The final protocol-defined analysis of the phase III PALLAS trial confirmed the negative results of the second interim analysis, showing no benefit of palbociclib plus endocrine therapy in the adjuvant breast cancer setting. Michael Gnant, MD, of the Medical University of Vienna, reported these findings at the 2021 San Antonio Breast Cancer Symposium.^1,2

Michael Gnant, MD

“The benefits previously observed in the metastatic setting with palbociclib did not translate into the earlier curative adjuvant setting. The addition of palbociclib to adjuvant endocrine therapy did not prolong invasive disease–free survival, and there was also no additional benefit seen in specific subgroups of the trial population,” Dr. Gnant said.

Exploring why PALLAS is a negative trial, Dr. Gnant discounted the possibility of inadequate drug exposure. “We can put this myth to rest,” he said. “The landmark analysis demonstrated that even in those patients who received the full intended dose, or most of it, there was no significant invasive disease–free survival benefit.”

About PALLAS

As Dr. Gnant commented: “In hormone receptor–positive breast cancer, CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors have markedly improved outcomes in the metastatic setting; thus, these drugs are now standard of care in the advanced setting. It appeared only logical to try to advance these benefits to the curative adjuvant setting, and this is the reason for large clinical trials such as PALLAS and Penelope-B for palbociclib and monarchE for abemaciclib.”

PALLAS included 5,761 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 “high risk” (59%), although the study also included a subset of patients with node-negative disease (13%).

Patients were randomly assigned to receive 2 years of palbociclib at 125 mg once daily on days 1 to 21 of a 28-day cycle plus the provider’s or patient’s choice of endocrine therapy (n = 2,883) or endocrine therapy alone (n = 2,877). The primary endpoint was invasive disease–free survival in the intention-to-treat population.

There were two interim analyses before the final analysis, which was based on 469 events. A future -analysis will look for benefit in the patients with node-negative disease; PALLAS is the only CDK4/6 inhibitor trial that has enrolled such patients.

Second Interim and Final Analyses

The second preplanned interim analysis, previously reported,³ was performed after 67% of the total number of expected invasive disease–free survival events was reached. At a median follow-up of 23.7 months, the 3-year invasive disease–free survival was 88.2% in the palbociclib group vs 88.5% in the control group (hazard ratio [HR] = 0.93; P = .51). No differences were observed as well in recurrence-free survival, and no clinicopathologic subgroups appeared to benefit more from the addition of palbociclib to endocrine therapy.

The final primary endpoint result, reported in San Antonio, showed that at a median of 31 months, the invasive disease–free survival curves are almost superimposable, with approximately 84% of each arm free of an event (HR = 0.96).

In prespecified subgroups, no differences were observed between the arms. Although hazard ratios for palbociclib/endocrine therapy vs endocrine therapy alone appeared to be better in patients with the lowest-stage disease, node-negative disease, or without receipt of chemotherapy, “none of them passed the test of heterogeneity at this point in time,” Dr. Gnant said. The secondary endpoints of breast cancer–specific survival, distant recurrence–free survival, locoregional relapse, and overall survival also revealed no advantage for the palbociclib regimen.

Treatment was well tolerated in the early disease setting, and none of the study’s 176 deaths were related to study treatment. Adverse events were similar to those observed in the metastatic setting.

Why Do PALLAS and monarchE Findings Differ?

PALLAS (and Penelope-B)⁴ did not show a benefit with palbociclib in the adjuvant setting, in contrast to monarchE,⁵ which was positive for abemaciclib, another CDK4/6 inhibitor. “Why are these results different?” Dr. Gnant questioned.

Several reasons have been postulated, but he discounted most of them. As Dr. Gnant explained, dose reductions and eventual stopping rules in the pivotal PALLAS protocol were much stricter than are used now in clinical practice. As a result, the rates of early discontinuation of palbociclib were substantial: 30% in 1 year and 45% in 2 years. “This relatively high proportion of patients who did not receive palbociclib for the full 2 years was interpreted by some as a potential reason for the disappointing result at the second interim analysis,” he stated. However, now inadequate exposure to palbociclib has been ruled out based on the competing risk analysis.

Differences in patient selection are also “definitely not” the cause of the differences in outcomes, Dr. Gnant continued. Penelope-B evaluated a high-risk population with residual tumor after surgery and also showed no benefit for palbociclib; this trial also had a “markedly lower” treatment discontinuation rate than PALLAS but was still negative. Differences in the molecules is also not likely the cause, he added, since these two CDK4/6 inhibitors produced almost identical progression-free survival benefits in the first-line and second-line settings of advanced breast cancer.

“There is one clear difference between how we use CDK inhibitors in these large trials, however,” Dr. Gnant proposed. Both palbociclib and ribociclib are given in a 3-week-on, 1-week off schedule, whereas abemaciclib is given continuously. “Particularly in the early breast cancer setting, when we are not targeting proliferating disease but [inhibiting the] awakening of dormant cells, this could be an explanation for the observed differences in outcomes. At this point, however, this remains scientific speculation.”

Collaboration and Translational Efforts

Dr. Gnant noted that because enthusiasm for PALLAS was so high, the trial was a “role model of collaboration” involving 21 countries. “All the recruitment projections were outperformed by this incredible collaborative effort,” he said. It resulted in almost 6,000 patients enrolling within 3 years and the acquisition of a “huge biomaterial collection” of specimens for translational research.

These translational projects include RNA sequencing, high throughout genomic sequencing and circulating tumor DNA analysis of all patients, and validation of biomarker assays and predefined signatures. Several clinical science projects are also ongoing or planned. 

DISCLOSURE: Dr. Gnant has served as a consultant to LifeBrain; has received personal fees and travel support from Amgen, Daiichi Sankyo, AstraZeneca, Eli Lilly, NanoString, Novartis, Pierre Fabre, and TLC Biopharmaceuticals; and his spouse is employed by Sandoz.

REFERENCES

1. Gnant M, Dueck CC, 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.

2. Gnant M, Dueck AC, Frantal S, et al: Adjuvant palbociclib for early breast cancer: The PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. December 7, 2021 (early release online).

3. Mayer EL, Dueck AC, Martin M, et al: Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): Interim analysis of a multicentre, open-label, randomised phase 3 study. Lancet Oncol 22:212-222, 2021.

4. Loibl S, Marmé F, Martin M, et al: Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—The Penelope-B trial. J Clin Oncol 39:1518-1530, 2021.

5. Harbeck N, Rastogi P, Martin M, et al: Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 32:1571-1581, 2021.