In a preplanned analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with stage IIA breast cancer. 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. These results were presented during the October 2022 session of the ASCO Plenary Series by Angela DeMichele, MD, MSCE, the Alan and Jill Miller Professor in Breast Cancer Excellence and Co-Leader of the Breast Cancer Program at the Abramson Cancer Center at the University of Pennsylvania (Abstract 390216).
“Overall outcomes were excellent in both arms, which is an important benchmark for [patients with] estrogen receptor (ER)-positive disease treated with modern therapy,” said Dr. DeMichele, reporting that more than 92% of patients in both arms were free of invasive disease at 4 years.
Angela DeMichele, MD, MSCE
“These data provide an important benchmark for outcomes in ER-positive breast cancer in an international study population with modern therapy. 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. That’s an important outcome of PALLAS,” she added.
About PALLAS
The 5,796 patients with stage II/III disease in the global phase III PALbociclib CoLlaborative Adjuvant Study (PALLAS) were randomly assigned to receive either 2 years of palbociclib at 125 mg once daily for 3 weeks on a 28-day cycle plus the provider’s or patient’s choice of endocrine therapy for 5 years, or endocrine therapy alone for 5 years.
The current prespecified analysis investigated palbociclib plus endocrine therapy in the cohort of 1,010 patients with stage IIA disease. These patients were specifically enrolled to determine the benefit in patients diagnosed at lower risk, who may have more indolent disease. The analysis 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 Per Arm
Invasive disease–free survival events occurred in 31 patients who received palbociclib plus endocrine therapy and in 45 treated with endocrine therapy alone, resulting in a statistically nonsignificant difference at 4 years of 92.9% vs. 92.1% (hazard ratio [HR] = 0.75, 95% 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.
“No differential benefit was seen by histologic grade, receipt of chemotherapy, age, or anatomic clinical risk (T1/N1 vs T2/N0),” she said.
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% in the palbociclib arm vs 83.6% in the endocrine therapy–alone arm (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 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.
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 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.— Angela DeMichele, MD, MSCE
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Outcomes From PALLAS vs monarchE
A question that has plagued the research community is why the PALLAS trial was negative while the monarchE trial was positive, leading to the U.S. Food and Drug Administration approval of the CDK4/6 inhibitor abemaciclib in patients with high-risk early breast cancer.
“This is a question that many have pondered,” noted Dr. DeMichele, especially since the three available CDK4/6 inhibitors performed comparably in the metastatic setting.
Among the potential explanations are the greater proportion of higher-risk patients and Ki67 enrichment in monarchE, a group in whom abemaciclib may work better; the continuous administration of abemaciclib, which may lead to greater cell cycle arrest than intermittent dosing, as was done with palbociclib; and the possibility that the drugs are, indeed, different. CDK4/6 inhibitors might also work best in the setting of endocrine therapy resistance, and for various reasons, patients in PALLAS may have been less resistant, she suggested.
“Of course, we're just postulating reasons … 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,” Dr. DeMichele said.
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 today suggests that in such trials, we are likely overtreating a substantial fraction of patients who may never relapse. 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,” concluded Dr. DeMichele.
Future analyses of PALLAS will incorporate genomic risk and other molecular patterns from the extensive transPALLAS correlative program. Clinical follow-up and serial biosampling will continue for at least 10 years in all patients. Investigators aim to assess the impact of palbociclib exposure on late recurrence in patients with hormone receptor–positive disease.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
