The CDK4/6 inhibitor Palbociclib ( Ibrance ) in combination with Letrozole ( Femara ) has become a standard first-line treatment for patients with luminal metastatic breast cancer ( MBC ) ( PALOMA-1 & 2 trials ).
Meanwhile, the anti-estrogen Fulvestrant ( Faslodex ) has shown to be superior to Anastrozole in the same population ( FALCON trial ).
The aim of PARSIFAL trial was to identify the best endocrine agent to combine with Palbociclib in this first-line scenario.
A total of 486 patients with ER+/HER2- metastatic breast cancer with no prior therapy in the advanced setting and endocrine sensitive criteria ( relapse more than 12 months after the end of adjuvant endocrine therapy or diagnosed with de novo metastatic disease ) were randomly assigned ( 1:1 ratio ) to receive Palbociclib ( oral 125 mg/day; 3 weeks on / 1 week off ) plus Fulvestrant 500 mg/day ( I.M Days 0, 14, 28, and then every 28 day ) or Palbociclib plus Letrozole ( oral 2.5 mg/day ).
Patients were stratified by visceral involvement and type of disease presentation ( de novo / recurrent ).
Primary endpoint was investigator-assessed progression-free survival ( PFS ). Secondary endpoints included overall survival ( OS ), overall response rate ( ORR ), clinical benefit rate ( CBR ), and safety.
254 events were needed with 80% power to detect a hazard ratio ( HR ) less than or equal to 0.7 in favor of Palbociclib plus Fulvestrant ( 2-sided α = 0.05 ).
By March 9th, 2020, 256 PFS events occurred. Patients characteristics were well balanced. Median age was 62 years ( range: 25–90 ), 56.6% were ECOG 0, 40.7% had de novo metastatic disease, 48% had visceral disease, and 43.6% with greater than or equal to 3 organ sites involved.
At median follow-up of 32 months, median PFS was 27.9 months ( 95% confidence interval [ CI ], 24.2-33.1 ) with Palbociclib plus Fulvestrant and 32.8 months ( 95% CI, 25.8-35.9 ) with Palbociclib plus Letrozole ( HR=1.1; 95% CI, 0.9-1.5; P = 0.321 ).
No differences were observed for patients with or without visceral involvement ( HR=1.3 and HR=0.97 respectively, interaction P = 0.275 ), and for de novo or recurrent metastatic disease ( HR=1.1 and HR=1.1 respectively, P = 0.979 ).
The 4-year OS rate was 67.6% in Palbociclib + Fulvestrant and 67.5% in Palbociclib + Letrozole arm ( HR=1; 95% CI, 0.7-1.5; P = 0.986 ).
No differences were observed in overall response rate or clinical benefit rate between arms.
Grade greater than or equal to 3 adverse events were similar in both arms, being neutropenia and leukopenia the most frequent.
No treatment-related deaths were reported.
In conclusion, this study was not able to identify an improvement in PFS for Palbociclib plus Fulvestrant over Palbociclib plus Letrozole in patients with endocrine-sensitive ER+/HER2- metastatic breast cancer.
As both arms demonstrated comparable 4 years-overall survival, Palbociclib plus Fulvestrant is a reasonable alternative to Palbociclib plus Letrozole in this setting. ( Xagena )
Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020