Palbociclib regimen fails to extend invasive DFS in early breast cancer
Click Here to Manage Email Alerts
The addition of palbociclib to adjuvant endocrine therapy did not extend invasive DFS for patients with early hormone receptor-positive, HER2-negative breast cancer, according to results presented at San Antonio Breast Cancer Symposium.
“The benefits previously observed in the metastatic setting with palbociclib did not translate into the earlier adjuvant setting,” researcher Michael Gnant, MD, FACS, director and chairman of the department of surgery at the Comprehensive Cancer Center of Medical University of Vienna, said during a presentation. “Multiple potential possibilities are being actively explored.”
Prior studies showed the combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy extended PFS and OS among patients with metastatic hormone receptor-positive, HER2-negative breast cancer. The combination also appeared well-tolerated in that patient population.
Several large trials have assessed the efficacy of CDK 4/6 inhibitors in the curative setting for patients with early breast cancer.
Gnant and colleagues conducted the randomized phase 3 PALLAS trial to determine whether the addition of the CDK 4/6 inhibitor palbociclib (Ibrance, Pfizer) to adjuvant endocrine therapy would improve outcomes for patients with early hormone receptor-positive, HER2-negative disease.
The trial included 5,761 patients (median age, 52 years; range, 45-61) with stage II or stage III disease who had completed surgery with or without chemotherapy or radiotherapy. Most (82%) had higher-stage disease and had received chemotherapy (83%), and 59% were considered to have clinical high-risk disease.
Randomization occurred within 12 months of diagnosis and within 6 months of starting endocrine therapy, and mandatory tumor block had to be received by the central lab prior to randomization.
Researchers randomly assigned patients 1:1 to endocrine therapy alone or in combination with palbociclib dosed at 125 mg daily in a 3-weeks-on, 1-week-off schedule for up to 2 years.
Endocrine therapy could include an aromatase inhibitor or tamoxifen with the addition of a luteinizing hormone-releasing hormone agonist for premenopausal patients.
Invasive DFS served as the primary endpoint. Secondary endpoints included invasive DFS excluding second cancers of non-breast origin, distant RFS, locoregional RFS, OS and safety.
The final analysis, performed after median follow-up of 31 months, showed the addition of palbociclib did not improve invasive DFS at 4 years (84.2% vs. 84.5%; HR = 0.96; 95% CI, 0.81-1.14). Researchers reported no significant differences in any prespecified subgroups.
Analysis of secondary endpoints showed palbociclib conferred no significant benefit at 4 years with regard to invasive breast cancer-free survival (85.4% vs. 86%; HR = 0.99; 95% CI, 0.82-1.19), distant RFS (86.2% vs. 87.8%; HR = 1.05; 95% CI, 0.87-1.28), locoregional RFS (96.8% vs. 95.4%; HR = 0.84; 95% CI, 0.57-1.23) or OS (93.8% vs. 95.2%; HR = 1.32; 95% CI, 0.98-1.78).
Researchers identified no new safety signals with palbociclib treatment. The most common adverse events included neutropenia (83.5% with palbociclib-endocrine therapy vs. 5% with endocrine therapy alone), leukopenia (55.1% vs. 7.5%) and fatigue (41% vs. 19.3%).
A higher percentage of patients assigned palbociclib experienced serious adverse events (13% vs. 7.9%); however, none of the 176 deaths that occurred were related to study treatment, Gnant said.
Nearly one-third (30.2%) of patients had discontinued palbociclib at 12 months and 44.9% had discontinued at 24 months. However, data confirmed that longer palbociclib treatment duration or receipt of more than 70% dose intensity did not markedly extend invasive DFS, Gnant said.
The efficacy outcomes of the PALLAS trial varied from those of the randomized phase 3 monarchE trial, which included adult women and men with hormone receptor-positive, HER2-negative, node-positive resected early breast cancer at high risk for recurrence.
Researchers in monarchE assigned patients to endocrine therapy alone or in combination with the CDK 4/6 inhibitor abemaciclib (Verzenio, Eli Lilly). Results of a prespecified interim analysis showed a statically significant improvement in invasive DFS with abemaciclib.
“Why are the PALLAS results different from monarchE?” Gnant said. “A number of potential reasons have been discussed.”
A deeper comparison of the two trials rules out study population and drug exposure as possibilities, Gnant said.
“It could just be differences between the drugs themselves, but many consider this unlikely given the almost identical PFS results in the first- and second-line advanced breast cancer settings,” Gnant said.
However, there is “one clear difference” in how researchers used CDK 4/6 inhibitors in these large trials.
“While both palbociclib and ribociclib [Kisqali, Novartis] are given in a 3-weeks-on, 1-week-off schedule, abemaciclib is taken in a continuous manner,” Gnant said. “Particularly in the early breast cancer setting, when we are not targeting proliferating disease but awakening dormant cells, this could be an explanation for the observed differences in trial outcomes. At this point, however, this remains scientific speculation.”
Collapse
Gnant M, et al. Abstract GS1-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
Click Here to Manage Email Alerts