Patients with hormone receptor-positive and HER2-negative, aromatase inhibitor resistant metastatic breast cancer experienced improvement in progression-free survival on treatment with chemotherapy over palbociclib in combination with and endocrine therapy.
For patients with hormone receptor (HR)-positive and HER2-negative, aromatase inhibitor (AI) resistant metastatic breast cancer, chemotherapy demonstrated improved progression-free survival (PFS) and higher response rates compared with palbociclib (Ibrance) and endocrine therapy (ET), according to results from the phase 3 PEARL study, published in the Annals of Oncology.
On the other hand, palbociclib plus ET was better tolerated and was observed to provide a better quality of life (QoL) than capecitabine, the chemotherapy used in the randomized controlled trial, PEARL (NCT02028507).
“The PEARL trial did not provide evidence of PFS superiority of palbociclib plus fulvestrant or of palbociclib plus ET in patients without ESR1 mutations over capecitabine in AI-resistant MBC patients,” wrote the investigators led by Miguel Martin, MD of Instituto de Investigación Sanitaria Gregorio Marañón. “However, it is worth noticing that compared with capecitabine, palbociclib plus ET was associated with a significant delay in QoL deterioration, less treatment discontinuations due to AEs [adverse events], and a lower proportion of patients with related serious AEs.”
For this trial, 296 patients were in cohort 1, where they were randomized 1:1 to palbociclib plus exemestane versus capecitabine; and 305 patients were in cohort 2, where patients with ESR1 mutations were randomized 1:1 to palbociclib plus fulvestrant versus capecitabine.
There was a median follow-up of 18.9 months (range, 0-56.3) in the wild-type ESR1 population and 13.5 (range, 0-30.7) cohort 2. For patients who were ESR1 wild-type, the median PFS was 8.0 months (95% CI, 6.5-10.9) with palbociclib plus ET and 10.6 months (95% CI, 7.4-13.0) with capecitabine (adjusted HR [aHR], 1.11; 95% CI, 0.87-1.41; P =.404). For cohort 2, the median PFS was 7.5 months (95% CI, 5.7-10.9) in patients receiving palbociclib plus fulvestrant and 10.9 months (95% CI, 6.3-12.9) for patients receiving capecitabine (aHR, 1.13; 95% CI, 0.85-1.50; P =.398).
In both cohorts combined, there was a median PFS of 7.4 months (95% CI, 5.9-93.) in the palbociclib plus ET arm and 9.4 months (95% CI, 7.5-11.3) in the capecitabine arm (aHR, 1.11; 95% CI, 0.92-1.34; P =.38). In the ESR1-mutated population, the aHR was 1.12 (95% CI, 0.78-1.60; P =.54).
An objective response rate (ORR) of 27.8% was observed for palbociclib plus ET compared with 36.9% for capecitabine. There was an ORR of 26.7% for palbociclib and fulvestrant versus 33.3% for capecitabine in cohort 2.
According to the patient-reported outcomes from this trial, the median time to deterioration in global health status was 8.6 months in the palbociclib plus ET arm versus 6.2 months in the capecitabine arm (aHR, 0.67; 95% CI, 0.53-0.85; P =.001).
In terms of toxicity, the most common grade 3/4 adverse events (AEs) with palbociclib plus exemestane were neutropenia at 57.4%, febrile neutropenia at 1.3%, diarrhea at 1.3%, and fatigue. With palbociclib, the most common grade 3/4 AEs were neutropenia at 55.7%, anemia at 2.0%, and diarrhea at 1.3%. Finally, with capecitabine, the most common were hand/foot syndrome at 23.5%, neutropenia at 5.5%, fatigue at 5.5%, and diarrhea at 7.6%. There was a higher incidence of grade 3 or higher non-hematologic AEs in patients receiving capecitabine at 38.8% than in patients receiving palbociclib plus exemestane or fulvestrant, at 6.7% and 6.0%, respectively.
There were 80 patients still receiving the study treatment at the cut-off date of January 14, 2019. Ten were still on palbociclib and exemestane, 37 were on palbociclib and fulvestrant, and 33 were on capecitabine. Cohort 1 had a longer median time on capecitabine than palbociclib and exemestane, at 7.9 months and 6.3 months, respectively. Cohort 2 showed the opposite, with a median time of 6.3 months for capecitabine and 7.8 months for palbociclib and fulvestrant.
Disease progression was the main reason for discontinuation of treatment. For both cohorts, the number of patients who discontinued due to progressive disease was less in the capecitabine arms than the palbociclib and ET arms.
In cohort 1, palbociclib was given at 125 mg per day for 3 weeks followed by 25 mg per day of exemestane for 1 week versus capecitabine at 2500 mg/m2 per day (or 2500 mg/m2 per day for patients over age 70) for 2 weeks followed by 1 week off.
A few months after the start of the trial, new data showed that patients with ESR1 mutations may have suboptimal response to exemestane after progression on AIs. Another study suggested fulvestrant could be effective in these patients, so the investigators of PEARL modified the trial design before efficacy data were available. They created cohort 2 specifically for these patients and in this cohort, everything was the same as cohort 1 except instead of exemestane, patients received 500 mg of fulvestrant as an intramuscular injection on days 1 and 15 of the first cycle and then on day 1 of the cycles following.
After the addition of cohort 2, the primary end points of the trial were the PFS of palbociclib plus fulvestrant compared with capecitabine whether patients had ESR1 mutational status or not, and palbociclib plus exemestane or fulvestrant versus capecitabine in patients with wild-type ESR1 in their circulating tumor DNA upon study entry. Secondary end points included PFS with palbociclib plus ET compared with capecitabine regardless of ESR1 mutational status, ORR, safety, and patient-reported outcomes, among others.
The baseline patient characteristics were even between arms in both cohorts except for the number of involved sites, which was higher in the capecitabine arm of cohort 2.
Martin M, Zielinski C, Ruiz-Borrego M, et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol. Published December 29, 2020. Accessed January 13, 2021. https://bit.ly/3nCL1el