No OS Boost With Palbociclib and Endocrine Therapy in Premenopausal Breast Cancer

No improvement in overall survival (OS) was observed with palbociclib (Verzenio) plus endocrine therapy versus capecitabine in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer, according to an extended follow-up of the randomized Young-PEARL trial.

Among 174 patients, the mean OS was 54.8 months for patients who received the CDK4/6 inhibitor plus exemestane with ovarian function suppression compared with 57.8 months for those who received capecitabine (HR 1.02, 95% CI 0.69-1.51, P=0.92), reported Yeon Hee Park, MD, of the Samsung Medical Center and Sungkyunkwan University School of Medicine in Seoul, South Korea, and colleagues in Lancet Oncology.

“Although palbociclib plus endocrine therapy did not show a significant improvement in overall survival, CDK4/6 inhibitor plus endocrine therapy is an active treatment option for premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer compared with chemotherapy based on progression-free survival [PFS] benefits and favorable quality-of-life results,” they wrote.

Previous results from the study showed a median PFS of 19.5 months with palbociclib plus endocrine therapy versus 14 months with capecitabine (HR 0.74, 90% CI 0.57-0.98, P=0.036).

The authors noted that the median OS in the capecitabine arm was “remarkable” in a study population enriched with high-risk patients, and that in resource-limited settings, a capecitabine-first strategy “could serve as an alternative option without negatively affecting overall survival.”

In a commentary accompanying the study, Elisabetta Munzone, MD, and Carmine Valenza, MD, both of the European Institute of Oncology in Milan, wrote that the “trial meaningfully supports the role of CDK4/6 inhibitor plus endocrine therapy as upfront therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer” and suggested that the improvement in quality of life is one that “holds even greater importance in the premenopausal setting.”

They said the absence of an OS benefit with the CDK4/6 inhibitor plus endocrine therapy is “probably” attributable to the fact that 42% of patients in the capecitabine arm received a CDK4/6 inhibitor as part of subsequent treatment.

“These data … might suggest that postponing the CDK4/6 inhibitor still represents a valid option in the treatment sequencing of patients in this setting,” they wrote. “However, the increasing number of second-line targeted therapy options, along with the improvement in quality of life highlighted in the Young-PEARL trial, including delayed physical deterioration and improved symptom management, confirm the superiority of CDK4/6 inhibitors plus endocrine therapy over chemotherapy as first-line treatment for most premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer.”

The open-label, phase II Young-PEARL study was conducted at 14 institutions in South Korea from June 2016 to December 2018 and included 184 premenopausal women who had experienced disease recurrence during or after previous tamoxifen treatment. Of these patients, 174 were included in the modified intention-to-treat population (90 in the palbociclib plus endocrine therapy group and 84 in the capecitabine group).

Just over half of the participants were treatment-naive in the metastatic setting; about one-fifth had received prior chemotherapy in the metastatic setting.

In a multivariable analysis, the use of a CDK4/6 inhibitor after disease progression (irrespective of the line of therapy) was the only factor associated with longer OS (HR 0.06, 95% CI 0.00-0.94, P=0.045).

Regarding safety, one patient in the palbociclib group and three in the capecitabine group discontinued study treatment due to treatment-related adverse events. Treatment-related serious adverse events were reported in two patients in the palbociclib group. No treatment-related deaths occurred.

The most common grade 3 or higher adverse events were neutropenia (64% in the palbociclib group vs 18% in the capecitabine group) and decreased neutrophil count (32% vs 8%). Grade 3-4 non-hematologic adverse events were rare in both groups.

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