Palbociclib (Ibrance®; Pfizer), a cyclin-dependent kinase 4/6 inhibitors (CDK4/6 inhibitor), has become a leading agents in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC)*, while endocrine therapy has long been the standard of care (SOC) for the treatment of postmenopausal women diagnosed with HR+, HER2– ABC.

In the treatment of the disease, non-steroidal aromatase inhibitors (NSAI) have been the preferred first-line treatment option, while the selective estrogen-receptor down-regulator (antiestrogen) fulvestrant (Faslodex®; AstraZeneca) was generally preferred for endocrine-resistant patients. [1][2]

CDK4/6 inhibitor, in combination with NSAI radically changed treatment outcomes of HR+, HER2– ABC, doubling the time required to the progression of the disease. Hence, as a result of these outcomes, CDK4/6 inhibitors in combination with NSAI became the standard front-line regimen for the treatment of these patients.

Investigating therapeutic efficacy
To answer the question which is the optimal endocrine treatment (fulvestrant vs letrozole) would be better in combination with the CDK4/6 inhibitor palbociclib in previously untreated, endocrine-sensitive HR+, HER2– advanced breast cancer, investigators at MedSIR designed the PARSIFAL study (NCT02491983).

This study was  the first  international, randomized, open-label, controlled, multicenter phase II clinical trial designed to  investigate the therapeutic efficacy of fulvestrant or Letrozole (Femara®; Novartis) in combination with 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).[1][2]

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Results from the PARSIFAL-LONG study, a 5-year extended follow-up of the PARSIFAL study (NCT02491983) on endocrine-sensitive HR+, HER2– ABC, was designed to investigate and compare the safety and efficacy of palbociclib combined with fulvestrant or letrozole in women with ER+, HER2- locally advanced or metastatic breast cancer.[1]

The result of the study demonstrated that, with a median follow-up of 59.7 months, the two combined option therapies (palbociclib-letrozole and palbociclib-fulvestrant) as first-line treatments for metastatic breast cancer, did not show significant differences in progression-free survival and overall survival when palbociclib.

Because the investigators did not observe difference between groups, both groups were combined, and it was determined that the median progression-free survival was 33.2 months (95%CI, 27.7-39.5), with a median overall survival was 65.4 months (95%CI, 57.8-72.0).

Letrozole vs fulvestrant
The PARSIFAL-study was an international, randomized, open-label, controlled, multicenter phase II clinical trial specifically designed to explored the optimal endocrine agent (letrozole vs fulvestrant) to combine with palbociclib in patients with untreated, endocrine-sensitive, hormone receptor positive/HER2-negative advanced breast cancer in the first-line setting.

The trial failed to demonstrate an improvement in progression-free survival of palbociclib-fulvestrant over palbociclib-letrozole, with a median follow-up of 2.7 years. At data cutoff, overall survival data were immature.

Extending the study
PARSIFAL-LONG extended the efficacy assessment of the PARSIFAL study with a median follow up of 5.0 years. It included a total of 389 patients, which represents 80.5% of all patients initially enrolled in PARSIFAL. Among them, 86 patients (22.1%) had a progression within the first year of treatment (early progressors), with a median overall survival of 24 months. The remaining 303 patients (77.9%) were progression-free on palbociclib-based regiments at 12 months and showed an improved median overall survival of 81.5 months.

Patients who experienced a progression during the 5-year follow-up were then assessed based on the time that they progressed. Those who progressed within the first year had an overall survival of 18 months compared to 27 months for patients that progressed after a year (hazard ratio, 0.67, 95%CI, 0.51-0.90, p=0.007), indicating that early progression (<12 months) on a palbociclib-based regimen is a strong predictor for overall survival.

These results of the study were presented at the 46th annual San Antonio Breast Cancer Symposium (SABCS) by Antonio Llombart-Cussac, MS, Ph,D.,co-founder of MEDSIR, a Spanish company specialized in the strategic design of independent clinical research, and Head of the Oncology Department at Arnau de Vilanova Hospital, part of the Catalan Health Institute, serving Lleida, the Upper Pyrenees and Aran.

This year, MEDSIR had a significant participation at the conference by showcasing 5 studies including PARSIFAL-LONG, DEBBRAH, ATRACTIB, PARALEAL and MiRaDor.

“Upon combining the two arms, our overall survival and progression-free survival values align comparably with other CDK4/6 inhibitors,” noted Llombart-Cussac.

“Early progression with a palbociclib-based regimen serves as a robust early clinical biomarker for survival,” he added.

Study design
A total of 389 patients from 32 of the original 47 sites participated in this trial, which is the only study for a CDK4/6 regimen that recruited patients exclusively across European countries including SpainFranceItalyGreat Britain, Deutschland and Czech Republic.

The PARSIFAL-LONG study provides valuable insights, expanding the understanding of the magnitude of benefit and further reinforces the evidence supporting palbociclib in combination with endocrine therapy as a first-line treatment for patients with hormone receptor-positive/HER2-negative metastatic breast cancer.


Note: * HR+/HER2- breast cancer express hormone receptors (HR+), but do not express HER2 protein (HER2-). According to the US National Cancer Institute and based on 2016–2020 cases, this is the most common subtype with an age-adjusted rate of 87.2 new cases per 100,000 women.

Clinical trial
Palbociclib in Combination With Fulvestrant or Letrozole in Patients With ER+, HER2- Advanced Breast Cancer (PARSIFAL) – Identifier: NCT02491983

Highlight of Prescription Information
Palbociclib (Ibrance®; Pfizer) [Prescribing Information]
Fulvestrant (Faslodex®; AstraZeneca)[Prescribing Information]
Letrozole (Femara®; Novartis)[Prescribing Information]

[1] Llombart-Cussac A, Pérez-García JM, Bellet M, Dalenc F, Gil-Gil M, Ruíz-Borrego M, Gavilá J, Sampayo-Cordero M, Aguirre E, Schmid P, Marmé F, Di Cosimo S, Gligorov J, Schneeweiss A, Albanell J, Zamora P, Wheatley D, Martínez-de Dueñas E, Amillano K, Malfettone A, Cortés J; PARSIFAL Steering Committee and Trial Investigators. Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Dec 1;7(12):1791-1799. doi: 10.1001/jamaoncol.2021.4301. Erratum in: JAMA Oncol. 2021 Nov 1;7(11):1729. PMID: 34617955; PMCID: PMC8498933.
[2] Di Cosimo S, Pérez-García JM, Bellet M, Dalenc F, Gil Gil MJ, Ruiz Borrego M, Gavilá J, Sampayo-Cordero M, Aguirre E, Schmid P, Marmé F, Gligorov J, Schneeweiss A, Albanell J, Zamora P, Wheatley D, Martínez-De Dueñas E, Carañana V, Amillano K, Mina L, Malfettone A, Cortés J, Llombart-Cussac A. Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial. Oncologist. 2023 Jan 18;28(1):23-32. doi: 10.1093/oncolo/oyac205. PMID: 36239405; PMCID: PMC9847524.

Photo courtesy: © 2016 – 2023 SABCS/AARC

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