Real-world treatment patterns and effectiveness of palbociclib plus an aromatase inhibitor in patients with metastatic breast cancer aged 75 years or older

Background Elderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2− mBC aged ≥ 75 years treated in routine clinical practice in the United States. Methods This retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis). Results A total of 961 patients aged ≥ 75 years with HR+/HER2− mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51–0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59–0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55–0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM. Conclusion This real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2− mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2− mBC.


Introduction
Breast cancer is the leading cancer diagnosis in the United States (US) and commonly affects older adults, with a median age of 63 years at diagnosis (1, 2).Patients aged ≥ 65 years accounted for approximately 45% of new breast cancer diagnoses (65-74 years, 26.5%; ≥ 75 years, 18.9%) and 62% of breast cancer deaths (65-74 years, 24.4%; ≥ 75 years, 38.0%) in the US in recent years (1).Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) disease is the most common breast cancer subtype, and the proportion of patients with the HR +/HER2− subtype increases with age, from 64.8% among patients aged < 50 years to 80.1% among patients aged ≥ 75 years (3).Despite the high incidence of breast and other cancers in the elderly population (1, 4), these patients have been largely underrepresented in clinical trials in oncology, including registrational trials for new cancer therapies (5)(6)(7).For example, an analysis of accrual to breast cancer trials conducted by the Alliance for Clinical Trials in Oncology found that < 20% of trial participants were ≥ 65 years of age and < 10% were ≥ 70 years of age (8).Thus, a greater understanding of treatment benefits and risks is needed for the elderly population of patients with breast cancer.
Clinical trials often have stringent eligibility criteria that can limit the diversity in demographic and clinical characteristics of enrolled patient populations (14)(15)(16).As a result, clinical trial findings can have limited generalizability to real-world clinical practice (14,17).Therefore, real-world evidence is needed to inform the use of therapies in patient populations that are often underrepresented in clinical trials, such as older adults (18,19).Palbociclib REAl-world first-LIne comparaTive effectiveness studY eXtended (P-REALITY X) used the Flatiron Database to compare the effectiveness of 1L palbociclib plus an AI versus an AI alone in patients with HR+/HER2− mBC in routine clinical practice in the US (20).Notably, in the P-REALITY X study, the median age of patients after stabilized inverse probability treatment weighting (sIPTW) was 70 years in both treatment groups, which is 8-9 years older than the median age in the PALOMA-2 trial (20,21).After sIPTW, median OS was significantly prolonged in patients treated with palbociclib plus an AI versus an AI alone (49.1 vs. 43.2months; HR, 0.76 [95% CI, 0.65-0.87];P < 0.0001) (20).Patients treated with palbociclib plus an AI also had significantly prolonged median real-world PFS (rwPFS) after sIPTW than those treated with an AI alone (19.3 vs. 13.9 months; HR, 0.70 [95% CI, 0.62-0.78];P < 0.0001).
Prior real-world studies have examined the comparative effectiveness of 1L palbociclib plus ET versus ET alone in elderly patients with HR+/HER2− mBC (22,23).For example, a recent retrospective analysis of the Flatiron Database found that women aged ≥ 65 years with HR+/HER2− mBC treated with 1L palbociclib plus letrozole had significantly prolonged median rwPFS (22.2 (22,24).
Treating elderly patients with mBC presents many challenges, including frequent comorbidities, increased risk of drug-induced toxicity, and concerns regarding polypharmacy and drug-drug interactions (25,26).Therefore, more robust long-term data from large real-world studies are needed to better understand dosing patterns and clinical outcomes of elderly patients with HR+/HER2− mBC receiving 1L palbociclib plus an AI in routine clinical practice, especially among those aged ≥ 75 years.The analysis presented herein aimed to describe palbociclib dose patterns and compare the effectiveness of 1L palbociclib plus an AI versus an AI alone in the subgroup of patients aged ≥ 75 years in the P-REALITY X study.

Study design and data source
P-REALITY X (NCT05361655) was a retrospective observational cohort study of electronic health records (EHRs) obtained from the Flatiron Health Analytic Database.This longitudinal database contains de-identified patient data from > 280 cancer clinics representing > 3 million actively treated patients with cancer in the US.Detailed methods for the P-REALITY X study have been published previously (20).In the subanalysis of P-REALITY X presented herein, we identified patients aged ≥ 75 years with HR+/HER2− mBC who started palbociclib plus an AI or an AI alone as 1L therapy between February 2015 and March 2020.Patients were evaluated from the start of treatment with palbociclib plus an AI or an AI alone to September 30, 2020 (data cut-off date), death, or last visit, whichever came first.

Outcomes
Outcomes evaluated in this analysis included palbociclib treatment patterns, OS, rwPFS, and time to chemotherapy (TTC).Palbociclib treatment patterns, including the starting dose and dose adjustments, were captured from EHRs during the observation period.OS was defined as the number of months from the start of treatment with palbociclib plus an AI or an AI alone until death.The date of death was determined using a composite of multiple data sources, which were benchmarked against the National Death Index.Patients who did not die were censored at the data cut-off date.rwPFS was defined as the number of months from the start of palbociclib plus an AI or an AI alone to death due to any cause or disease progression, whichever occurred first (20,27).Disease progression was assessed by the treating clinician based on radiology, tissue biopsy, laboratory evidence, or clinical assessment.If patients did not die or experience disease progression, those with ≥ 2 lines of therapy (LoT) were censored at the date of initiation of the next LoT, and those with 1 LoT were censored at their last visit date during the study period.TTC was defined as the number of months from the start of palbociclib plus an AI or an AI alone to chemotherapy, death from any cause, last visit, or end of the study, whichever occurred first.If a patient did not have evidence of subsequent chemotherapy and did not die, the patient was censored at the latest available date or data cut-off date, whichever occurred later.Notably, safety was not assessed in this analysis because safety data were not available in the database for the P-REALITY X study.

Statistical analysis
Descriptive statistics were used to describe patient characteristics and palbociclib treatment patterns.Three methods were used for comparative analyses between treatment groups: (1) an unadjusted analysis that did not control for baseline demographic and clinical characteristics, (2) sIPTW (primary analysis) to balance baseline demographic and clinical characteristics, and (3) 1:1 propensity score matching (PSM) as a sensitivity analysis.Both sIPTW and PSM methodologies used propensity scores, defined as the probability of treatment assignment based on observed baseline demographic and clinical variables (28,29).Propensity scores were computed using a multivariable binomial logistic regression model, which included the following variables: age group, sex, race/ethnicity, practice type, disease stage at initial diagnosis, Eastern Cooperative Oncology Group performance status, bone disease, visceral disease, the interval from initial breast cancer diagnosis to mBC diagnosis, and the number of metastatic sites.Time-to-event endpoints, including OS, rwPFS, and TTC, were summarized using the weighted Kaplan-Meier method and displayed graphically.The weighted Cox proportional hazards model was used to compute HR and corresponding 95% CI for time-to-event endpoints.

Patients
A total of 961 patients aged ≥ 75 years with HR+/HER2− mBC were included in this analysis, of whom 313 (32.6%) received palbociclib plus an AI and 648 (67.4%) received an AI alone as 1L therapy (Table 1).The median age was 80.0 years for both groups and > 90% of patients were treated in the community practice setting.Median follow-up duration before sIPTW or PSM adjustment was 23.7 months and 21.4 months for patients treated with palbociclib plus an AI and an AI alone, respectively.More patients treated with palbociclib plus an AI (n = 133/313; 42.5%) had de novo mBC compared with those treated with an AI alone (n = 219/648; 33.8%) before sIPTW and PSM analysis.Patient characteristics were generally balanced between treatment groups after sIPTW and PSM (Table 1).

Palbociclib starting dose and dose adjustment
Among the 306 patients treated with palbociclib plus an AI who had a documented palbociclib starting dose, 230 (75.2%) patients started palbociclib at 125 mg/day, 53 (17.3%) at 100 mg/day, and 23 (7.5%) at 75 mg/day (Table 2).Patient characteristics by initial palbociclib dose are presented in Supplementary Table S1.There was some variation in patient characteristics across dose cohorts, such as differences in median age and the proportions of patients with visceral or bone-only disease.However, the small sample sizes of patients with a starting dose of 100 or 75 mg/day precluded us from comparative analyses.
In total, 121 of 306 patients (39.5%) with a documented palbociclib starting dose experienced dose adjustments.Of the patients who initiated palbociclib at a dose of 125, 100, and 75 mg/day, 97 (42.2%), 19 (35.8%), and 5 (21.7%) patients experienced dose adjustments, respectively (Figure 1).For patients who received an initial palbociclib dose of 125, 100, and 75 mg/day and experienced any dose adjustment, the median number of days to the first dose adjustment was 72, 59, and 62 days, respectively.

Subsequent treatments
During the follow-up period, 136 of 313 (43.5%) patients in the palbociclib plus an AI group and 361 of 648 (55.7%) patients in the AI alone group received subsequent treatment.Second-line (2L) treatments following 1L palbociclib plus an AI or an AI alone are presented in Table 3.Among patients in the palbociclib plus an AI group receiving any 2L treatment (n = 136), 44.1% received a CDK4/6 inhibitor and 19.1% received chemotherapy as 2L treatment.Among patients in the AI alone group receiving any 2L treatment (n = 361), 39.6% received a CDK4/6 inhibitor and 10.0% received chemotherapy as 2L treatment.

Discussion
Treatment decision-making for elderly patients with HR+/HER2− mBC requires particularly careful consideration of many factors, including comorbidities, possible drug-drug interactions, functional status, and the likelihood of drug-induced toxicities (25,26).Unfortunately, data to inform the clinical management of elderly patients are limited because these patients are generally underrepresented in clinical trials in oncology (5)(6)(7).As a result, real-world data are needed to help evaluate the effectiveness and inform on the use of palbociclib in elderly patients with HR+/HER2− mBC.In this analysis, we evaluated real-world palbociclib treatment patterns and compared the effectiveness of 1L palbociclib plus an AI versus an AI alone in patients aged ≥ 75 years with HR+/HER2− mBC in the P-REALITY X study.We found that approximately 75% of patients aged ≥ 75 years with HR+/HER2− mBC started palbociclib at a dose of 125 mg/day in the real-world setting, and approximately 40% of patients experienced dose adjustment.Compared with an AI alone, 1L palbociclib plus an AI was associated with significantly improved OS, rwPFS, and TTC before and after sIPTW or PSM adjustment.Palbociclib plus an AI is indicated as initial endocrine-based therapy for the treatment of adult patients with HR+/HER2− mBC, irrespective of patient age (10), and these real-world data further support the use of this regimen as a standard 1L treatment option for the elderly population.
The PFS data from this real-world analysis are generally consistent with the results from other clinical trials and realworld studies that compared 1L palbociclib plus AI versus AI alone in elderly patients with HR+/HER2− mBC (12,23,27,30).In the subgroup of patients aged ≥ 65 years in the PALOMA-2 study (n = 262), PFS was significantly prolonged in patients receiving 1L palbociclib plus letrozole versus placebo plus letrozole, at a median of 30.6 months versus 19.1 months, respectively (HR, 0.60 [95% CI, 0.43−0.86];P < 0.005) (12).In addition, a pooled analysis of data from the PALOMA-1 and PALOMA-2 studies showed significant improvement in median PFS with palbociclib plus letrozole versus  Overall survival in the unadjusted (A), sIPTW (B), and PSM (C) analyses.AI, aromatase inhibitor; CI, confidence interval; HR, hazard ratio; OS, overall survival; PSM, propensity score matching; sIPTW, stabilized inverse probability treatment weighting.
In addition to the comparative studies described above, several prior single-arm, real-world studies have evaluated rwPFS and OS in elderly patients with advanced or mBC receiving palbociclib (31-35).In a national United Kingdom retrospective study of patients aged ≥ 75 years with ER+/HER2− advanced breast cancer receiving 1L palbociclib plus AI (N = 276), 12-and 24-month rwPFS rates were 75.9% and 64.9%, respectively, and OS rates were 85.1% and 74.0%, respectively (31).A retrospective analysis at a French comprehensive cancer center evaluated outcomes in patients aged ≥ 70 years who received palbociclib plus ET for HR+/HER2− advanced breast cancer (32).In this heavily pretreated cohort (N = 52), with a median of 3 (range, 0−9) previous treatments for advanced metastatic disease, median PFS was 9 months (95% CI, 6−NR), and median OS was NR (22 months−NE).In a retrospective analysis of patients receiving palbociclib in any LoT at MD Anderson Cancer Center (N = 605), older patients (using an age cut-off of either 65 or 70 years) had significantly improved rwPFS compared with younger Real-world progression-free survival in the unadjusted (A), sIPTW (B), and PSM (C) analyses.AI, aromatase inhibitor; CI, confidence interval; HR, hazard ratio; PSM, propensity score matching; rwPFS, real-world progression-free survival; sIPTW, stabilized inverse probability treatment weighting.Toxicity management is particularly important when treating elderly patients with HR+/HER2− mBC (25, 26).For example, postponing the initiation of salvage chemotherapy can help spare patients from the toxicities and detrimental effects on quality of life associated with chemotherapy (25, 36).In our study, TTC was significantly prolonged with palbociclib plus an AI versus an AI alone before and after sIPTW and PSM adjustment.We also analyzed palbociclib dose reductions, which can be used to mitigate hematologic adverse events associated with palbociclib treatment, such as neutropenia (37).In prior real-world studies evaluating palbociclib plus ET use in elderly patients, palbociclib dose reductions were most frequently attributed to neutropenia, but could also result from other hematologic or non-hematologic toxicities, such as thrombocytopenia or fatigue (31, 35).We found that approximately 25% of patients had a starting palbociclib dose lower than 125 mg/day, and approximately 39% of patients who started with a dose of 125 mg/day experienced a dose reduction.In the palbociclib plus letrozole arm in the PALOMA-2 trial, a similar proportion of patients (39.4%) experienced a dose reduction (12).Importantly, dose reductions did not compromise efficacy in PALOMA-2, and PFS was similar among patients who did or did not experience a dose reduction (37).In a retrospective analysis of the MD Anderson Cancer Center database, palbociclib dose reductions were more commonly observed in elderly versus younger patients.However, these dose reductions did not significantly affect rwPFS (adjusted HR, 0.7; P = 0.07) (33).Further studies are needed to explore the effect of palbociclib dose reductions on other effectiveness and safety outcomes in elderly patients.Detailed safety assessments were not possible in our analysis because safety data were not retrieved/abstracted in the database for the P-REALITY X study.Although beyond the scope of our current study, several studies in the real-world or clinical setting have previously demonstrated that palbociclib is generally welltolerated in elderly patients (30-33, 35, 38) and that quality of life and functional status are preserved in elderly patients receiving treatment with palbociclib (30, 39).Prior analyses of clinical trial or real-world data have reported rates of treatment discontinuation due to toxicity ranging from 3% to 13% among elderly patients receiving palbociclib plus ET (30-32, 35).
To our knowledge, the P-REALITY X study is the largest multisite comparative effectiveness study to date comparing 1L palbociclib plus an AI versus an AI alone for patients with HR+/HER2− mBC in a realworld setting.Strengths of the present study include the diversity of the patient population captured in the Flatiron Database, the large sample size of patients aged ≥ 75 years (n = 961), the contemporaneous control group, and the long median follow-up time.The OS endpoint in the Flatiron Database is a consensus variable across multiple data sources (including the Social Security Death Index, obituaries, EHRs, and commercial death data) and validated through comparisons with the National Death Index (40,41).Furthermore, the consistency in significant findings in the unadjusted analysis, the primary analysis with sIPTW, and the sensitivity analysis with PSM contribute to the study's internal validity.However, this real-world study also has several potential limitations.This was a retrospective database analysis, which may have potential bias in treatment selection, incomplete or missing data, limited information on comorbidities, and potential for inaccurate data capture.Disease progression was not assessed as scheduled in clinical trials and was not based on Response Evaluation Criteria in Solid Tumors; therefore, rwPFS data are limited by each treating clinician's interpretation of radiographic scans or pathology results and the lack of standardization in the timing of these assessments.Although sIPTW and PSM were used to balance patient characteristics, the potential effects of unmeasured confounders could not be adjusted for in the analysis.Lastly, results from this analysis may not be generalizable to patients outside the Flatiron network.

Conclusions
Overall, this comparative analysis of 1L palbociclib plus an AI versus an AI alone indicates that palbociclib plus an AI is associated with improved effectiveness with prolonged OS, rwPFS, and TTC in patients with HR+/HER2− mBC who are aged ≥ 75 years.These findings support palbociclib in combination with endocrine therapy as a standard-of-care treatment for elderly patients with HR+/HER2− mBC.

FIGURE 1
FIGURE 1Palbociclib dose adjustments among patients with a documented palbociclib starting dose (n = 306).

TABLE 1
Patient characteristics.
a Variable used in propensity score estimation.bVisceraldisease was defined as metastatic disease in the lung and/or liver; patients could have other sites of metastases.No visceral disease was defined as no lung or liver metastases.c Bone-only disease was defined as metastatic disease in the bone only.d Multiple metastases at the same site were counted as 1 site (e.g., if a patient had 3 bone metastases in the spine, it was considered only 1 site).AI, aromatase inhibitor; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IQR, interquartile range; mBC, metastatic breast cancer; NA, not applicable; NCI, National Cancer Institute; PSM, propensity score matching; SD, standard deviation; sIPTW, stabilized inverse probability treatment weighting.
a Refers to cases where dose change directions included an unknown change or a combination of dose reductions and increases over time (e.g., dose reduction followed by a dose increase, or vice versa).IQR, interquartile range; SD, standard deviation.