PALMIRA Trial Shows No Significant PFS Benefit From Palbociclib Rechallenge in HR+/HER2- Advanced Breast Cancer

A randomized phase II trial has found that rechallenging with palbociclib in combination with a second-line endocrine therapy (ET) did not significantly improve progression-free survival (PFS) compared to ET alone in patients with hormone receptor–positive, HER2-negative advanced breast cancer (HR+/HER2- ABC) who had previously progressed on a palbociclib-containing regimen.

The PALMIRA trial, led by Antonio Llombart-Cussac, MD, PhD, and colleagues, enrolled 198 patients across 41 centers in 6 countries. All participants had demonstrated clinical benefit from a first-line regimen combining palbociclib and ET (either response or stable disease lasting at least 24 weeks) or had relapsed in the adjuvant setting. Patients were randomized in a 2:1 ratio to receive palbociclib rechallenge plus fulvestrant or letrozole (n=136) or ET alone (n=62). The primary endpoint was investigator-assessed PFS.

At the time of final analysis, the median PFS was 4.9 months (95% CI, 3.6-6.1) in the palbociclib plus ET arm and 3.6 months (95% CI, 2.5-4.2) in the ET-alone arm (HR, 0.84; 95% CI, 0.66-1.07; P=0.149). Although this modest numerical improvement favored palbociclib rechallenge, it did not reach statistical significance.

Clinical benefit rate (CBR) was 41.9% (95% CI, 33.5-50.7) with palbociclib plus ET versus 27.4% (95% CI, 16.9-40.2) with ET alone (P=0.044). However, the objective response rate remained low in both arms at 4.4% (all partial responses) with palbociclib plus ET and 1.6% with ET alone.

No new safety signals emerged. Grade 3 and above treatment-emergent adverse events (TEAEs) occurred in 47.4% of patients receiving palbociclib plus ET, compared with 10% in the ET-alone group. As expected, neutropenia was the most common high-grade toxicity with palbociclib, occurring in 38.5% of patients. Treatment discontinuation due to adverse events was 3.7% in the combination arm and 1.7% in the control arm.

Although exploratory subgroup analyses suggested a possible benefit from palbociclib rechallenge in patients with visceral involvement, age younger than 65 years, or a prior palbociclib duration of 12 months or longer, none of these findings were conclusive. The authors noted that most patients (approximately 86%) had received at least 12 months of first-line palbociclib.

“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,” the authors wrote.

These results are consistent with the phase II PACE trial, which also found no PFS improvement with palbociclib plus fulvestrant versus fulvestrant alone after prior CDK4/6 inhibition. In contrast, other CDK4/6 inhibitors, such as ribociclib and abemaciclib, have demonstrated more promising results in the post-CDK4/6i setting. In the phase II MAINTAIN trial and phase III postMONARCH study, rechallenge with ribociclib or abemaciclib led to statistically significant improvements in PFS when combined with ET.

Commenting on the findings, JCO Senior Deputy Editor Kathy D. Miller, MD, wrote, “These negative results are consistent with the previously reported PACE trial and differ significantly from trials showing a benefit (albeit modest) from the use of ribociclib or abemaciclib after progression on prior [CDK4/6 inhibitor] regimens. Combined with the differing results in the adjuvant setting, preferential use of palbociclib is not justified.”

A planned biomarker analysis from the PALMIRA trial may help identify subgroups that could derive more benefit from palbociclib rechallenge.

Reference:

Llombart-Cussac A, et al. JCO 0, JCO-24-01865. doi:10.1200/JCO-24-01865