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Palbociclib With Adjuvant Endocrine Therapy in Early Breast Cancer
TAKE-HOME MESSAGE
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The authors of this large, international, randomized, phase III trial evaluated the addition of 2 years of palbociclib to adjuvant endocrine therapy in 5760 patients with HR-positive, HER2-negative, early-stage breast cancer. Invasive disease–free survival was similar in the two treatment groups, but increased toxicity was observed with the addition of palbociclib.
- Additional studies are needed to understand biological differences between early- and advanced-stage breast cancer to potentially explain these findings given the efficacy previously seen in metastatic disease.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.
METHODS
PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).
FINDINGS
Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.
INTERPRETATION
At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.
Additional Info
Disclosure statements are available on the authors' profiles:
Palbociclib With Adjuvant Endocrine Therapy in Early Breast Cancer (PALLAS): Interim Analysis of a Multicentre, Open-Label, Randomised, Phase 3 Study
Lancet Oncol 2021 Jan 15;[EPub Ahead of Print], EL Mayer, AC Dueck, M Martin, G Rubovszky, HJ Burstein, M Bellet-Ezquerra, KD Miller, N Zdenkowski, EP Winer, G Pfeiler, M Goetz, M Ruiz-Borrego, D Anderson, Z Nowecki, S Loibl, S Moulder, A Ring, F Fitzal, T Traina, A Chan, HS Rugo, J Lemieux, F Henao, A Lyss, S Antolin Novoa, AC Wolff, M Vetter, D Egle, PG Morris, EP Mamounas, MJ Gil-Gil, A Prat, H Fohler, O Metzger Filho, M Schwarz, C DuFrane, D Fumagalli, KP Theall, DR Lu, CH Bartlett, M Koehler, C Fesl, A DeMichele, M GnantFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Oncology
CDK 4/6 inhibitors added to endocrine therapy are highly effective in HR-positive, HER2-negative MBC, with comparable results across palbociclib, ribociclib, and abemaciclib in both endocrine-sensitive and -resistant populations. This transformational class of agents began to be studied in early-stage breast cancer as adjuvant therapy in high-risk patients. PALLAS is a large trial of about 9000 patients randomized to receive either palbociclib or placebo for 2 years plus choice of standard adjuvant endocrine therapy. The current report reflects the second planned interim analysis at 2 years of follow-up. The study population included 59% considered high risk with more than four positive lymph nodes, or one to three positive lymph nodes with T3 or T4 lesions.
The PALLAS trial is negative; 3-year invasive disease–free survival (iDFS) is 88.2% for palbociclib versus 88.5% for endocrine therapy alone, and, at this time, has statistically passed the futility boundary, meaning it cannot become positive with further follow-up. Early discontinuation of palbociclib occurred in 42% of patients, with 15% stopped at 6 months and 30% discontinued at 12 months.
These results contrast starkly with the interim results of monarchE, an adjuvant study of 2 years of abemaciclib, an alternative CDK 4/6 inhibitor added to standard endocrine therapy. As published in JCO in 2020, monarchE met is primary endpoint of improvement in iDFS with a HR of 0.75 and improved 2-year iDFS of 92.9 for abemaciclib vs 88.7% for placebo. Distant relapse-free survival was also statistically and clinically significant for abemaciclib over placebo. Only 16.6% of patients discontinued abemaciclib early at this early follow-up.
The results in these two well-controlled, large-scale global adjuvant trials are strikingly different. Several possibilities may account for the positive results in monarchE and the negative PALLAS findings. First, monarchE had a higher-risk population than PALLAS and CDK 4/6 inhibition may be more effective in these patients. Second, the discontinuation rate was very high in PALLAS, and patients may simply had not taken the drug long enough to see the effect. Third, the schedule of the drugs are different; palbociclib is given discontinuously and abemaciclib continuously. In the adjuvant setting, continuous inhibition of CDK 4/6 may be necessary for best results. Fourth, there are well-known differences in the relative inhibition of CDK 4 and 6 between the two agents, and this difference may be exploited in the adjuvant setting. These drugs may therefore act differently in the micrometastatic state of adjuvant therapy rather than the macrometastatic state of clinically evident MBC. Fifth, it is possible that downstream secondary immune effects of CDK 4/6 inhibition may play a role in clinical relapse in the adjuvant setting, leading to varying results. Sixth, the monarchE study remains immature, and it will be important to see longer follow-up to confirm that the curves stay meaningfully separated over time. Finally, there may be as yet undefined differences in these agents that reflect other aspects of the complex estrogen signaling pathway and resistance mechanisms, which have not been considered.
Once again, we are humbled by clinical extrapolation that gets proven erroneous when the carefully designed trials are conducted. Oncology must continue to be based on clearly defined evidence. On the bright side, we may soon have a powerful weapon to reduce recurrence in high-risk HR-positive, HER2-negative early-stage breast cancer.