# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=English - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Creator=Elsevier - Custom.CrossMarkDomains[1]=elsevier.com - Custom.CrossmarkMajorVersionDate=2010-04-23 - Custom.CreationDate--Text=27th April 2026 - Custom.ElsevierWebPDFSpecifications=7.0.1 - Custom.robots=noindex - Custom.doi=10.1016/j.breast.2026.104769 - Custom.CrossMarkDomains[2]=sciencedirect.com - Custom.CrossmarkDomainExclusive=true - ModDate=D:20260427112018Z - Author=the PALMARES-2 study group - Title=Real-world effectiveness of CDK4/6 inhibitors in older patients with HR+/HER2- advanced breast cancer: a sub-analysis of the multicenter, PALMARES-2 study - Keywords=HR+/HER2-advanced breast cancer,CDK4/6 inhibitors,Older patients,Real-world PFS,Palbociclib - CreationDate=D:20260421210709Z - Producer=Acrobat Distiller 8.1.0 (Windows) - Subject=The Breast, 87 (2026) 104769. doi:10.1016/j.breast.2026.104769 - ali:license_ref=http://creativecommons.org/licenses/by-nc/4.0/ - crossmark:crossmarkdomains=elsevier.comsciencedirect.com - crossmark:crossmarkdomainexclusive=true - crossmark:doi=10.1016/j.breast.2026.104769 - crossmark:majorversiondate=2010-04-23 - dc:format=application/pdf - dc:identifier=10.1016/j.breast.2026.104769 - dc:publisher=Elsevier Ltd - dc:description=The Breast, 87 (2026) 104769. doi:10.1016/j.breast.2026.104769 - dc:subject=HR+/HER2-advanced breast cancer,CDK4/6 inhibitors,Older patients,Real-world PFS,Palbociclib - dc:title=Real-world effectiveness of CDK4/6 inhibitors in older patients with HR+/HER2- advanced breast cancer: a sub-analysis of the multicenter, PALMARES-2 study - dc:creator=the PALMARES-2 study group,Francesca Ligorio,Leonardo Provenzano,Giuseppe Fotia,Maria Vittori Dieci,Giuseppe Curigliano,Mario Giuliano,Andrea Botticelli,Matteo Lambertini,Gianpiero Rizzo,Rebecca Pedersini,Marianna Sirico,Nicla La Verde,Alessandra Gennari,Alberto Zambelli,Angela Toss,Marta Piras,Monica Giordano,Barbara Tagliaferri,Daniele Generali,Donata Sartori,Giacomo Mazzoli,Flavia Jacobs,Giovanna Armani,Caterina Sposetti,Christian Zurlo,Alice Menichetti,Gaia Griguolo,Valeria Faso,Laura Boldrini,Elisabetta Munzone,Antonio Marra,Edoardo Chiappe,Simone Scagnoli,Simona Pisegna,Camilla Capasso,Carmine De Angelis,Grazia Arpino,Carmen Criscitiello,Valentina Guarneri,Giancarlo Pruneri,Luigi Mariani,Gianpaolo Bianchini,Daniela Miliziano,Matteo De Monte,Chiara Corti,Pier Paolo Berton Giachetti,Ambra Carnevale Schianca,Jalissa Katrini,Maria Silvia Cona,Vincenza Cantile,Angela Grieco,Miriam Pirolo,Maria Zappulo,Maria Anna Rachele De Giglio,Marta Laganà,Deborah Cosentini,Ugo De Giorgi,Andrea Vingiani,Antonino Belfiore,Alice Abate,Valentina Bianchessi,Giuseppe Capri,Giulia Valeria Bianchi,Filippo de Braud,Paolo Baili,Ilaria Cavallo,Cristina Ferraris,Gabriele Martelli,Secondo Folli,Gianfranco Scaperrotta,Catherine Depretto,Angioletta Lasagna,Ornella Ponzoni,Stefano Maccarone,Carla Strina,Silvia Coccato,Rosalinda Coviello,Claudio Vernieri - jav:journal_article_version=VoR - pdf:creationdate--text=27th April 2026 - pdf:producer=Acrobat Distiller 8.1.0 (Windows) - pdf:keywords=HR+/HER2-advanced breast cancer,CDK4/6 inhibitors,Older patients,Real-world PFS,Palbociclib - pdfx:creationdate--text=27th April 2026 - pdfx:crossmarkdomains=sciencedirect.comelsevier.com - pdfx:crossmarkdomainexclusive=true - pdfx:crossmarkmajorversiondate=2010-04-23 - pdfx:elsevierwebpdfspecifications=7.0.1 - pdfx:doi=10.1016/j.breast.2026.104769 - pdfx:robots=noindex - prism:aggregationtype=journal - prism:coverdate=2026-06-01 - prism:coverdisplaydate=1 June 2026 - prism:doi=10.1016/j.breast.2026.104769 - prism:issn=0960-9776 - prism:pagerange=104769 - prism:publicationname=The Breast - prism:startingpage=104769 - prism:url=https://doi.org/10.1016/j.breast.2026.104769 - prism:volume=87 - tdm:policy=https://www.elsevier.com/tdm/tdmrep-policy.json - tdm:reservation=1 - xmp:createdate=2026-04-21T21:07:09 - xmp:creatortool=Elsevier - xmp:metadatadate=2026-04-27T11:20:18 - xmp:modifydate=2026-04-27T11:20:18 - xmpmm:documentid=uuid:1b499bed-4ce8-4c0c-b682-0d58baae1cbe - xmpmm:instanceid=uuid:b6ed5266-03cb-4855-90c0-636283357f42 - xmprights:marked=True ## Contents ### Page 1 # Real-world effectiveness of CDK4/6 inhibitors in older patients with HR+/ HER2- advanced breast cancer: a sub-analysis of the multicenter, PALMARES-2 study Francesca Ligorio,,, Leonardo Provenzano,,, Giuseppe Fotia,,, Maria Vittori Dieci, ![orcid]() , Giuseppe Curigliano,, Mario Giuliano, Andrea Botticelli, Matteo Lambertini, ![orcid]() , Gianpiero Rizzo, Rebecca Pedersini, Marianna Sirico ![orcid]() , Nicla La Verde, Alessandra Gennari,, Alberto Zambelli, ![orcid]() , Angela Toss,, Marta Piras, Monica Giordano, Barbara Tagliaferri ![orcid]() , Daniele Generali, ![orcid]() , Donata Sartori ![orcid]() , Giacomo Mazzoli,, Flavia Jacobs ![orcid]() , Giovanna Armani, Caterina Sposetti, ![orcid]() , Christian Zurlo, ![orcid]() , Alice Menichetti, Gaia Griguolo, ![orcid]() , Valeria Faso,, Laura Boldrini, ![orcid]() , Elisabetta Munzone, Antonio Marra ![orcid]() , Edoardo Chiappe,, Simone Scagnoli ![orcid]() , Simona Pisegna,, Camilla Capasso, Carmine De Angelis, Grazia Arpino ![orcid]() , Carmen Criscitiello ![orcid]() , Valentina Guarneri,, Giancarlo Pruneri,, Luigi Mariani, the PALMARES-2 study group, Claudio Vernieri,, * Corresponding author. Fondazione IRCCS Istituto Nazionale dei Tumori dei Milano, via Venezian 1, 20133, Milano, Italy.E-mail addresses: claudio.vernieri@istitutotumori.mi.it, claudio.vernieri@unimi.it (C. Vernieri). ### Page 2 ## A R T I C L E I N F O ### Keywords: HR+/HER2-advanced breast cancer CDK4/6 inhibitors Older patients Real-world PFS Palbociclib ## A B S T R A C T ### Background: Older patients with Hormone Receptor–positive, HER2-negative advanced breast cancer (HR+/ HER2 aBC) are often frailer than younger patients. Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) is the standard first-line treatment regardless of age; however, CDK4/6i real-world effectiveness in older patients is unknown. ### Patients and methods: PALMARES-2 (NCT06805812) is a large real-world study investigating first-line ET plus CDK4/6i effectiveness in HR+/HER2 aBC patients. We compared real-world progression-free survival (rwPFS) between older (>75 years) and younger (≤75 years) patients in the whole study cohort, as well as in palbociclib, ribociclib, or abemaciclib sub-cohorts. Cox regression models and inverse probability of treatment weighting (IPTW) were used to adjust for prognostic covariates. ### Results: Older patients accounted for 302 (15.2%) of the PALMARES-2 study cohort (n = 1982). Compared with younger patients, older patients were less likely to have ECOG PS 0 or bone-only disease, and more likely to receive palbociclib. At multivariable analysis, older patients had better rwPFS when compared to younger pa-tients (aHR 0.77; 95% CI 0.67–0.90, p = 0.001). In younger patients, ribociclib and abemaciclib were more effective than palbociclib, whereas in older patients palbociclib showed similar effectiveness to abemaciclib and superior effectiveness to ribociclib (p for interaction <0.001). Among patients treated with palbociclib, older patients had improved rwPFS compared with younger patients (aHR 0.69; 95% CI 0.57–0.84, p < 0.001). ### Conclusion: First-line ET plus CDK4/6i is highly effective in older patients with HR+/HER2 aBC. Based on effectiveness and clinical manageability, palbociclib represents a particularly suitable option in this population. ## 1. Introduction The prevalence of advanced breast cancer (aBC), and in particular of Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative Breast Cancer (HR+/HER2- BC), is raising among older women []. Approximately 20% of breast cancer diagnoses occur in women aged 70 years or older at the time of diagnosis []. Moreover, demographic projections based on global cancer estimates indicate that breast cancer burden is expected to rise substantially by 2040, with the number of new cases projected to increase by over 40%, and aging of the global population is a major driver of this trend, underscoring the increasing public health impact of breast cancer in older women []. Importantly, the lack of consensus on the definition of older patients, together with their underrepresentation in clinical trials, results in relative paucity of information on the efficacy of available cancer treatments in this population. []. In the last decade, palbociclib, ribociclib and abemaciclib in com-bination with ET have become the standard-of-care, first-line therapy for the vast majority of patients with HR+/HER2-aBC regardless of their age and other clinically relevant variables, such as tumor endocrine sensitivity/resistance, burden of disease, metastatic sites. []. Indeed, ET plus CDK4/6i combinations are overall safe treatments that significantly improved patient PFS and, in the case of ribociclib and abemaciclib, also OS when compared to ET alone []. In RCTs, the addition of each of the three CDK4/6i to ET improved clinical outcomes also in older patients []. Since older patients are characterized by more comorbidities and a more common use of concomitant medications, balancing the impact of treatments on quality of life with their efficacy and survival prolonga-tion is a clinically relevant issue. This is especially important for a class of drugs, such as CDK4/6i, which are meant to be administered for years to patients with metastatic disease [,,,]. Due to the lack of head-to-head efficacy comparisons of palbociclib, ribociclib and abemaciclib, real world studies represent an excellent opportunity to investigate the performance of each of these drugs in whole cohort of patients with HR+/HER2-aBC [], as well as in specific clinical subgroups. In the context of the multicenter, real-world PALMARES-2 study, we recently showed that abemaciclib and ribociclib are associated with better real-world Progression-free Survival (rwPFS) when compared to palbociclib in a large Italian cohort of HR+/HER2-aBC patients treated with first-line ET plus CDK4/6i []. Here, we compared the real-world effectiveness of all CDK4/6i, or of each of them (palbociclib, ribociclib or abemaciclib), in older (>75 years) versus (vs.) younger (≤75 years) patients with HR+/HER2-aBC enrolled in the PALMARES-2 study. ## 2. Patients and methods ### 2.1. Study design and patients PALMARES-2 (NCT06805812) is a retrospective/prospective, multicenter, real-world observational study aimed at investigating the effectiveness of first-line ET plus CDK4/6i in consecutive patients with HR+/HER2- aBC [,]. Patient enrolment included both retrospec-tive and prospective cases, whereas all clinical, pathological and treatment-related variables (See Data Collection in Supplementary methods) were collected retrospectively from electronic medical re-cords. This analysis was performed at the first PALMARES-2 data cut-off (Jan 31st 2024), when 1982 aBC patients were enrolled from 18 Italian Institutions. A globally shared definition of older patients does not exist []. In the present study we used 75 years as the threshold to define older (>75 years) and younger (≤75 years) patients [,]. We selected this age cut-off to identify a subgroup of patients more likely to represent a clinically frail population with a higher burden of comorbidities, greater use of concomitant medications, and an increased risk of drug–drug interactions, all factors that may significantly influence treatment tolerability and clinical outcomes. Moreover, patients in this age group are underrepresented in randomized clinical trials, limiting the gener-alizability of trial-based evidence to this population []. ### 2.2. Study objectives The primary objective of the study was to compare rwPFS in older2 PALMARES-2 study group listed at the end of the Acknowledgements. ### Page 3 (>75 years) vs. younger (≤75 years) patients with HR+/HER2-aBC treated with first-line ET plus CDK4/6i. In detail, we compared rwPFS in older vs. younger patients treated with any CDK4/6i or, specifically, with palbociclib, ribociclib or abemaciclib. rwPFS was defined as the time between ET plus CDK4/6i initiation and disease progression, as defined by radiological, clinical and/or biochemical parameters according to the treating physician judgment, or patient death for any reason, whichever occurred first. Patients not undergoing a rwPFS event at the data cut-off were censored at the last follow-up date. Secondary study objectives were. - 1) to compare overall survival (OS), defined as the time between initiation of CDK4/6i therapy and patient death from any cause, in older vs. younger patients. Patients alive at last follow-up date were censored; - 2) to compare rwPFS associated with the three CDK4/6 inhibitors in older vs. younger patients; - 3) to compare rwPFS between older and younger patients within each CDK4/6 inhibitor subgroup. Additional exploratory analyses included: rwPFS comparison be-tween older and younger patients in the cohorts of patients with endocrine-sensitive or endocrine-resistant disease; analysis of the fre-quency of dose reductions/treatment discontinuations according to age; number and type of subsequent lines of therapy in the two age cohorts; analysis of breast cancer-specific survival (BCSS), as defined as the time between treatment initiation and patient death attributable to breast cancer; patients alive at last follow-up, or who died from causes unre-lated to breast cancer, were censored at the date of last contact or at the date of non–breast cancer death, respectively. ### 2.3. Statistical analyses Categorical variables were summarized as proportions, and their distribution in older vs. younger patients was compared using the χ2 test. Continuous variables were summarized as medians and inter-quartile ranges (IQRs), and Wilcoxon rank sum test was used for sta-tistical comparisons. Median patient follow-up was computed through the reverse Kaplan-Meier method []. Survival curves were repre-sented using the Kaplan-Meier method, and the log-rank test was used to compare survival distributions of different groups. Multivariable Cox proportional-hazards regression models were used to investigate differences in individual clinical outcomes between groups after adjustment for the following clinically relevant variables: Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0, 1, ≥2); tumor histology (ductal, lobular, other); ER, PgR, and Ki-67 expression (as continuous variables); HER2 expression (0 vs. low); diagnosis of de novo aBC; presence of liver metastases, lung metastases or bone metastases; endocrine resistance []. Adjusted Hazard ratios (aHRs) and relative 95% CIs were provided. Adjusted survival curves were estimated and plotted []. To account for the random effects related to the multicenter nature of the study, we used the clusterfunction from the survival package in R. Centers were clustered ac-cording to the number of enrolled patients (high-vs. intermediate-vs. low-volume centers) []. To confirm the results of multivariable Cox regression models, we also used the Inverse Probability of Treatment Weighting (IPTW) [,] method to balance clinically-relevant characteristics before comparing survival outcomes. Once the weighted pseudo-population of patients was obtained, IPTW-adjusted Kaplan Meier curves were plotted to compare rwPFS among groups. Covariates whose values were missing in less than 5% of patients were imputed by using median or mode values (for numerical or cate-gorical variables, respectively), while covariates with missing values exceeding 5% were excluded from the analysis []. All statistical tests were two-sided, with a p-value (p) < 0.05 considered statistically sig-nificant. All statistical analyses were performed using R and R Studio (version 4.3.1) software, with the following packages: readr, readxl, tibble, dplyr, tidyr, lubridate, stringr, data.table, gtsummary, survival, surv-miner, ggplot2, adjustedCurves, forestploter, ipw. ## 3. Results ### 3.1. Patient characteristics Among 1982 patients enrolled in the PALMARES-2 study at the first data cut-off, older patients accounted for 15.2% (n = 302) of the whole study cohort (). When compared to younger pa-tients, older patients were less likely to have an ECOG PS of 0 (56% vs. 79%, p < 0.001) or bone-only disease (17% vs. 25%, p = 0.002), while they were more likely to have tumors of lobular histology (25% vs. 17%, p = 0.002), lung metastases (36% vs. 25%, p < 0.001), de novo advanced disease at diagnosis (35% vs. 28%, p = 0.025) and to have received palbociclib (57% vs. 37%, p < 0.001) (). With the only exception of de novo aBC, all variables more frequently reported in older vs. younger patients were previously found to be associated with worse clinical outcomes in the whole PALMARES-2 study cohort [,]. Other covariates, such as ER, PgR, Ki67 and HER2 expression in tumor cells, or tumor endocrine sensitivity/resistance, were similarly distrib-uted in the older and younger cohorts (). Older patients were characterized by a higher number of comor-bidities when compared to younger patients and, more importantly, also when compared to patients aged 65-75 years (), thus confirming that this patient subgroup represents a clinically distinct and frailer population. A description of concomitant medications ac-cording to age group is reported in; older patients exhibited a significantly higher concomitant medication burden. Among patients treated with palbociclib, the most commonly prescribed CDK4/ 6i in the older population, older patients were less likely to have an ECOG PS of 0 (53% vs. 76%, p < 0.001), bone-only metastases (19% vs. 27%, p = 0.029) or endocrine-resistant disease (29% vs. 42%, p = 0.002) when compared to younger patients, while they were more likely to have de novo aBC (40% vs. 23%, p < 0.001) or lung metastases (34% vs. 24%, p = 0.009). ### 3.2. Real-world progression-free survival in older vs. younger patients At a median follow up of 26.5 months (95% CI 24.8 - 29) and 32.8 months (95% CI 30.6 – 34.4) in older vs. younger patients, respectively, median rwPFS was 34.9 months (95% CI 29.5–52.8) in older patients and 33.8 months (95% CI 30.4–36.4) in younger patients. After adjust-ment for clinically-relevant covariates, multivariable Cox regression model revealed that older patients had significantly better rwPFS than younger patients (adjusted Hazard Ratio [aHR]: 0.77; 95% CI: 0.67 –0.90, p = 0.001) (A and B). Older patients had more commonly undergone CDK4/6i dose reduction during the course of the treatment (63% vs. 48%, p < 0.001) and treatment discontinuation prior to disease progression (8.3% vs. 4.3%, p = 0.004) (). In older patients, the rates of dose reductions and treatment discontinuations due to treatment toxicity were similar across treatment groups (). rwPFS was better in older vs. younger patients also in the subsets of patients with endocrine-sensitive (aHR 0.76; 95% CI: 0.61-0.94, p =0.013) or endocrine-resistant (aHR 0.80; 95% CI: 0.79-0.81 p < 0.001) disease (). ### 3.3. Overall survival in older vs. younger patients With 73 (24.2%) and 391 (23.3%) OS events in older vs. younger patients, respectively, median OS was 61.1 (95% CI 48.2-NR) and 66.6 (95% CI 62.2-NA) months in older and younger patients, respectively (p ### Page 4 = 0.011). After adjusting for relevant covariates, older patients had significantly worse OS when compared to younger patients (aHR 1.18; 95% CI 1.11 1.26, p < 0.001) (). Causes of death were evaluated in the overall cohort and according to age group. Deaths were classified as breast cancer–related, due to treatment-related toxicity, or from other causes. A trend towards a higher proportion of deaths due to treatment-related toxicity (2.7% vs. 0.5%) and other non–breast cancer causes (14% vs. 9.7%) was observed in older as compared with younger patients (p = 0.052). To further explore whether differences in OS were driven by competing causes of death in the older population, an exploratory analysis of BCSS was performed. Unadjusted and adjusted Kaplan–Meier BCSS curves are shown in. Although median BCSS was not reached in either group due to immature data, BCSS appeared to be worse in older patients. To explain the discrepancy between rwPFS and OS/BCSS in older vs. younger patients, we exam-ined subsequent systemic treatments. Older patients received a lower number of subsequent lines of systemic therapy (both endocrine-based and non-endocrine therapies, including chemotherapy and ADCs) after disease progression to first-line ET plus CDK4/6i when compared to younger patients (). ### 3.4. Effectiveness comparisons of individual CDK4/6i in older and younger patient cohorts Among older patients, the use of palbociclib was associated with similar rwPFS when compared to abemaciclib, and with better rwPFS when compared to ribociclib (). Conversely, ribociclib and abemaciclib were associated with better rwPFS when compared to palbociclib in younger patients (). For this reason, we studied whether patient age interacts with the type of CDK4/6i molecule in affecting clinical outcome. For this anal-ysis, we grouped patients treated with ribociclib and abemaciclib in the same cohort because ribociclib and abemaciclib were previously shown to be associated with similar clinical outcomes in the whole PALMARES- 2 study cohort [], and because we observed that they are similarly effective in the subsets of older or younger patients (). We found a significant interaction between the type of CDK4/6i and patient age in affecting rwPFS (p for interaction <0.001), with riboci-clib/abemaciclib being significantly more effective than palbociclib in younger patients (aHR 0.77, 95% CI: 0.67-0.89, p < 0.001) (A and B;). On the other hand, ribociclib/abema-ciclib and palbociclib were similarly effective in older patients at both univariate and multivariable analysis (aHR 0.99; 95% CI: 0.92-1.06, p =0.73) (A and B;). ### 3.5. Impact of patient age on palbociclib effectiveness Given the observed interaction between the type of CDK4/6i and age in affecting rwPFS, and since palbociclib was the most commonly pre-scribed CDK4/6i in older patients (), we conducted a sub-analysis to investigate whether palbociclib shows different real-world effective-ness in older vs. younger patients. Among 789 patients treated with palbociclib (n = 616 younger; n =173 older), older patients had significantly better rwPFS than younger patients at both univariate (median rwPFS: 38.9 vs. 26.6 months, respectively; HR = 0.69, p = 0.006) () and multivariable (aHR = 0.69; 95% CI: 0.57-0.84; p < 0.001) (A,) analysis. After IPTW-based covariate balancing in older and younger patients (), in the palbociclib cohort older patients had better rwPFS when compared to younger ones (median rwPFS 35.9 months, 95% CI 29.5 - 55.1 vs. 26.8 months, 95% CI 23.7 - 30.6, respectively; p = 0.006) (B). On the other hand, OS was not different in older vs. younger patients receiving palbociclib (aHR 1.01, 95% CI 0.81-1.25, p = 0.97). In contrast with what observed in patients treated with palbociclib, we did not find statistically significant rwPFS differences between older and younger patients treated with abemaciclib (aHR 0.85; 95% CI: 0.59-1.22, p = 0.37) or ribociclib (aHR 0.93; 95% CI: 0.76-1.13, p = 0.45). ## 4. Discussion In this large real-world study, we showed that palbociclib, ribociclib and abemaciclib in combination with first-line ET are highly effective in HR+/HER2-aBC patients who are older than 75 years. We also found an interaction between age and the type of CDK4/6i, with ribociclib/abe-maciclib being more effective than palbociclib in younger patients. On the other hand, palbociclib is similarly effective as abemaciclib, and more effective than ribociclib, in older patients. Finally, subgroup ana-lyses in each CDK4/6i category showed that palbociclib is the only ### Page 5 CDK4/6i associated with significantly better rwPFS in older vs. younger patients. In age-stratified subgroup analyses performed in the context of registration trials [,], older patients were defined on the basis on an age cut-off of 65 years, a threshold that does not necessarily identify a group of patients characterized by higher frailty. In the present analysis, we defined the older population using a threshold of 75 years to identify a patient cohort characterized by more comorbidities (), higher number of concomitant therapies (), and reduced physiological reserve, all factors that may affect treat-ment tolerability and clinical decision-making [,,]. We found that first-line ET plus CDK4/6i therapy is associated with significantly better rwPFS in older patients than in younger patients; conversely, older patients had worse OS, which likely reflects a higher number of potentially life-threatening comorbidities and a lower like-lihood of receiving subsequent lines of therapy (especially ### Page 6 chemotherapy or ADCs) after tumor progression on CDK4/6i-based therapy, likely because of overall higher frailty and more expected toxicities from these drugs. The analysis of causes of death revealed a higher proportion of non–breast cancer–related deaths, including treatment-related toxicity, among older patients. However, results of exploratory BCSS analyses suggest that differences in OS cannot be explained solely by competing causes of death. Instead, factors such as higher attrition rates and reduced exposure to subsequent lines of therapy after progression to first-line ET + CDK/6i may in part explain survival outcomes in older patients. The observation that older patients had worse OS and BCSS despite having better rwPFS reinforces the conclusion that older age is not a good prognostic factor per se, but it specifically predicts better patient outcomes during first-line ET plus CDK4/6i. Although our study was not designed to investigate biological mechanisms, the observation that patients older than 75 years experi-enced better rwPFS suggests that this subgroup may be characterized by specific tumor biological features or age-related factors: 1) HR+/HER2- aBC arising in older patients may have specific biological characteristics that make them more sensitive to ET plus CDK4/6i, but that are not captured by canonical biological variables, such as ER, PgR, Ki-67 and HER2 expression. For instance, these tumors may more strongly rely on the activation of the ER pathway, and they could be consequently more sensitive to the combined inhibition of the ER and CDK4/6i axes; 2) HR+/HER2- BCs arising in older patients have been reported to have less frequent TP53 gene mutations or basal-like biology, which are both associated with worse prognosis during ET plus/minus CDK4/6i treat-ment; [,] 3) systemic hormonal status is different in older vs. younger patients, with older patients having lower blood oestrogen concentration [], thus potentially resulting in higher sensitivity to ET plus CDK4/6i; 4) older patients may metabolize CDK4/6i less efficiently, thus potentially resulting in higher blood concentrations and higher effectiveness of these drugs []. Together, results of this study indicate that CDK4/6i in combination with ET are by far the most effective treatment that older patients with HR+/HER2- BC can receive during the course of their disease, as more than half of their expected median survival (median OS: 61.1 months) is spent while receiving ET plus CDK4/6i (median rwPFS: 34.9 months) treatment. For this reason, our findings strongly support the use of ET plus CDK4/6i in HR+/HER2-aBC patients older than 75 years, con-firming that CDK4/6i are the preferred treatment option also in this cohort of patients with higher frailty and more comorbidities []. The issue related to ET and CDK4/6i sequences has recently been addressed in prospective studies, such as the SONIA trial []. This is a highly relevant topic, particularly given concerns regarding treatment toxicities and their impact on quality of life, drug-drug interactions, factors which may be especially meaningful in older adults, and the increasing attention to economic sustainability. While the SONIA trial showed that first-line ET followed by second-line ET + CDK4/6i, or first-line ET + CDK4/6i followed by second-line ET are associated with similar long-term clinical outcomes, it also has important limitations. Most notably, the substantial attrition between first- and second-line therapy in older patients, as also evident in our real-world cohort, may prevent many of these patients from receiving CDK4/6 inhibitors if their use is deferred. Overall, results from our large real-world cohort showed that older patients achieve clinically meaningful outcomes when treated with ET plus CDK4/6i combination. Subgroup analyses of this study showed that palbociclib, but not ribociclib or abemaciclib, is associated with significantly better rwPFS in older than in younger patients. These results can be due to a specific sensitivity of HR+/HER2-tumors arising in older patients to palbociclib plus CDK4/6i, or to differences in the metabolism of the three CDK4/6i on the basis of patient age [,,]. Differences in dose intensity and safety management across CDK4/6 inhibitors could have played a role in terms of treatment outcomes in older patients. In our cohort, the frequency of dose reductions among older patients was comparable across palbociclib, ribociclib, and abemaciclib cohorts (), although limited sample size may preclude the detection of subtle drug-specific differences. Alternatively, the differential effectiveness of palbociclib, ribociclib and abemaciclib in older vs. younger patients could result from longer follow-up in the palbociclib cohort, thus making clinical outcomes in this subgroup more reliable and mature. Longer follow-up of the PALMARES-2 and other ongoing real-world studies will be important to test these hypotheses. The findings of our study are clinically relevant for several reasons: 1) patients who are older than 75 years are more commonly frail, have more comorbidities and are more susceptible to undergo toxicities while receiving cancer treatments [,]; 2) older patients are exposed to higher risk of drug-drug interactions, which may modify the pharma-cokinetics and tolerability profile of therapies []. Therefore, it is especially important to balance treatment tolerability, toxicities and efficacy to choose the most appropriate systemic therapy in older pa-tients with HR+/HER2-aBC. Our finding that palbociclib, the safest and most manageable among available CDK4/6i, and also a CDK4/6i asso-ciated with a low risk of causing drug-drug interactions, is at least as effective as the other CDK4/6i, supports the conclusion that palbociclib can be recommended to the majority of HR+/HER2-aBC patients who are older than 75 years []. The present study has several limitations: a) its observational nature; b) an imbalance of numerosity and clinically relevant features in pa-tients treated with palbociclib or other CDK4/6i; c) longer follow-up for patients treated with palbociclib when compared to patients treated with ribociclib or abemaciclib; d) the lack of formal geriatric assessment tools (e.g., ADL, IADL, G8) to comprehensively capture frailty beyond chronological age. Although comorbidity burden and concomitant medications were available, these variables cannot replace validated geriatric scales; e) a relatively shorter follow-up in patients aged >75 years, which may partially limit the maturity of outcome estimates in this subgroup. In conclusion, palbociclib, ribociclib and abemaciclib are highly effective in older patients with HR+/HER2-aBC. Based on excellent effectiveness of palbociclib in older patients, as well as on its higher manageability and tolerability when compared to other CDK4/6i, pal-bociclib in combination with ET can be considered the preferable treatment option for the majority of patients older than 75 years. ## CRediT author statement Claudio Vernieri: conceptualization, writing. - All authors (Daniela Miliziano, Matteo De Monte, Chiara Corti, Pier Paolo Berton Giachetti, Ambra Carnevale Schianca, Jalissa Katrini, Maria Silvia Cona, Vincenza Cantile, Angela Grieco, Miriam Pirolo, Maria Zappulo, Maria Anna Rachele De Giglio, Marta Lagan`a, Deborah Cosentini, Ugo De Giorgi, Andrea Vingiani, Antonino Belfiore, Alice Abate, Valentina Bianchessi, Giuseppe Capri, Giulia Valeria Bianchi, Filippo de Braud, Paolo Bai, Ilaria Cavallo, Cristina Ferraris, Gabriele Martelli, Secondo Folli, Gian-franco Scaperrotta, Catherine Depretto, Angioletta Lasagna, Ornella Ponzoni, Stefano Maccarone, Carla Strina, Silvia Coccato, and Rosalinda Coviello): provision of study material or patients, collection and as-sembly of data, final approval of the manuscript. ## Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki, and it was approved by the Institutional Review Board and Ethics Committee of the “Fondazione IRCCS Istituto Nazionale dei Tumori of Milan” (INT 101/23). Patients alive at the time of data collection and/or analysis signed a specific informed consent form for the use of their personal data for research purposes. The Ethics Com-mittee authorized the collection and analysis of data from patients who ### Page 7 were not alive when the study was conducted and who already autho-rized the use of data collected as per clinical practice for research purposes. ## Consent for publication Not applicable. ## Availability of data and materials The datasets generated and/or analysed during the current study are available from the corresponding author upon a reasonable request. ## Funding This research was in part supported by the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori; and by Italian Health Ministry (funds of Ricerca Corrente [D/22/01D to C.V.]). ## *PALMARES-2 study group Gianpaolo Bianchini35, Daniela Miliziano1,3, Matteo De Monte1,3, Chiara Corti3,27, Pier Paolo Berton Giachetti3,6, Ambra Carnevale Schianca3,6, Jalissa Katrini3,6, Maria Silvia Cona14, Vincenza Cantile7, Angela Grieco7, Miriam Pirolo7, Maria Zappulo7, Maria Anna Rachele De Giglio7, Marta Lagan`a12, Deborah Cosentini12, Ugo De Giorgi36,37, Andrea Vingiani3,32, Antonino Belfiore32, Alice Abate1, Valentina Bianchessi1, Giuseppe Capri1, Giulia Valeria Bianchi1, Filippo de Braud1,3, Paolo Baili38, Ilaria Cavallo38, Cristina Ferraris39, Gabriele Martelli39, Secondo Folli39, Gianfranco Scaperrotta40, Catherine Dep-retto40, Angioletta Lasagna11, Ornella Ponzoni19, Stefano Maccarone23, Carla Strina24, Silvia Coccato26, Rosalinda Coviello22. 35 Faculty of Medicine and Surgery, Universit`a Vita-Salute San Raffaele, Via Olgettina, 58, 20132, Milan, Italy; 1Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1 20133, Milan, Italy; 3 Department of Oncology and Hematology-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy; 27 Department of Medical Oncology, Dana- Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, US; 6 Division of Early Drug Development for Innovative Therapy, IRCCS European Institute of Oncology, Via Ripamonti 435 20141, Milan, Italy; 14 Department of Oncology, Polo Ospedaliero Luigi Sacco, ASST Fatebenefratelli Sacco, Via Giovanni Battista Grassi, 74, 20157, Milan, Italy; 7 Department of Clinical Medicine and Surgery, Universit`a degli Studi di Napoli Federico II, C.so Umberto I, 40, 80138, Naples, Italy; 12 Medical Oncology Department, ASST Spedali Civili of Brescia, Piazzale Spedali Civili, 1 25123, Brescia, Italy; 36 Department of Experimental Medicine, University of Salento, Piazza Tancredi, 7, 73100, Lecce, Italy; 37 Clinical and Experimental Oncology Unit,“Vito Fazzi” Hospital, Piazza Filippo Muratore, 1, 73100, Lecce, Italy; 32 Breast Oncology Unit, Humanitas Research Hospital, Via Manzoni, 56, 20089 Rozzano (MI), Italy; 38 Analytical Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy; 39 Breast Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy; 40 Breast Radiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy; 11 Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi, 19, 27100, Pavia, Italy; 19Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo, 71, 41125, Modena,Italy; 23 Medical Oncology Unit, ICS Maugeri IRCCS, Via Sal-vatore Maugeri, 10, 27100, Pavia, Italy; 24 Breast Cancer Unit, Azienda Socio Sanitaria Ter-ritoriale di Cremona, Viale Concordia, 1, 26100, Cremona, Italy; 26 Oncology Unit, AULSS3 Veneziana, Via Luigi Mariutto, 76, 30035, Mirano, Italy; 22 SC Oncologia, ASST-Lariana, Via Napoleona, 60, 22100, Como, Italy. ## Declaration of competing interest F.L.: personal fee as invited speaker: Novartis, Pfizer, Eli-Lilly, Accademia di Medicina. Advisory Board: Novartis. L.P. personal fee as invited speaker MSD, Pfizer and Novartis. M.V.D.: personal fees for consultancy/advisory role from: Eli Lilly, Pfizer, Novartis, Seagen, Gilead, MSD, Exact Sciences, AstraZeneca, Daiichi Sankyo, Roche. G.C.: consulting fees from Roche, Novartis, Lilly, Pfizer, Astra Zeneca, Daichii Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, BMS, Gilead, Sanofi, Menarini; Payment or honoraria for lec-tures, presentations, speakers bureaus, manuscript writing or educa-tional events by Lilly, Pfizer, Relay, Gilead, Novartis and support for attending meetings and/or travel from Daichii Sankyo. M.G.: consulting/advisory role for Roche, AstraZeneca, Lilly, Daichii Sankyo, Novartis, Pfizer, Seagen, MSD, Eisai; honoraria from Novartis, Pfizer, Lilly, AstraZeneca, Daichii Sankyo; travel, accommodation, ex-penses from Lilly, Pfizer, AstraZeneca. M.L.: reported having an advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Pierre Fabre, Menarini and Exact Sciences; receiving speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Knight, Ipsen, Menarini and AstraZeneca; receiving travel grants from Gilead, Roche, and Daii-chi Sankyo; receiving research funding (to his institution) from Gilead; and having nonfinancial interests as the chair of the European Society for Medical Oncology (ESMO) Young Oncologists Committee (YOC) and as a member of the national council of the Italian Association of Medical Oncology. N.L.V.: grant from Eisai; speaker bureau from GSK; travel expenses for conference from Gentili, Celgene, and Pfizer; advisory role from Novartis and Celgene; advisory role, travel expenses for conference from Pfizer; advisory board from MSD, Roche, Novartis, Astrazeneca, and Daiichi Sanyo. A.G.: Research grants from Pharmanutra, AAA; advisory boards, activities as a speaker, travel grants, consultancy from Roche, Novartis, Pfizer, Eli Lilly, Daiichi Sankyo, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Stemline. A.Z.: honoraria for advisory board and consultancy for Roche, Novartis, Lilly, Pfizer, Seagen, Daiichi Sankyo, Astra Zeneca, Gilead, Merck, Exact Sciences, Gentili, Menarini Stemline. A.T.: advisory role for Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, and MSD; speaker honoraria from Lilly, Novartis, Pfizer; Travel Grants from Gilead, Daiichi Sankyo and Novartis. M.P.: travel support from Pfizer and Novartis. B.T.: speaker honoraria from Novartis, Daiichi Sankyo, Eli Lilly, Pfizer, Seagen. Travel grants from Novartis, Roche, Pfizer, Daiichi Sankyo. D.G.: consulting/Advisor for Roche, Lilly, Novartis, Pfizer, Menarini, Stellantis; honoraria from Novartis, Pfizer, Lilly, AstraZeneca, Roche, Istituto Gentili; travel/accommodation from Novartis, Lilly, Pfizer, Roche. G.G.: invited speaker for Novartis, Eli Lilly, MSD; advisory role for Gilead, Seagen, Menarini. E.M: honoraria for Consulting or Advisory Role:Exact Sciences, MSD Oncology, Daiichi Sankyo, AstraZeneca, Pfizer, Seagen, Ipsen. Travel, Accommodations, Expenses: Roche, Pfizer,Lilly, Novartis, Gilead Sci-ences, AstraZeneca, Pierre Fabre. A.M.: honoraria as a consultant, advisor, or speaker from Roche and Menarini/Stemline; travel and accommodation support from AstraZeneca. C.D.A.: advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Daicii-Sankyo, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, GSK, GILEAD, and Daiichi- Sankyo. Travel Grants from Gilead and research support (to the Insti-tution) from Novartis, Gilead, and Daiichi-Sankyo outside the submitted work. G.A.: honoraria from Roche, Pfizer, AstraZeneca, Novartis, Celgene, Eli Lilly, Amgen, and Eisai. S.P.: Speaker for. Novartis, Eli Lilly, Pfizer, Roche, Gilead, Gentili, Sophos. Advisory Board for: Seagen, Daichii-Astra Zeneca. S.S.: speaker fees from Novartis, Pfizer, Roche, Lilly, BMS, and MSD. C.C.: personal fees for consulting, advisory role, and speakers’ ### Page 8 bureau from Lilly, Roche, Novartis, MSD, Seagen, Daiichi Sankyo, AstraZeneca, Gilead and Pfizer. G.P.: personal fees from Foundation One, Illumina and Lilly. S.S.: speaker fees from Novartis, Pfizer, Roche, Lilly, BMS, and MSD. S.P.: Speaker for. Novartis, Eli Lilly, Pfizer, Roche, Gilead, Gentili, Sophos. Advisory Board for: Seagen, Daichii-Astra Zeneca. V.G.: honoraria from Eli Lilly, Daiichi Sankyo, GSK, Gilead, Novartis, Exact sciences, Roche, Astra Zeneca, Menarini StemLine, Zentiva; advisory role for Eli Lilly, Daiichi Sankyo, Menarini Stemline, Exact Sciences, Gilead, Astra Zeneca, MSD, Novartis, Pierre Fabre, Pfizer- Seagen, Roche; payment for expert testimony from Eli Lilly; patents for HER2DX (Institution); C.V.: role in advisory boards for Pfizer, Novartis, Eli Lilly, Daiichi Sankyo, Astra Zeneca, Menarini Stemline, Roche, Gilead; consultancy activity for Eli Lilly, Pfizer, Gilead, Astra Zeneca Novartis; honoraria as a speaker from Novartis, Eli Lilly, Pfizer, Astra Zeneca, Menarini Stemline, MSD, Istituto Gentili, Daiichi Sankyo; research grants from Roche and Daiichi Sankyo/Astra Zeneca (to the Institution). All remaining authors have declared no conflicts of interest. ## Acknowledgments We thank the “Associazione Italiana per la Ricerca sul Cancro”(AIRC), Fondazione Gianmaria e Sabrina Giuliani, Fondazione IRCCS Istituto Nazionale dei Tumori, the European Union (Horizon 2020), the European Research Council (ERC) and the Italian Health Ministry of health. We thank all collaborators from the Italian study centers taking part to this study. We especially thank all patients who took part in this study and their families. ## List of abbreviations - aHR adjusted Hazard Ratio - CDK4/6i Cyclin-Dependent Kinase 4/6 inhibitors - ECOG PS Eastern Cooperative Oncology Group Performance Status - ET Endocrine Therapy - HR+/HER2-aBC Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer - IPTW Inverse Probability of Treatment Weighting - OS Overall Survival - rwPFS real-world Progression-Free Survival - IQRs interquartile ranges ## Appendix A. 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