Adding Palbociclib to Endocrine Therapy Fails to Improve iDFS in ER+ Breast Cancer

Angela DeMichele, MD

The addition of 2 years of palbociclib (Ibrance) to adjuvant endocrine therapy did not prolong invasive disease-free survival (iDFS) in patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer, according to an analysis of the phase 2 cohort in the PALLAS trial (NCT02513394).¹

Findings from PALLAS analysis were presented during the 2022 October ASCO Plenary Series by Angela DeMichele, MD, MSCE, co-leader, Breast Cancer Research Program, and co-director, 2-PREVENT Breast Cancer Translational Center of Excellence atAbramson Cancer Center, University of Pennsylvania. In addition to there being no benefit observed in iDFS, the secondary end points of the trial also did not improve.

“Invasive disease-free survival for patients in the palbociclib arm was 92.9% vs 92.1% for those patients in the endocrine therapy alone arm. Thus, at a median follow-up to 50 months, there was no significant difference in the four-year iDFS observed between the treatment arms,” stated DeMichele in the presentation. “For the stage IIA cohort, there was no differential benefit seen by histologic rate, receipt of chemotherapy, age, or anatomic clinical risk.”

In patients with metastatic disease, a CDK4/6 inhibitor combined with endocrine therapy has shown to prolong progression-free survival (PFS) and overall survival (OS) while also being well tolerated. While abemaciclib (Verzenio) is currently FDA-approved for this indication, other trials are ongoing to examine alternative agents, including the PALLAS trial.

The prospective, 2-arm, multicenter, randomized, open-label, phase 3 PALLAS trial evaluated the addition of 2 years of adjuvant palbociclib to standard adjuvant endocrine therapy for patients with ER-positive, HER2-negative early breast cancer. Investigators looked to determine whether this addition of palbociclib would improve outcomes compared with endocrine therapy alone in these patients.

Patients were eligible for enrollment if they had stage 2 or 3 disease, had completed all definitive therapy, excluding endocrine therapy, were within 12 months of diagnosis, within 6 months of starting adjuvant endocrine therapy, and all patients must have submitted a paraffin embedded tumor block.

The study randomized patients 1:1 to receive either standard endocrine treatment with the addition of palbociclib at 125 milligrams daily given 3 weeks on, 1 week off, or standard endocrine therapy alone. The treating physician decided on which endocrine therapy to give to patients. This included any standard of care regimen that had a planned duration of treatment lasting at least 5 years.

The primary end point of the trial was iDFS with secondary end points of distant recurrence-free survival, locoregional recurrence-free survival, overall survival, and safety.

Between September 2015, and November 2018, a total of 5796 patients were enrolled in the PALLAS trial. The stage IIA cohort was closed to screening in September 2017, before the trial fully enrolled all patients.

Among those in the stage IIA cohort of the trial receiving palbociclib and endocrine therapy (n = 503), the median age of patients was 55 years old (range, 29-84) while in the endocrine therapy arm alone (n = 507) was 53 years (range, 30-85), and 51 (range, 22-90) in the stage IIB/III cohort (n = 4,729). Most patients between arms were women. In the palbociclib plus endocrine therapy arm, 54.2% of patients were postmenopausal compared with 53.3% in the endocrine therapy alone group and 52.7% in the stage IIB/III cohort. In the stage IIB/III group, 88.4% of patients had received prior chemotherapy vs 56.1% in the palbociclib and endocrine therapy arm and 55% in the endocrine therapy alone arm.

At the time of the first interim analysis, there were 187 events while at the time of the second interim analysis and median follow-up of 23.7 months, there were 351 events. The final analysis occurred at 31 months of follow-up and had 516 events. For the stage IIA, this analysis was triggered when an 8% iDFS event rate was reached in the endocrine therapy alone (45 events). This resulted in a new follow-up data cutoff of 43.1 months for the full trial and 50 months for the stage IIA cohort.

Findings for the stage IIA cohort showed that iDFS for patients given palbociclib plus endocrine therapy arm was 92.9% vs 92.1% for those given endocrine therapy alone (HR, 0.75; 95% CI, 0.48-1.19; P = .23). At a median follow-up of 50 months, there was no significant difference in the 4-year iDFS between the either arm.

There was no differential benefit seen by histologic rate, receipt of chemotherapy, age, or anatomic clinical risk. Further, at a median follow-up of 43 months, there was no iDFS benefit observed when adding 2 years of palbociclib to standard endocrine therapy compared with endocrine therapy alone. DeMichele noted that there was also no benefit observed for the secondary end points of distant relapse-free survival, local regional relapse-free survival, or overall survival. However, outcomes were excellent for patients in both arms of the trial.

Regarding iDFS at 4 years for the stage IIB/III cohort, there was no significant difference between arms with patients who received palbociclib having an iDFS of 85.3% vs 83.6% for those given endocrine therapy alone (HR, 0.91; 95% CI, 0.77-1.07; P=.24).

Overall, the addition of palbociclib to adjuvant endocrine therapy did not prolong iDFS when compared with endocrine therapy alone at a median follow-up of 50 months for patients with stage IIA disease. These findings also show the differences seen in prognosis by stage, as the stage IIA groups had substantially better outcomes than the IIB/III groups, regardless of treatment.

“These data provide an important benchmark for outcomes and 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,” stated DeMichele during her presentation.

Reference:

DeMichele A. 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: 2022 January ASCO Plenary Series. January 25, 2022.