Second-Line Endocrine Therapy With or Without Palbociclib Rechallenge in Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: PALMIRA Trial

Abstract

Purpose: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy (ET) represents the standard first-line treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC). However, there is no definitive consensus on the preferred second-line treatment option. The PALMIRA trial investigated whether palbociclib rechallenge with an alternative ET would improve the antitumor activity in patients progressing after a first-line palbociclib-containing regimen.

Methods: This international, randomized, open-label, phase II study enrolled 198 patients with hormone receptor-positive/HER2-negative ABC with disease progression after first-line palbociclib plus ET (aromatase inhibitor or fulvestrant). Patients were eligible if they showed clinical benefit to the previous regimen (response or stable disease ≥24 weeks) or had progressed on a palbociclib-based therapy in the adjuvant setting. Patients were randomly assigned (2:1 ratio) to either palbociclib rechallenge plus second-line ET (fulvestrant or letrozole) or second-line ET alone. Stratification factors were previous ET and visceral involvement. The primary end point was investigator-assessed progression-free survival (PFS).

Results: Between April 2019 and October 2022, 136 and 62 patients were randomly assigned to palbociclib plus ET or ET alone, respectively. Median investigator-assessed PFS was 4.9 months (95% CI, 3.6 to 6.1) with palbociclib plus ET versus 3.6 months (95% CI, 2.5 to 4.2) with ET alone (hazard ratio, 0.84 [95% CI, 0.66 to 1.07]; P = .149). Grade ≥3 treatment-emergent adverse events were higher with palbociclib plus ET (47.4% v 10.0%), without new safety signals.

Conclusion: Palbociclib rechallenge plus an alternative ET did not significantly improve PFS compared with ET alone in patients with hormone receptor-positive/HER2-negative ABC progressing on a first-line palbociclib-based ET regimen.

Trial registration: ClinicalTrials.gov NCT03809988.

FIG 1.

CONSORT diagram. Patient enrollment and disposition. ^aThe patient was randomly assigned but did not meet selection criteria (history of bleeding diathesis with anticoagulation treatment). Consequently, the patient did not receive the study treatment. ET, endocrine therapy; TEAEs, treatment-emergent adverse events.

FIG 2.

Kaplan-Meier curve for investigator-assessed progression-free survival at 158 events. ET, endocrine therapy, HR, hazard ratio; mPFS, median progression-free survival; PFS, progression-free survival.

FIG 3.

Forest plot of PFS according to stratification factors and baseline characteristics. ECOG PS, Eastern Cooperative Oncology Group performance status; ET, endocrine therapy; HR, hazard ratio; NA, not applicable; PFS, progression-free survival.