Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer—The Penelope-B Trial

Abstract

PURPOSE About one third of patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) will relapse. Thus, additional therapy is needed. Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor demonstrating efficacy in the metastatic setting. PATIENTS AND METHODS PENELOPE-B ( NCT01864746 ) is a double-blind, placebo‐controlled, phase III study in women with hormone receptor–positive, human epidermal growth factor receptor 2–negative primary breast cancer without a pathological complete response after taxane‐containing NACT and at high risk of relapse (clinical pathological staging-estrogen receptor grading score ≥ 3 or 2 and ypN+). Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib 125 mg once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET). Primary end point is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with a two-sided efficacy boundary P < .0463 because of two interim analyses. RESULTS One thousand two hundred fifty patients were randomly assigned. The median age was 49.0 years (range, 19-79), and the majority were ypN+ with Ki-67 ≤ 15%; 59.4% of patients had a clinical pathological staging-estrogen receptor grading score ≥ 3. 50.1% received aromatase inhibitor, and 33% of premenopausal women received a luteinizing hormone releasing hormone analog in addition to either tamoxifen or an aromatase inhibitor. After a median follow-up of 42.8 months (92% complete), 308 events were confirmed. Palbociclib did not improve iDFS versus placebo added to ET-stratified hazard ratio, 0.93 (95% repeated CI, 0.74 to 1.17) and two-sided weighted log-rank test (Cui, Hung, and Wang) P = .525. There was no difference among the subgroups. Most common related serious adverse events were infections and vascular disorders in 113 (9.1%) patients with no difference between the treatment arms. Eight fatal serious adverse events (two palbociclib and six placebo) were reported. CONCLUSION Palbociclib for 1 year in addition to ET did not improve iDFS in women with residual invasive disease after NACT.

Breast cancer

“…126 The PENELOPE-B trial did not show that the addition of 1 year of palbociclib to standard adjuvant endocrine therapy improves 3 year invasive-disease free survival in patients at high risk of relapse after neoadjuvant chemotherapy (81•2% with palbociclib vs 77•7% with placebo). 127 In the PALLAS study, palbociclib given for 2 years did not improve the outcome (3 years invasive disease-free survival) of early breast cancer in patients at intermediate and high risk of recurrence (88•2% for palbociclib plus endocrine therapy vs 88•5% for endocrine therapy alone; hazard ratio [HR] 0•93 [95% CI 0•76-1•15]; p=0•51). 128 The monarchE study, in which abemaciclib was used in an exclusively high-risk breast cancer popula tion, did show a 3•5% absolute difference in 2 year invasive disease-free survival rates after a median follow-up of 15 months: 92•2% for abemaciclib versus 88•7% for endocrine therapy alone (HR 0•75 [95% CI 0•60-0•93]; p=0•01), which is rather short for a HER2-negative, hormone receptor-positive breast cancer population.…”

The role of CDK4/6 inhibitors in early breast cancer

“…The first-generation CDK4/6i adjuvant trials selected patients harboring “classical” prognostic high-risk clinic-pathological characteristics. Results from PALLAS, PENELOPE-B and MONARCH-E trials have been recently published [ 27 , 29 , 30 , 32 ], generating considerable debate. The three trials, with IDFS as primary objective, provided diverging results.…”

“…However, in the MONARCH-E study, after a median FU of 15.5 months, abemaciclib demonstrated to significantly reduce the risk of recurrence, with an absolute difference of 3.5% in the IDFS rate at 2 years being 92.2% (abemaciclib arm) vs 88.7% (control arm) with a HR=0.75; 95% CI, 0.60-0.93 (p=0.01) [29]. In the J o u r n a l P r e -p r o o f -7 -PENELOPE-B trial, at the time of final analysis, after a median FU of 42.8 months, IDFS events had occurred and the study did not meet its primary endpoint: the addition of 1 year-palbociclib to SOC adjuvant therapy in women with HR + /HER2 -BC at high risk of relapse after NCT did not improve IDFS (HR=0.93, 95% CI [0.74, 1.16]; p=0.525) [30].…”

“…Four major trials have explored the role of CDK4/6i in the adjuvant setting. Three of them, PALLAS and PENELOPE-B for palbociclib, and MONARCH-E for abemaciclib have recently presented results from their interim or final analyses [ [27] , [28] , [29] , [30] ]. NATALEE (NCT03701334) for ribociclib is still ongoing [ 31 ].…”

“…The PENELOPE-B trial included 1250 patients with HR + /HER2 – early BC with residual disease after NCT and considered at high risk by the clinical-pathological stage-estrogen/grade (CPS-EG score), defined as CPS-EG score of ≥3, or score 2 if nodal status at surgery is ypN + . Patients were randomized between February 2014 and December 2017 to receive 13 cycles (approximately 1 year) of palbociclib in combination with standard ET vs standard adjuvant ET alone and were stratified by nodal status at surgery, age at first diagnosis, centrally measured Ki67, global region of participating sites, and risk status [ 30 ].…”