Egle, Daniel

Abstract Background: The PALLAS trial (ABCSG-42, AFT-05, BIG-14-03) investigates adjuvant palbociclib plus endocrine therapy (ET) versus ET alone in patients (pts) with HR+/HER2− early breast cancer. While palbociclib improves outcomes in metastatic settings, final analysis from PALLAS did not demonstrate benefit in survival outcomes from the addition of palbociclib to ET. A number of pts discontinued palbociclib before the planned 2 year duration though degree of palbociclib exposure was not associated with clinical outcomes. This analysis explores factors predictive of palbociclib early discontinuation and dose reductions, including baseline characteristics, toxicities, and patient-reported outcomes (PROs). Methods: Using the safety population of 5736 pts (2840 receiving palbociclib + ET), we assessed early palbociclib discontinuation within a competing-risks framework (competing events: progression, death). Cumulative incidence curves (Aalen-Johansen estimates) and cause-specific hazard models were used to explore associations with clinical and demographic factors (age, menopausal status, stage, race, endocrine therapy type), key toxicities (neutropenia, anemia, nausea), and baseline PROs (patient assessed quality of life [QoL], anxiety, fatigue, pain, frailty/ dependency, depression, and low income. financial difficulties). An automated model selection based on the Akaike information criterion (AIC) starting from the cause-specific hazard model incorporating all considered predictors including PROs. Results: Early discontinuation of palbociclib not due to progression or death occurred in 1171 pts (41.3%); an additional 343 pts (12.1%) stopped due to results of a futility analysis. In 108 (3.8%) and 2 (0.1%) pts treatment was discontinued due to progression or death. Median time to early discontinuation was 7.7 months in pts that discontinued treatment (median interquartile range 3.45-13.60). Very early discontinuation (≤3 months) occurred in 261 pts (9.2%). Dose reductions to 100mg and 75mg occurred in 1566 pts (55.2%) and 951 pts (33.6%) of 2840 pts, respectively. In univariable analyses, higher age, lower N-stage, and specific baseline PROs (baseline QoL, fatigue, anxiety, depression, frailty/ dependency and financial difficulties) were linked with increased risk of discontinuation. The best-fitting multivariable model identified age, nodal stage (N-stage), low quality of life (QoL), and low income as key predictors of early treatment discontinuation. Conclusions: In the PALLAS trial, our findings highlight the importance of integrating PROs into risk prediction of early treatment discontinuation. Additionally, when starting pts on oral targeted therapies in the adjuvant setting, symptom control, social work and financial counseling resources may support pts at higher risk of non-adherence. This is in line with findings from the ESMO Breast QoL analysis (Bjelic-Radisic et al.), which emphasized the added value of subjective patient-reported outcomes alongside objective clinical parameters in understanding treatment burden and adherence. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT02513394. Citation Format: M. Vetter, A. Wiencierz, M. Gnant, D. Hlauschek, C. Kurzeder, C. Grasic Kuhar, N. Zdenkowski, E. Shinn, J. Suga, D. Egle, J. Meisel, S. Antolin-Novoa, E. Munzone, T. Haddad, S. Loibl, A. Holynskyj, C. Fesl, A. Dueck, A. DeMichele, E. Mayer, on behalf of the PALLAS groups and investigators (ABCSG, AFT, BIG,PReCOG, GBG, NSABP). Predictors of early discontinuation of adjuvant palbociclib in early HR+/ HER2- breast cancer: final analysis of the PALLAS trial integrating patient-reported outcomes [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-14.

Abstract Background: As the development and use of oral anticancer agents increases, it is critical to understand patient adherence to both standard and investigational agents. The open label, phase 3 multicenter PALLAS trial investigates whether adding 2 years of the CDK4/6 inhibitor palbociclib (P) to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) over adjuvant ET alone in patients (pts) with HR- positive, HR2-negative, stage II-III breast cancer. Pts were randomly assigned to either Palbociclib (125 mg/day, 3 weeks on, 1 week off, in a 28-day cycle) plus ongoing provider/patient-choice adjuvant ET (P+ET) versus ET alone. We examined patient-reported adherence to ET +/- P during the first two years of study treatment. Methods: Adherence outcomes were measured in English-speaking pts in the U.S., UK, Ireland and Australia, Spanish-speaking pts in Spain and Mexico, and German-speaking pts in Germany and Austria. Adherence measures included drug diaries completed at each cycle, pill counts (for P only) collected at each study visit, and the Morisky Medication Adherence Scale-4 item and the McHorney Adherence Estimator questionnaires completed at cycles 2, 3, 6, 12, 18, and 24 (22 months). Mean adherence for each cycle was defined as the average proportion of prescribed pills taken (via drug diary) across all patients who initiated that cycle. Persistence was defined as the duration of drug initiation to treatment cessation (via drug diary). Generalized estimating equations were used to model the “most adherent” pts on the Morisky (score = 5 vs score <5) and “low risk” for adherence problems on the McHorney (score=0 vs score >0) to compare the average difference between arms over time for ET, adjusting for baseline demographic and clinical variables. Results: 81% (N=4688) of PALLAS pts were included in this analysis. Median persistence to ET was 23.6 months in P + ET (n=2169), 23.7 months in ET alone (2136) and 20.4 months for P (n=2194). The number of pts who initiated each cycle for ET declined over time and was similar between arms; the decline was more marked for P (Table 1). Mean adherence range as measured by drug diary was 98.2-99.3% for ET in P+ET and 98.0 - 99.4% in ET alone; and for P, ranged from 93.4 - 98.8%. The adherence and persistence results were nearly identical whether measured by drug diary or pill count for P. The observed percent “most adherent” for P measured by the Morisky scale ranged from 71.9% - 79.6% and the percent “low risk” for adherence problems measured by the McHorney scale, 64.0% - 73.4%. The percent of pts “most adherent” and “low risk” for adherence problems to ET was higher, on average over time, in the P+ET group compared to ET alone (75% vs 68%, p<0.01; 75% vs 72%, p=.05, respectively). Conclusions: Self-reported mean adherence for both P + ET and ET alone was strikingly high for pts who remained on therapy; persistence was also high with ET during the 2-year treatment period. Current analyses suggest that nonadherence to either P or ET was likely not a major contributor to the iDFS results seen in the overall PALLAS trial. These results illustrate the importance of measuring and monitoring patient adherence to oral study agents. Support: AFT, Pfizer; ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). https://acknowledgments.alliancefound.org Table 1.Adherence and persistence in PALLAS over the 24 month treatment periodPalbocicilb + ETETPalbociclibETETTreatment cycleMean Adherence (SD)N*Mean Adherence (SD)NMean Adherence (SD)N193.4 (13.8)229098.7 (6.1)230999.0 (5.2)2343294.7 (13.3)218198.8 (6.4)220398.4 (7.1)2206397.4 (10.1)211298.7 (7.3)214298.8 (6.3)2168497.6 (10.2)203598.6 (7.8)211099.0 (5.7)2154597.6 (11.1)197598.3 (7.9)209398.1 (8.3)2148698.1 (8.7)189998.7 (6.6)203798.5 (8.2)2116798.1 (9.3)185599.0 (6.3)201298.6 (7.3)2102898.0 (9.1)181098.2 (8.2)199798.1 (8.2)2092998.4 (7.4)173399.0 (6.4)196298.8 (6.8)20511098.3 (8.6)171499.2 (4.9)194699.0 (5.5)20381198.3 (8.0)169198.5 (7.3)193798.2 (8.2)20311298.7 (6.2)161299.1 (5.3)191098.7 (7.5)19861398.5 (7.7)159698.9 (6.4)189398.8 (7.1)19691497.9 (9.3)157698.4 (7.3)188298.0 (9.1)19611598.5 (6.9)151499.2 (4.6)185499.0 (6.0)19281698.2 (8.7)148699.1 (4.6)183599.1 (5.7)19131798.1 (9.8)147998.3 (7.8)182698.5 (6.4)19031898.7 (6.8)141699.3 (4.1)176899.2 (5.3)18601998.7 (7.3)140899.3 (3.8)175699.4 (3.1)18482098.4 (8.9)139798.9 (5.3)174298.7 (5.8)18382198.5 (7.5)130199.0 (6.1)167698.8 (7.1)17842297.8 (9.7)124698.8 (6.2)164799.2 (5.7)17692398.1 (8.8)118098.2 (8.5)161998.4 (8.0)17552498.8 (7.2)108699.0 (6.3)146898.9 (7.1)16192598.8 (6.7)99699.2 (5.2)143298.8 (7.1)15892697.9 (11.2)84599.1 (5.7)140998.6 (8.8)1578ET=Endocrine therapy * Number of pts who initiated the treatment cycle. Citation Format: Eileen Shinn, David Zahrieh, Angela DeMichele, Nick Zdenkowski, Julie Lemieux, Jun Mao, Vesna Bjelic-Radisic, Michelle Naughton, Georg Pfeiler, Karen Gelmon, Ingrid Mayer, Daniel Egle, Gabriele Zoppoli, Tiffany Traina, Miguel Martin Jiménez, Silvia Antolin Novoa, Tufia Haddad, Arlene Chan, Alistair Edward Ring, Antonio Wolff, Jose JuanPonce Lorenzo, Dhanusha Sabanathan, Hal Burstein, Zbigniew Ireneusz Nowecki, Gunda Pristauz-Telsnigg, Adam Brufsky, Meritxell Bellet-Ezquerra, Theodoros Foukakis, Yelena Novik, Gabor Rubovszky, Karoline Muehlbacher, Otto Metzger, Theodora Goulioti, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Dominik Hlauschek, Christian Fesl, Erica Mayer, Michael Gnant. Adherence with adjuvant endocrine therapy with or without Palbociclib in the PALLAS trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-01.