PARSIFAL, sponsored and designed by MEDSIR, is the first trial to investigate in a direct comparison of the therapeutic efficacy of fulvestrant or letrozole in combination with the CDK4/6 inhibitor palbociclib in patients previously untreated for their endocrine-sensitive, hormone receptor-positive (HR+), human-epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC).
Preliminary results of this study were presented in May 2020 at the 56th Congress of the American Society of Clinical Oncology (ASCO), and the impact of the final results has now been endorsed through their publication in JAMA Oncology.
“The oncology community have been awaiting these results with great interest, in order to determine the best endocrine agent to combine with palbociclib in this setting and following on from the results of FALCON, PALOMA-2, and MONALEESA-3 trials” said Dr. Cortés, Head of Breast Cancer Programme at the International Breast Cancer Centre of Barcelona, Spain, and co-leader of this study.
Endocrine therapy has been the standard of care for postmenopausal women with HR+, HER2– ABC, with non-steroidal aromatase inhibitors (NSAI) being the preferred first-line treatment option, whereas selective estrogen-receptor down-regulator fulvestrant has been preferably used for the treatment of endocrine-resistant patients.
Treatment of this tumor was revolutionized few years ago with the inclusion of a new type of drug, the CDK4/6 inhibitors. Matching NSAI with a CDK4/6 inhibitor doubled the time required to observe the progression of the disease. Based on these results, the combination of CDK4/6 inhibitors plus NSAI has become the standard front-line regimen for this population. Nevertheless, debate on the correct endocrine backbone has remained unsolved, where fulvestrant has shown better progression-free survival (PFS) compared with NSAI in postmenopausal endocrine-sensitive patients and considering the combination of fulvestrant and CDK4/6 inhibitors has proved an outstanding long term response and overall survival benefit.
PARSIFAL is a phase II trial that involved researchers from 47 centers around 7 European countries (Czech Republic, France, Germany, Italy, Russia, Spain, United Kingdom). A total of 486 patients with HR+, HER2– ABC that had not previously been treated for their advanced disease were randomized to receive palbociclib in combination with either fulvestrant (Arm A, 243 patients) or letrozole (Arm B, 243 patients) until progression of the disease, or unacceptable toxicity. The primary endpoint was investigator-assessed PFS.
Median time to progression was 27.9 months for the group of patients treated with fulvestrant plus palbociclib versus 32.8 months in the patients treated with letrozole plus palbociclib. Despite the significant antitumor activity, fulvestrant plus palbociclib failed to improve PFS over letrozole plus palbociclib in the study population. No clinically relevant differences in PFS were observed across pre-specified subgroups either. Importantly, both combinations showed very similar and acceptable toxicity profiles.
“PARSIFAL trial supports non-steroidal aromatase inhibitor use as the preferred endocrine partner for CDK4/6 inhibitors as initial therapy for this patient population” affirmed Dr. Llombart-Cussac, Head of the Medical Oncology Service at the Hospital Arnau de Vilanova, Valencia, Spain and co-leader of this research. “The addition of fulvestrant to CDK4/6 inhibitors is a consistent option for first-line therapy in endocrine-sensitive patients who are intolerant to aromatase inhibitors or in patients with PIK3CA wild-type tumors." said Dr. Llombart-Cussac.