned analysis of the stage IIA cohort. ASCO Plenary Series. Abstract 390216. Presented October 18, 2022.
2. Johnston SRD, Harbeck N, Hegg R, et al: Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2–, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 38:3987-3998, 2020.
3. Gnant M, Dueck AC, Frantal S, et al: Adjuvant palbociclib in HR+/HER2– early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 7, 2021.
Fabrice André, MD, PhD
Fabrice André, MD, PhD, Professor of Medical Oncology at the Gustave Roussy Cancer Center, Villejuif, France, and Chairman of the Biomarker Group at UNICANCER, provided comments on the stage IIA cohort of the PALLAS trial. “The key message from PALLAS1 is there is no...