Is Letrozole the Preferred CDK4/6 Partner for Endocrine-Sensitive, Advanced Breast Cancer?


Fulvestrant plus palbociclib did not significantly improve outcomes when compared with letrozole plus palbociclib in patients with endocrine-sensitive, advanced breast cancer, according to a study published in JAMA Oncology.

The study showed numeric, but not statistically significant, improvements in objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with letrozole.

These results confirm letrozole as “the preferred palbociclib partner in this patient population,” according to researchers.

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They noted that previous studies raised the question of the optimal endocrine partner for CDK4/6 inhibitors in patients with endocrine-sensitive breast cancer.

The phase 2 PARSIFAL trial ( Identifier: NCT02491983) was designed to test palbociclib in combination with fulvestrant or letrozole in this patient population.

The trial enrolled 486 patients with hormone receptor-positive, ERBB2-negative, endocrine-sensitive, advanced breast cancer with no prior treatment in the metastatic setting. The patients were randomly assigned to palbociclib with fulvestrant (243 patients) or letrozole (243 patients).

Baseline characteristics were balanced between the treatment arms. For the entire cohort, the median age was 63 years (range, 25-90 years), 92.4% of patients were postmenopausal, 94.9% were White, and 77.4% had measurable disease.

The primary endpoint was investigator-assessed PFS. At a median follow-up of 32 months, there was no significant difference in PFS between the treatment groups.

The median PFS was 27.9 months with fulvestrant-palbociclib and 32.8 months with letrozole-palbociclib (hazard ratio, 1.13; 95% CI, 0.89-1.45; P =.32). There was no significant difference in this outcome across all prespecified subgroups.

Similarly, there was no significant difference in ORR with fulvestrant or letrozole — 46.5% and 50.2%, respectively (P =.41) — and no significant difference in 3-year OS — 79.4% and 77.1%, respectively (P =.99).

The rate of grade 3-4 adverse events (AEs) was similar between the fulvestrant and letrozole arms — 80.9% and 78.5%, respectively — and the same was true for serious AEs — 29.9% and 21.1%, respectively.

The researchers acknowledged that “the optimal strategy for systemic treatment of hormone receptor-positive, ERBB2-negative advanced breast cancer remains debatable.”

However, they contended that “meaningful” improvements in PFS associated with a higher ORR and no negative effect on quality of life have established a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor as the preferred regimen.

Disclosures: This research was supported by Pfizer, AstraZeneca, and Medica Scientia Innovation Research. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Llombart-Cussac A, Perez-Garcia JM, Bellet M, et al. 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. Published online October 7, 2021. doi:10.1001/jamaoncol.2021.4301

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