Real-world data for a CDK4/6 inhibitor, Palbociclib, as 1st- or 2nd-line therapy in HR+/HER2− metastatic breast cancer: A multicenter prospective cohort study

Real-world data for a CDK4/6 inhibitor, Palbociclib, as 1st- or 2nd-line therapy in HR+/HER2− metastatic breast cancer: A multicenter prospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-world data for a CDK4/6 inhibitor, Palbociclib, as 1st- or 2nd-line therapy in HR+/HER2− metastatic breast cancer: A multicenter prospective cohort study Takashi Ishikawa, Yukari Uemura, Hirohito Seki, Masahiro Kitada, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8764760/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Palbociclib (PAL), the first CDK4/6 inhibitor approved for breast cancer, improves progression-free survival (PFS) in hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) when added to an aromatase inhibitor or fulvestrant, but also increases toxicity compared to endocrine therapy alone. Use of PAL in 1st-line treatment increases the burden on patients and adds to costs compared to use as 2nd-line treatment, due to the longer period of 1st-line treatment. Therefore, data on use of PAL in a real-world setting are required to assess the merits of 1st- and 2nd-line therapy in the sequence of treatment for MBC. Methods A prospective observational study was performed in patients with postmenopausal metastatic or unresectable breast cancer using PAL in 1st-, 2nd-, or 3rd-line treatment. The primary endpoint was PFS (start of PAL to progression or death). Secondary endpoints included PFS2 (start of 1st-line endocrine treatment to second progression) and adverse events. Results The study included 593 patients treated with PAL (246 1st-line, 282 2nd-line, 65 3rd-line) from April 2019 to January 2023. Median PFS was 25.8 (95%CI: 21.4), 18.0 (14.0-22.7), and 12.0 (7.7–17.4) months, for 1st-, 2nd- and 3rd-line use respectively. Median PFS2 was 36.9 (27.7-not reached) and 57.9 (43.4–65.3) months in the 1st- and 2nd-line cohorts. Neutropenia of grade ≥ 3 occurred in 70% of patients, and > 80% required dose reductions. Conclusions PFS for the 1st-line cohort was similar to that in PALOMA-2, while the 2nd-line cohort had better outcomes than those in PALOMA-3, even when modelled for potential bias since some patients on 1st-line endocrine monotherapy would have received chemotherapy rather than 2nd-line PAL. Overall, the findings in this study of real-life treatment of patients with HR+/HER2- MBC support randomized control trial data that challenge the need to use a CDK4/6 inhibitor in the 1st-line setting for all patients. Clinical Trial Registration: UMIN000035863 Breast cancer Palbociclib Prospective cohort Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background PALOMA-1 was an open-label phase 2 randomized clinical trial (RCT) that, in 2015, was the first to report that a combination of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib (PAL) with letrozole significantly improved progression-free survival (PFS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), compared to 1st-line letrozole alone [ 1 ]. This finding was confirmed in 2016 in the multinational PALOMA-2 phase 3 RCT [ 2 ]. Also in 2016, in the PALOMA-3 phase 3 RCT, the combination of PAL and fulvestrant was shown to significantly improve PFS over fulvestrant alone in the 2nd-line setting [ 3 ]. Significant improvement in overall survival (OS) has not been shown for PAL [ 4 , 5 ], but addition of PAL to anti-hormonal agents is consistently beneficial for PFS in patients with MBC. One concern with PAL is the high incidence of hematologic adverse events (AEs), particularly neutropenia and increased fatigue [ 1 – 3 ]. Moreover, a higher rate of these events has been found in Japanese patients compared to the overall population in the PALOMA-2 and − 3 trials [ 6 , 7 ]. The main aims in treatment of patients with MBC, which is still an incurable disease, are to prolong life and improve quality of life (QoL). There are many treatment options available in HR+ advanced breast cancer, making it important to ask the question “What is the best sequence of treatments that will keep patients alive longest with the best QoL?”. Although most current guidelines advocate 1st-line use of CDK4/6 inhibitors, this recommendation was challenged by the SONIA trial, the first reports from which were published in 2024 [ 8 ]; these showed similar PFS after two treatment lines (PFS2) and similar OS if CDK4/6 inhibitors are used as 2nd-line treatment following endocrine therapy (ET). The SONIA trial protocol, which was first reported in 2018, addressed this question using a study design representing daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to ET will benefit patients most [ 9 ]. Real-world data have confirmed the PFS efficacy of PAL observed in the RCTs [ 10 – 15 ]. However, these studies were all retrospective. Soon after publication of the SONIA trial protocol, we started a prospective cohort study of PAL in postmenopausal HR+/HER2- MBC in 2019. This study was based on the hypothesis that the efficacy, safety, and QoL of PAL treatment in daily clinical practice are not inferior to those in RCTs [ 2 , 3 ]. We also examined if PAL might affect the efficacy and safety of subsequent treatment. Thus, the reality of early-line treatment with PAL was investigated to examine the need for 1st-line PAL in all patients. PAL was used rather than ribociclib or abemaciclib. The other two CDK 4/6 inhibitors had also shown improvements in PFS in the 1st- and 2nd-line setting, but at the time of study initiation OS was unknown for all three agents and PAL was the most widely used CDK 4/6 inhibitor. OS was subsequently reported for ribociclib, PAL and abemaciclib in 2021 [ 16 ], 2022 [ 17 ] and 2024 [ 18 ], respectively. A recent review of CDK 4/6 inhibitors discussed potential differences between these agents in terms of endocrine sensitivity after CDK 4/6 inhibitors, mechanisms and biomarkers of resistance, and pharmacogenomics and ethnicity [ 19 ]. This current study is not a comparison of different CDK 4/6 inhibitors, but was set up to assess whether all patients with MBC require a CDK 4/6 inhibitor as 1st-line therapy. Materials and Methods A prospective, multicenter cohort study was designed to evaluate the efficacy, safety and QoL of PAL treatment in daily clinical practice, as described in detail elsewhere [ 20 ]. In summary, three Cohorts (A, B, and C) were categorized by 1st-, 2nd-, and 3rd- (or later) line PAL treatment for postmenopausal metastatic or unresectable breast cancer. Patients Postmenopausal women diagnosed with unresectable and/or metastatic HR+/HER2- breast cancer were prospectively enrolled from designated hospitals in Japan from April 1, 2019 to January 31, 2023. As previously reported [ 20 ], Cohort A (1st-line PAL) included patients who had not received prior ET in the metastatic setting and were > 1 year post-completion of adjuvant ET (i.e., similar to PALOMA 2); Cohort B (2nd line PAL) included patients who had been treated with 1st-line ET for metastasis (regardless of the effect of therapy or reason for discontinuation) or who recurred < 1 year after adjuvant ET or during adjuvant therapy (regardless of the duration of adjuvant ET) (i.e., similar to PALOMA 3); and Cohort C (3rd- or later-line PAL) included patients with metastatic disease treated previously with ≥ 2 lines of ET (regardless of response or reason for discontinuation). Patients received PAL in combination with aromatase inhibitors, fulvestrant or tamoxifen. PAL was administered once daily for 3 weeks followed by 1 week off in 28-day cycles, and was discontinued due to disease progression (PD), unacceptable toxicity, study withdrawal, or death. Dose interruptions and reductions were allowed to manage toxic effects. Assessments Demographic and clinical characteristics at enrollment were assessed, including: date of surgery, pathology of surgical specimen (including HR/HER2 status), metastatic site, date of diagnosis of recurrence, pretreatment in the adjuvant or metastatic setting, prior treatment, physical findings (height, body weight and performance status after the 1st cycle), diagnostic imaging for breast cancer lesions, laboratory data, AEs prior to PAL treatment, concomitant medications, and PROs/HRQoL. Efficacy Tumors were assessed locally at screening and every 12 weeks by imaging (ultrasound, computed tomography, magnetic resonance imaging and/or bone scan) and clinical assessment. AEs were assessed for incidence, severity, timing, grade, and association with PAL. Hematology and blood chemistry assessments were performed every two weeks for the first two cycles and at the beginning of each cycle thereafter. Safety AEs were recorded using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 (JCOG edition). Regardless of grade, the following AEs were recorded because they are possibly associated with PAL combined with ET in patients with breast cancer: constipation, diarrhea, oral mucositis, nausea, vomiting, malaise, pain, arthralgia, insomnia, vaginal discharge, vaginal dryness, hot flashes, alopecia, and rash. Other AEs of grade 2 or higher were also recorded. Study Endpoints The primary endpoint was PFS calculated from the date of PAL initiation to the date of PD or death from any cause. Secondary endpoints were PFS2, clinical benefit rate (CBR) (% of cases not classified as PD for 6 months), OS, AEs, patient-reported outcomes (PROs) and health-related quality of life (HRQoL). PFS, CBR and AEs were also assessed in subsequent treatment after use of PAL. PFS2 was defined from the start of 1st ET for advanced disease until the 2nd objective disease progression. Given that no OS benefit has been reported for PAL we focus on PFS and AEs, which are relevant to all CDK 4/6 inhibitors. PROs and HRQoL were also assessed during PAL-combined ET and subsequent treatment using PRO-common terminology criteria for adverse events (PRO-CTCAE), European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ C30), and EQ-5D (EuroQol 5 Dimension). These results will be reported elsewhere. Statistical Analysis The statistical analysis plan has been described in detail in a previous publication [ 15 ]. In summary, for Cohort A, assuming a median PFS of 25 months, similar to PALOMA-2 [ 2 ], if 310 patients are enrolled in a 3-year registration period and a 5-year study duration, the 90% confidence interval (CI) for PFS ≤ 8 months would have a probability of 85%. Similarly, for Cohort B, assuming a median PFS of 9.5 months (similar to that reported in PALOMA-3 [ 3 ]), if 180 patients were enrolled in a 3-year registration period and a 5-year study duration, the 90% CI for PFS ≤ 4.5 months has a 90% probability. For Cohort C, for which 3rd-line data were limited, the expected PFS was set at 7.5 months. We assumed a median PFS of 9.5 months in this study and if 120 cases were enrolled in a 3-year registration period and a 5-year study duration, the 90% CI for PFS ≤ 4 months would have an 85% probability. Among the registered cases, patients who received at least one dose of the planned PAL treatment, after excluding duplicate and erroneous registrations, were included in the analysis population. For the primary endpoint of PFS, Kaplan-Meier survival curves were estimated for each cohort. Median PFS was estimated along with the 90% CIs. PFS2 was also analyzed. For Cohort A, PFS2 was defined as the time from enrollment to the second objective disease progression in subsequent treatment after PAL treatment. PFS2 was calculated using only the cases that proceeded to 2nd-line treatment. For Cohort B, PFS2 was defined as the time from the start of previous endocrine monotherapy until objective disease progression while on PAL treatment (Fig. 1 ). For safety, the worst grade of each AE was summarized. Results Clinical and pathological characteristics Between April 2019 and January 2023, a total of 700 patients were enrolled from 69 centers across Japan. After excluding cases with contraindications, which were mainly violations of ET before addition of PAL, the final distribution was 246 in Cohort A, 282 in Cohort B, and 65 in Cohort C (Fig. 2 ). Patient demographics and background factors are shown in Table 1 . In Cohorts A, B and C, the median age was 68, 66, and 68 years, respectively, while neoadjuvant or adjuvant chemotherapy was administered in 25.6%, 55.0%, and 46.2% of cases, respectively. Because this study was initiated before insurance coverage for PAL was approved, chemotherapy was used prior to PAL treatment in the metastatic setting in 6.1%, 10.6%, and 32.3% of cases, respectively. (Table 1 ). Adjuvant ET was administered in 38.2%, 84.4%, and 63.1% of cases in Cohorts A, B and C, respectively (Table 1 ). Letrozole and fulvestrant were mostly used as an anti-hormone agent in combination with PAL, at rates of 72.8% and 21.1% in Cohort A, 20.6% and 72.0% in Cohort B, and 30.8% and 41.5% in Cohort C. Tamoxifen was used in only 1.2%, 0.7% and 1.5% of cases in Cohorts A, B and C, respectively (Supplementary Table 1). Regarding the disease site, in Cohorts A, B and C, 38.3%, 58.9%, and 58.1% of the patients had visceral metastases; while 71.1%, 65.6% and 66.2% had measurable diseases; and 1.7%, 8.1%, and 4.7% had bone disease only (Table 1 ). In Cohort B, 126/282 cases (44.7%) relapsed during adjuvant ET and 156/282 (55.3%) relapsed during primary endocrine monotherapy for metastases; both subgroups of Cohort B are included in PFS1 for 2nd-line PAL treatment while only the latter 156 patients are included for PFS2 for endocrine monotherapy followed by 2nd-line PAL treatment (Fig. 1 ). Table 1 Patient demographics and background factors Item Cohort A Cohort B Cohort C N = 246 N = 282 N = 65 Age (years) Median (range) 68 (38–92) 66 (41–92) 68 (44–95) Height (cm) Median (range) 155 (135.5-171.5) 154 (137–170) 154 (136.3-169.3) Weight (kg) Median (range) 54.0 (33.4–86.9) 53.0(23.9–99.0) 54.0 (37–114) Histology Ductal 195 (79.3%) 229 (81.2%) 49 (75.4%) Lobular 24 (9.8%) 29 (10.3%) 6 (9.2%) Others 8 (3.3%) 10 (3.5%) 2 (3.1%) Unknown 19 (7.7%) 14 (5%) 8 (12.3%) Adjuvant chemotherapy Yes 63 (25.6%) 155 (55%) 30 (46.2%) No 172 (69.9%) 121 (42.9%) 32 (49.2%) Unknown 11 (4.5%) 6 (2.1%) 3 (4.6%) Adjuvant endocrine therapy Yes 94 (38.2%) 238 (84.4%) 41 (63.1%) No 140 (56.9%) 35 (12.4%) 18 (27.7%) unknown 12 (4.9%) 9 (3.2%) 6 (9.2%) Endocrine therapy after recurrence Yes 0 (0%) 126 (44.7%) 65 (100%) No 246 (100%) 156 (55.3%) 0 (0%) Chemotherapy after recurrence Yes 15 (6.1%) 30 (10.6%) 21 (32.3%) No 229 (93.1%) 252 (89.4%) 44 (67.7%) Unknown 2 (0.8%) 0 (0%) 0 (0%) Measurable disease Any measurable disease 175 (71.1%) 185 (65.6%) 43 (66.2%) Lung or liver involvement 67 (38.3%) 109 (58.9%) 25 (58.1%) Bone only 3 (1.7%) 15 (8.1%) 2 (4.7%) Others 105 (60%) 62 (33.5%) 16 (37.2%) Clinical outcomes At the follow-up data cut-off of September 30, 2023, PAL treatment was ongoing in 103/246 (41.9%) cases in Cohort A, 92/282 (32.6%) in Cohort B, and 11/65 (16.9%) in Cohort C. Dose reductions were required in 68/246 (27.6%), 59/282 (20.1%) and 15/65 (23.1%) patients, respectively. After a median follow-up of 22.5 months, the median PFS was 25.8 months (95% CI: 21.4-not reached) in Cohort A, 18.0 months (14.0-22.7) in Cohort B, and 12.0 months (7.7–17.4) in Cohort C (Fig. 3 ). CBR was 217/246 (88.2%) (95% CI 83.5–92.0), 221/282 (78.4%) (95% CI 73.1–83.0), and 46/65 (70.8%) (95% CI 58.2–81.4) in Cohorts A, B and C, respectively (Table 2 ). The 90% CIs of PFS were 21.7–41.4 for Cohort A, 14.5–21.7 for Cohort B, and 8.1–16.0 for Cohort C, all slightly narrower than the 95% CIs noted above. OS data was immature, with only 130 deaths (21.9%): 41 (16.7%) in Cohort A, 67 (23.8%) in Cohort B, and 22 (33.8%) in Cohort C. We do not report OS given the immaturity of the OS data and, as noted above, the absence of a significant OS benefit for PAL in the 1st- and 2nd-line RCTs (i.e., PALOMA 2 and 3). Table 2 Clinical outcomes in cohorts A, B and C Cohort No PD for 6 months CBR (%)* 95% CI (lower-upper limits)** A (N = 246) 217 88.2% 83.5%-92.0% B (N = 282) 221 78.4% 73.1%-83.0% C (N = 65) 46 70.8% 58.2%-81.4% *% of patients with CR, PR, or SD at 6 months based on imaging diagnosis **Clopper-Pearson exact confidence intervals In Cohort A the median PFS2 was 36.4 (95% CI: 27.8-) months (Fig. 5 ). In Cohort B, PFS2 was calculated in the 126/282 cases that relapsed during 1st-line endocrine monotherapy for metastases (Table 1 ). The median PFS2, including the time on prior 1st-line endocrine monotherapy, was 57.9 (95% CI 45.2–65.1) months (Fig. 4 ). A post-hoc sensitivity analysis of PFS2 in Cohort B was performed as high risk patients who continued with chemotherapy instead of PAL after progressing on 1st-line endocrine monotherapy were excluded, and so data for these patients were not collected. In the SONIA trial [ 8 ], 51/374 patients in the 2nd-line arm were unable to receive CDK4/6 inhibitors in the planned 2nd-line setting and ultimately received chemotherapy or other treatments. Assuming 20 similar cases, the same proportion as the SONIA trial in our Cohort B, we simulated PFS durations of 5, 10 and 15 months for these 20 patients. The Kaplan-Meier curves of the three “virtual B Cohorts” all lie between Cohorts A and B and more closely resemble PFS2 of Cohort A (Fig. 5 ). Safety The common AEs were neutropenia, leukopenia, fatigue, alopecia and stomatitis. Among non-hematologic events, fatigue, alopecia and stomatitis occurred in > 20% of patients in all cohorts (Supplementary Table 2). However, grade 3 events were rare. During the study-treatment period, there were 155 deaths: 149 due to disease progression and 6 with other causes, including one due to interstitial pneumonia. For hematological AEs, leukocytopenia and neutropenia were equally common in all 3 cohorts, with total rates of grade 3 or higher leukocytopenia and neutropenia of 41.3% and 73.5%, respectively (Table 3 ). The dose was reduced in > 80% of cases, and < 20% were able to maintain the 125 mg dose at the 4th cycle (Supplementary Table 3). There were no other serious hematological toxicities, but there were a few cases of grade 3 or higher liver deterioration (Table 3 ). Table 3 Hematological adverse events of grade 3 or above Adverse event Grade Cohort A Cohort B Cohort C Total N = 246 N = 282 N = 65 N = 593 Anemia 3 11 (4.5%) 15 (5.3%) 1 (1.5%) 27 (4.6%) 4 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) ≥ 3 11 (4.5%) 15 (5.3%) 1 (1.5%) 27 (4.6%) Leukocytopenia 3 89 (36.2%) 120 (42.6%) 27 (41.5%) 236 (39.8%) 4 2 (0.8%) 7 (2.5%) 0 (0.0%) 9 (1.5%) ≥ 3 91 (37.0%) 127 (45.0%) 27 (41.5%) 245 (41.3%) Neutropenia 3 143 (58.1%) 179 (63.5%) 39 (60.0%) 361 (60.9%) 4 27 (11.0%) 40 (14.2%) 8 (12.3%) 75 (12.6%) ≥ 3 170 (69.1%) 219 (77.7%) 47 (72.3%) 436 (73.5%) Thrombocytopenia 3 2 (0.8%) 9 (3.2%) 1 (1.5%) 12 (2.0%) 4 1 (0.4%) 3 (1.1%) 0 (0.0%) 4 (0.7%) ≥ 3 3 (1.2%) 12 (4.3%) 1 (1.5%) 16 (2.7%) Liver dysfunction: AST(U/L) 3 13 (5.3%) 5 (1.8%) 0 (0.0%) 18 (3.0%) 4 0 (0.0%) 1 (0.4%) 0 (0.0%) 1 (0.2%) ≥ 3 13 (5.3%) 6 (2.1%) 0 (0.0%) 19 (3.2%) Liver dysfunction: ALT(U/L) 3 22 (8.9%) 15 (5.3%) 3 (4.6%) 40 (6.7%) 4 3 (1.2%) 2 (0.7%) 0 (0.0%) 5 (0.8%) ≥ 3 25 (10.2%) 17 (6.0%) 3 (4.6%) 45 (7.6%) Discussion This prospective study was conducted to assess the efficacy and safety of PAL with ET in postmenopausal patients in a real-world setting. The study overlapped in recruitment years with the SONIA RCT. PFS in Cohort A was similar to that in PALOMA-2 at 24.8 months in the 1st-line setting. Despite the similar entry criteria (i.e., patients who had not received prior ET in the metastatic setting and were > 1 year post-completion of adjuvant ET), PALOMA-2 included ~ 20% of patients with recurrent breast cancer during and within 12 months after completion of adjuvant ET [ 2 ]. PALOMA-2 also did not include patients who received chemotherapy after relapse, whereas Cohort A included 6.1% of such cases. However, taken together with other real-world retrospective studies [ 10 – 15 ], the median PFS is > 20 months when used in 1st-line treatment in a real-world setting. The median PFS periods in Cohorts B and C of 18.0 and 12.0 months, respectively, were longer than that reported in PALOMA 3 (median 9.5 months), but similar to 2nd-line studies of abemaciclib (Monarch 2; median 16.4 months) [ 21 ] and ribociclib (Monalessa 3; median 20.5 months) [ 22 ]. The median PFS in Cohort B was almost double that in the PALOMA-3 trial [ 3 ]. For comparison with PALOMA-3, a combined analysis of Cohorts B and C may be appropriate because PALOMA-3 included patients with 3rd-line treatment. PFS in Cohort C was also longer than that in PALOMA-3. It is not surprising that 2nd-line treatment outcomes vary more across trials compared to those for 1st-line treatment because of differences in patient background. For example, about 20% of patients in the PALOMA-3 and Monarch 2 studies were pre- or perimenopausal, whereas all patients in this study were postmenopausal. A large-scale retrospective study in Japanese patients reported PFS for 2nd-line PAL of 14.5 months [ 12 ]. Taken together with our prospective study, PFS of 2nd- or 3rd-line PAL may be more favorable in the real world setting in Japan compared with the PALOMA-3 trial. RCTs on all three CDK4/6 inhibitors have shown clear evidence of improved PFS in 1st-line therapy [ 2 , 16 , 17 ]. However, none of these 1st-line studies allowed crossover to a CDK4/6 inhibitor in the control group after progression on 1st-line ET, despite evidence for a benefit from 2nd-line CDK 4/6 inhibitors from prior studies. As a result, these RCTs without crossover do not inform patients or caregivers about the optimal sequence of treatments that keep patients alive longest with the best possible QoL. In addition, from a societal perspective, it is likely that using expensive drugs early and for longer in PFS1 has higher costs. The SONIA study addressed this question, using a RCT of an aromatase inhibitor ± CDK4/6 inhibitor in 1st-line therapy with a protocol that included crossover to fulvestrant in 2nd-line therapy with a CDK4/6 inhibitor for patients who had not received it as 1st-line [ 8 ]. The primary endpoint of the trial, median PFS2, showed no difference between the two arms (31.0 vs. 26.8 months), but with 72% higher Grade 3 or 4 side-effects and an increase of $ 200,000 per patient for use of the CDK 4/6 inhibitor as 1st-line therapy. A recent presentation at ESMO 2025 suggested no difference in OS after median follow-up of 58.5 months, with median OS of 47.9 months for a 1st-line CDK 4/6 inhibitor and 48.1 months for a 2nd-line CDK 4/6 inhibitor (HR = 0.91; 95% CI 0,77–1.07; p = 0.24) [ 23 ]. Our prospective observational study included only postmenopausal patients. In the SONIA trial 905 patients (87%) were postmenopausal, with no significant difference in this subgroup (HR 1.00; 99% CI 0.80–1.25; P = 0.01 vs. premenopausal subgroup). In addition to increased grade 3 or 4 side-effects with a 1st-line CDK 4/6 inhibitor, there is a significant financial disadvantage due to increased time on PAL in the 1st-line setting. All of these factors collectively indicate that early use of PAL does not benefit patients. The median PFS2 in our study was 36.9 and 57.9 months in Cohorts A and B, respectively, whereas the SONIA trial found PFS of 31.0 and 26.8 months for sequential use of a CDK 4/6 inhibitor in the 1st- and 2nd-lines, respectively. Thus, PFS 2 in Cohort A is similar to the results in the SONIA trial for 1st-line use of a CDK 4/6 inhibitor, whereas PFS2 in Cohort B is significantly greater than the 2nd-line results in SONIA. PFS2 may be overestimated due to the eligibility criteria for Cohort B, which allowed patients to receive 1st-line endocrine monotherapy followed by PAL as 2nd-line therapy. A potential selection bias may have arisen from clinicians’ preference to administer chemotherapy rather than 2nd-line ET + CDK4/6 inhibitor for patients with a poor response to 1st-line ET, thereby excluding them from Cohort B. Thus, a post hoc sensitivity analysis was conducted with reference to the SONIA trial [ 8 ], in which we modelled a similar percentage of patients in the SONIA trial who were unable to receive CDK4/6 inhibitors in the planned 2nd-line setting and ultimately received chemotherapy or other treatments. This reduced PFS2 for the group using PAL as 2nd-line therapy to closer to the median PFS2 for 1st-line PAL therapy (Fig. 5 ). The result for Cohort B further supports the SONIA study and indicates the validity of 2nd-line treatment as an option for clinicians to use if they deem it appropriate. Regarding side-effects, neutropenia was a frequent AE in all cohorts, with a 10% higher rate of grade 3 or higher neutropenia than in PALOMA-2 and − 3 [ 2 , 3 ]. Thus, the dose was reduced in > 80% of cases. However, no febrile neutropenia occurred, and other AEs were reasonably tolerable, including non-hematological AEs. Based on the clinical outcomes of this trial, PAL treatment was considered to have been successfully implemented with appropriate dose reductions in response to neutropenia. Low grade symptoms such as fatigue, oral mucositis and lower GI symptoms (e.g., constipation and diarrhea) were common (i.e., 5–10%) on the CDK 4–6 inhibitor regimen. The main strength of this study is that it supports the findings of the SONIA RCT using real-world data. There are many patients in whom recurrence can be initially controlled for a significant period with endocrine monotherapy. Thus, use of ET, while observing the hormone sensitivity of each case and adding PAL if poor sensitivity to ET is determined, is a rational approach that provides effective early ET at lower cost and with less toxicity, while knowing that 2nd-line ET + CDK 4/6 inhibitor therapy will be available with no detriment to OS. A further strength of this study is that the real-life data is in patients drawn from a different geographic region and ethnic population than those in the SONIA RCT. This study has several limitations. First, it is not randomized, which limits interpretation of the efficacy of adding PAL, particularly as 2nd line, since patients with poorer responses to 1st-line endocrine monotherapy might have been given chemotherapy rather than ET + PAL. This also means that patients included in Cohort B may have had a higher sensitivity to ET as the disease was well controlled with ET before PAL treatment, compared to the 2nd-line CDK 4–6 inhibitor arm in the SONIA trial. However, we used a sensitivity analysis to try to account for this bias. A further limitation is that a longer observation period would have been useful to examine clinical outcomes for HR+/HER- MBC (e.g., OS), but enrollment was delayed from the initial protocol due to the Coronavirus pandemic. Thus, the median PFS2 was not observed, although the primary endpoint of median PFS1 was observed. Fourth, 91 cases were excluded from analyses because of a violation of adding PAL after starting anti-endocrine agents. In routine clinical practice, anti-endocrine agents could be started prior to PAL; however, the protocol did not allow for this in order to categorize the cohort rigorously in this prospective study. In conclusion, this study confirmed that real-world post-menopausal patients with HR+HER2- MBC have outcomes that are comparable to those observed in prior clinical trials. The results of the ongoing investigation of PROs/HRQoL are awaited, but PAL treatment was successfully implemented with appropriate dose reductions in response to neutropenia. Results with the use of PAL in the 2nd-line setting following the 1st-line endocrine monotherapy were as good as those with PAL in the 1st-line setting. Thus, we support the SONIA concept, which raises concerns about the current widespread 1st-line recommendation for PAL without randomized crossover trials. Declarations Ethics approval and consent to participate: This study was approved by the protocol review committee of the Comprehensive Support Project for Oncological Research of Breast Cancer on March 10, 2018 (approval number T2018-0026) and registered in the UMIN Clinical Trials Registry as UMIN000035863 on February 20, 2019. Ethical approval was obtained from all institutions. The study was conducted in accordance with the legal and regulatory requirements and the general principles of the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), the Guidelines of Good Clinical Practice (International Conference on Harmonization 1996), and the Declaration of Helsinki (World Medical Association 1996 and 2008). Written informed consent was obtained from all participants. Consent for publication Not applicable. Author Contribution T.I., K.N., and H.M. conceived and designed the study.T.I., K.N., Y.K., H.M., and Y.U. analyzed the data.Y.U. performed the statistical analysis.H.S., T.I., M.K., T.S., K.M., S.T., D.T., T.Y., M.K., Y.K., A.Y., U.T., H.N., H.K., K.Y., R.N., N.T., and K.N. contributed to patient accrual.T.I. and H.M. wrote the original draft of the manuscript and were responsible for interpretation of the data and manuscript revisions.All authors reviewed and approved the final manuscript. Acknowledgement We thank all the patients who participated in this trial and their families; all members of the study committee; and the staff at all 69 hospitals and the CSPOR data center. We express our sincere and deepest gratitude to Dr. Gabe S. Sonke and Dr. John F.R. Robertson for their invaluable, insightful, and critical review of this manuscript. Data Availability Data associated with the study will be made available upon request to the corresponding author, with appropriate restrictions to maintain patient privacy. References Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol. 2015;16:25–35. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425–39. Slamon DJ, Diéras V, Rugo HS, Harbeck N, Im SA, Gelmon KA, et al. Overall survival with palbociclib plus letrozole in advanced breast cancer. J Clin Oncol. 2024;42:994–1000. Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926–36. Mukai H, Shimizu C, Masuda N, Ohtani S, Ohno S, Takahashi M, et al. Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients. Int J Clin Oncol. 2018;24:274–87. Masuda N, Inoue K, Nakamura R, Rai Y, Mukai H, Ohno S, et al. Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. Int J Clin Oncol. 2019;24:262–73. Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024;636:474–80. van Ommen-Nijhof A, Konings IR, van Zeijl CJJ, Uyl-de Groot CA, van der Noort V, Jager A, et al. Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer – the SONIA study: Study protocol for a randomized controlled trial. BMC Cancer. 2018;18:1146. Kish JK, Ward MA, Garofalo D, Ahmed HV, McRoy L, Laney J, et al. Real-world evidence analysis of palbociclib prescribing patterns for patients with advanced/metastatic breast cancer treated in community oncology practice in the USA one year post approval. Breast Cancer Res. 2018;20:37. Varella L, Eziokwu AS, Jia X, Kruse M, Moore HCF, Budd GT, et al. Real-world clinical outcomes and toxicity in metastatic breast cancer patients treated with palbociclib and endocrine therapy. Breast Cancer Res Treat. 2019;176:429–34. DeMichele A, Cristofanilli M, Brufsky A, Liu X, Mardekian J, McRoy L, et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US real-world clinical practice. Breast Cancer Res. 2021;23:37. Yoshinami T, Nagai SE, Hattori M, Okamura T, Watanabe K, Nakayama T, et al. Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study. Breast Cancer. 2024;31:621–32. Nagai SE, Hattori M, Yoshinami T, Masuda H, Okamura T, Watanabe K, et al. Overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- advanced breast cancer in the first-or second-line setting: a multicenter observational study (P-BRIDGE study). Breast cancer (Tokyo Japan). 2025;32:705–15. Martínez-Jañez N, Ezquerra MB, Manso Sanchez LM, Carrasco FH, Torres AA, Morales S, et al. First-line therapy with palbociclib in patients with advanced HR+/HER2- breast cancer: The real-life study PALBOSPAIN. Breast Cancer Res Treat. 2024;206:317–28. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, et al. Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2–) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290–1. Finn RS, Rugo HS, Dieras VC, Harbeck N, Im SA, Gelmon KA, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL + LET) versus placebo plus letrozole (PBO + LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2 – ABC): analyses from PALOMA-2. J Clin Oncol. 2022;40(17):LBA1003. Goetz MP, Toi M, Huober J, Sohn J, Trédan O, Park IH, et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2 – advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024;35:718–27. O'Sullivan CC, Clarke R, Goetz MP, Robertson J. Cyclin-dependent kinase 4/6 inhibitors for treatment of hormone receptor-positive, ERBB2-negative breast cancer: A review. JAMA Oncol. 2023;9:1273–82. Narui K, Ishikawa T, Taira N, Uemura Y, Mukai H. Prospective cohort study of palbociclib treatment in postmenopausal patients with unresectable and metastatic hormone receptor-positive breast cancer: Study protocol for a CSPOR-BC palbociclib cohort trial. World J Oncol. 2022;13:190–4. Sledge GW, Masakazu Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017;35(25):2875–84. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465–72. Wortelboer N, Ommen-Nijhof AV, Konings IR, Noort VVD, Pol EVD, Páez C, et al. Overall survival with first versus second-line use of CDK4/6 inhibitors in HR+/HER2- advanced breast cancer. Ann Oncol. 2025;36:S402–3. ∙. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 25 Mar, 2026 Reviews received at journal 27 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers invited by journal 10 Feb, 2026 Editor assigned by journal 05 Feb, 2026 Submission checks completed at journal 05 Feb, 2026 First submitted to journal 02 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8764760","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":590520955,"identity":"b7801c98-7b11-46fb-98c5-60ee5bb88c91","order_by":0,"name":"Takashi 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University","correspondingAuthor":false,"prefix":"","firstName":"Naruto","middleName":"","lastName":"Taira","suffix":""},{"id":590521026,"identity":"41eea620-26d8-447c-9814-628084637d70","order_by":18,"name":"Kazutaka Narui","email":"","orcid":"","institution":"Yokohama City University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kazutaka","middleName":"","lastName":"Narui","suffix":""},{"id":590521028,"identity":"6fc9e43c-83e9-4869-97fb-1b474f8168b1","order_by":19,"name":"Hirofumi Mukai","email":"","orcid":"","institution":"National Cancer Center East","correspondingAuthor":false,"prefix":"","firstName":"Hirofumi","middleName":"","lastName":"Mukai","suffix":""}],"badges":[],"createdAt":"2026-02-02 12:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8764760/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8764760/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102760928,"identity":"f4c5d7b7-99cf-4ac4-a065-b9c9d4ae8765","added_by":"auto","created_at":"2026-02-16 10:33:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":10298,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival (PFS) and progression-free survival 2 (PFS2). PFS2 was defined as the time from enrollment to the second objective disease progression in the subsequent treatment after PAL treatment. Cohort B contained two types of patients: “Recurrent” cases with metastatic disease during primary endocrine therapy for metastasis and “Adjuvant” cases during adjuvant endocrine therapy or \u0026lt;1 year after completion of adjuvant endocrine therapy. PFS2 in cohort B was investigated in “Recurrent” cases.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/b62f4d37edc09d0a6bff0377.png"},{"id":102760929,"identity":"fa18c31b-cf07-4ea4-9063-bcdfa44f807b","added_by":"auto","created_at":"2026-02-16 10:33:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":13440,"visible":true,"origin":"","legend":"\u003cp\u003eConsort diagram. Protocol violations were mainly due to initiation of hormonal therapy prior to the prescription of palbociclib at the time of enrollment\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/9304b27210762d89abd3e50c.png"},{"id":102760931,"identity":"f4ffeba8-f6fe-4c4a-83ec-7b1ad701356d","added_by":"auto","created_at":"2026-02-16 10:33:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":63592,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of progression-free survival in cohort A, B, and C\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/9b88dfd0fae52ff5125503b7.png"},{"id":102760932,"identity":"d5e91d92-0e73-4c6c-847a-be9048a67177","added_by":"auto","created_at":"2026-02-16 10:33:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44074,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of PFS after two treatment lines (PFS2) in cohorts A and B.\u003c/p\u003e\n\u003cp\u003ePFS2 in cohort A: time from enrollment to the second objective disease progression in subsequent treatment after PAL treatment. PFS2 in cohort B: time from the start of previous endocrine monotherapy until objective disease progression while on PAL treatment.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/4c48fa36b96685743e699482.png"},{"id":102760933,"identity":"9dca7032-4648-4e6f-ab68-bad0f9eaca4a","added_by":"auto","created_at":"2026-02-16 10:33:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":76651,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of hypothetical PFS2 in cohort B. According to the data in the CDK4/6-second group in the SONIA trial, 20 hypothetical cases assuming PFS of 5, 10 and 15 months were added to PFS2 in cohort B.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/2b017df162186ecbb55397be.png"},{"id":104397329,"identity":"96bfaad4-dd24-4739-aaf6-a7f88af2a85a","added_by":"auto","created_at":"2026-03-11 11:46:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":949568,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/15a5a480-6d33-4576-8569-ff16c13caa36.pdf"},{"id":102760927,"identity":"86922f3d-52ec-4617-91df-476e340d0294","added_by":"auto","created_at":"2026-02-16 10:33:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":40475,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8764760/v1/94662c5f9c77be57eb935a4b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real-world data for a CDK4/6 inhibitor, Palbociclib, as 1st- or 2nd-line therapy in HR+/HER2− metastatic breast cancer: A multicenter prospective cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003ePALOMA-1 was an open-label phase 2 randomized clinical trial (RCT) that, in 2015, was the first to report that a combination of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib (PAL) with letrozole significantly improved progression-free survival (PFS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), compared to 1st-line letrozole alone [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This finding was confirmed in 2016 in the multinational PALOMA-2 phase 3 RCT [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Also in 2016, in the PALOMA-3 phase 3 RCT, the combination of PAL and fulvestrant was shown to significantly improve PFS over fulvestrant alone in the 2nd-line setting [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Significant improvement in overall survival (OS) has not been shown for PAL [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], but addition of PAL to anti-hormonal agents is consistently beneficial for PFS in patients with MBC. One concern with PAL is the high incidence of hematologic adverse events (AEs), particularly neutropenia and increased fatigue [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Moreover, a higher rate of these events has been found in Japanese patients compared to the overall population in the PALOMA-2 and \u0026minus;\u0026thinsp;3 trials [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe main aims in treatment of patients with MBC, which is still an incurable disease, are to prolong life and improve quality of life (QoL). There are many treatment options available in HR+ advanced breast cancer, making it important to ask the question \u0026ldquo;What is the best sequence of treatments that will keep patients alive longest with the best QoL?\u0026rdquo;. Although most current guidelines advocate 1st-line use of CDK4/6 inhibitors, this recommendation was challenged by the SONIA trial, the first reports from which were published in 2024 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; these showed similar PFS after two treatment lines (PFS2) and similar OS if CDK4/6 inhibitors are used as 2nd-line treatment following endocrine therapy (ET). The SONIA trial protocol, which was first reported in 2018, addressed this question using a study design representing daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to ET will benefit patients most [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eReal-world data have confirmed the PFS efficacy of PAL observed in the RCTs [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, these studies were all retrospective. Soon after publication of the SONIA trial protocol, we started a prospective cohort study of PAL in postmenopausal HR+/HER2- MBC in 2019. This study was based on the hypothesis that the efficacy, safety, and QoL of PAL treatment in daily clinical practice are not inferior to those in RCTs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. We also examined if PAL might affect the efficacy and safety of subsequent treatment. Thus, the reality of early-line treatment with PAL was investigated to examine the need for 1st-line PAL in all patients.\u003c/p\u003e \u003cp\u003ePAL was used rather than ribociclib or abemaciclib. The other two CDK 4/6 inhibitors had also shown improvements in PFS in the 1st- and 2nd-line setting, but at the time of study initiation OS was unknown for all three agents and PAL was the most widely used CDK 4/6 inhibitor. OS was subsequently reported for ribociclib, PAL and abemaciclib in 2021 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], 2022 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and 2024 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], respectively. A recent review of CDK 4/6 inhibitors discussed potential differences between these agents in terms of endocrine sensitivity after CDK 4/6 inhibitors, mechanisms and biomarkers of resistance, and pharmacogenomics and ethnicity [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This current study is not a comparison of different CDK 4/6 inhibitors, but was set up to assess whether all patients with MBC require a CDK 4/6 inhibitor as 1st-line therapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eA prospective, multicenter cohort study was designed to evaluate the efficacy, safety and QoL of PAL treatment in daily clinical practice, as described in detail elsewhere [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In summary, three Cohorts (A, B, and C) were categorized by 1st-, 2nd-, and 3rd- (or later) line PAL treatment for postmenopausal metastatic or unresectable breast cancer.\u003c/p\u003e \u003cp\u003ePatients\u003c/p\u003e \u003cp\u003ePostmenopausal women diagnosed with unresectable and/or metastatic HR+/HER2- breast cancer were prospectively enrolled from designated hospitals in Japan from April 1, 2019 to January 31, 2023. As previously reported [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], Cohort A (1st-line PAL) included patients who had not received prior ET in the metastatic setting and were \u0026gt;\u0026thinsp;1 year post-completion of adjuvant ET (i.e., similar to PALOMA 2); Cohort B (2nd line PAL) included patients who had been treated with 1st-line ET for metastasis (regardless of the effect of therapy or reason for discontinuation) or who recurred\u0026thinsp;\u0026lt;\u0026thinsp;1 year after adjuvant ET or during adjuvant therapy (regardless of the duration of adjuvant ET) (i.e., similar to PALOMA 3); and Cohort C (3rd- or later-line PAL) included patients with metastatic disease treated previously with \u0026ge;\u0026thinsp;2 lines of ET (regardless of response or reason for discontinuation). Patients received PAL in combination with aromatase inhibitors, fulvestrant or tamoxifen. PAL was administered once daily for 3 weeks followed by 1 week off in 28-day cycles, and was discontinued due to disease progression (PD), unacceptable toxicity, study withdrawal, or death. Dose interruptions and reductions were allowed to manage toxic effects.\u003c/p\u003e \u003cp\u003eAssessments\u003c/p\u003e \u003cp\u003eDemographic and clinical characteristics at enrollment were assessed, including: date of surgery, pathology of surgical specimen (including HR/HER2 status), metastatic site, date of diagnosis of recurrence, pretreatment in the adjuvant or metastatic setting, prior treatment, physical findings (height, body weight and performance status after the 1st cycle), diagnostic imaging for breast cancer lesions, laboratory data, AEs prior to PAL treatment, concomitant medications, and PROs/HRQoL.\u003c/p\u003e \u003cp\u003eEfficacy\u003c/p\u003e \u003cp\u003eTumors were assessed locally at screening and every 12 weeks by imaging (ultrasound, computed tomography, magnetic resonance imaging and/or bone scan) and clinical assessment. AEs were assessed for incidence, severity, timing, grade, and association with PAL. Hematology and blood chemistry assessments were performed every two weeks for the first two cycles and at the beginning of each cycle thereafter.\u003c/p\u003e \u003cp\u003eSafety\u003c/p\u003e \u003cp\u003eAEs were recorded using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 (JCOG edition). Regardless of grade, the following AEs were recorded because they are possibly associated with PAL combined with ET in patients with breast cancer: constipation, diarrhea, oral mucositis, nausea, vomiting, malaise, pain, arthralgia, insomnia, vaginal discharge, vaginal dryness, hot flashes, alopecia, and rash. Other AEs of grade 2 or higher were also recorded.\u003c/p\u003e \u003cp\u003eStudy Endpoints\u003c/p\u003e \u003cp\u003eThe primary endpoint was PFS calculated from the date of PAL initiation to the date of PD or death from any cause. Secondary endpoints were PFS2, clinical benefit rate (CBR) (% of cases not classified as PD for 6 months), OS, AEs, patient-reported outcomes (PROs) and health-related quality of life (HRQoL). PFS, CBR and AEs were also assessed in subsequent treatment after use of PAL. PFS2 was defined from the start of 1st ET for advanced disease until the 2nd objective disease progression. Given that no OS benefit has been reported for PAL we focus on PFS and AEs, which are relevant to all CDK 4/6 inhibitors. PROs and HRQoL were also assessed during PAL-combined ET and subsequent treatment using PRO-common terminology criteria for adverse events (PRO-CTCAE), European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ C30), and EQ-5D (EuroQol 5 Dimension). These results will be reported elsewhere.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis plan has been described in detail in a previous publication [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In summary, for Cohort A, assuming a median PFS of 25 months, similar to PALOMA-2 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], if 310 patients are enrolled in a 3-year registration period and a 5-year study duration, the 90% confidence interval (CI) for PFS\u0026thinsp;\u0026le;\u0026thinsp;8 months would have a probability of 85%. Similarly, for Cohort B, assuming a median PFS of 9.5 months (similar to that reported in PALOMA-3 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]), if 180 patients were enrolled in a 3-year registration period and a 5-year study duration, the 90% CI for PFS\u0026thinsp;\u0026le;\u0026thinsp;4.5 months has a 90% probability. For Cohort C, for which 3rd-line data were limited, the expected PFS was set at 7.5 months. We assumed a median PFS of 9.5 months in this study and if 120 cases were enrolled in a 3-year registration period and a 5-year study duration, the 90% CI for PFS\u0026thinsp;\u0026le;\u0026thinsp;4 months would have an 85% probability.\u003c/p\u003e \u003cp\u003eAmong the registered cases, patients who received at least one dose of the planned PAL treatment, after excluding duplicate and erroneous registrations, were included in the analysis population. For the primary endpoint of PFS, Kaplan-Meier survival curves were estimated for each cohort. Median PFS was estimated along with the 90% CIs. PFS2 was also analyzed. For Cohort A, PFS2 was defined as the time from enrollment to the second objective disease progression in subsequent treatment after PAL treatment. PFS2 was calculated using only the cases that proceeded to 2nd-line treatment. For Cohort B, PFS2 was defined as the time from the start of previous endocrine monotherapy until objective disease progression while on PAL treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For safety, the worst grade of each AE was summarized.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eClinical and pathological characteristics\u003c/p\u003e \u003cp\u003eBetween April 2019 and January 2023, a total of 700 patients were enrolled from 69 centers across Japan. After excluding cases with contraindications, which were mainly violations of ET before addition of PAL, the final distribution was 246 in Cohort A, 282 in Cohort B, and 65 in Cohort C (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Patient demographics and background factors are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In Cohorts A, B and C, the median age was 68, 66, and 68 years, respectively, while neoadjuvant or adjuvant chemotherapy was administered in 25.6%, 55.0%, and 46.2% of cases, respectively. Because this study was initiated before insurance coverage for PAL was approved, chemotherapy was used prior to PAL treatment in the metastatic setting in 6.1%, 10.6%, and 32.3% of cases, respectively. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Adjuvant ET was administered in 38.2%, 84.4%, and 63.1% of cases in Cohorts A, B and C, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Letrozole and fulvestrant were mostly used as an anti-hormone agent in combination with PAL, at rates of 72.8% and 21.1% in Cohort A, 20.6% and 72.0% in Cohort B, and 30.8% and 41.5% in Cohort C. Tamoxifen was used in only 1.2%, 0.7% and 1.5% of cases in Cohorts A, B and C, respectively (Supplementary Table\u0026nbsp;1). Regarding the disease site, in Cohorts A, B and C, 38.3%, 58.9%, and 58.1% of the patients had visceral metastases; while 71.1%, 65.6% and 66.2% had measurable diseases; and 1.7%, 8.1%, and 4.7% had bone disease only (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In Cohort B, 126/282 cases (44.7%) relapsed during adjuvant ET and 156/282 (55.3%) relapsed during primary endocrine monotherapy for metastases; both subgroups of Cohort B are included in PFS1 for 2nd-line PAL treatment while only the latter 156 patients are included for PFS2 for endocrine monotherapy followed by 2nd-line PAL treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographics and background factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eItem\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCohort C\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;246\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;282\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;65\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (38\u0026ndash;92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (41\u0026ndash;92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68\u0026nbsp;(44\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e155 (135.5-171.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e154 (137\u0026ndash;170)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e154 (136.3-169.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.0 (33.4\u0026ndash;86.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53.0(23.9\u0026ndash;99.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54.0 (37\u0026ndash;114)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDuctal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e195 (79.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e229 (81.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49 (75.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLobular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (9.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (3.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (12.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (25.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e155 (55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e172 (69.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e121 (42.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32 (49.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAdjuvant endocrine therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (38.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e238 (84.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41 (63.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140 (56.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (12.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (27.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (9.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEndocrine therapy after recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e126 (44.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e246 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e156 (55.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eChemotherapy after recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e229 (93.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e252 (89.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44 (67.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eMeasurable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny measurable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e175 (71.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e185 (65.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43 (66.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung or liver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (38.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e109 (58.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (58.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBone only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (33.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (37.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eClinical outcomes\u003c/p\u003e \u003cp\u003eAt the follow-up data cut-off of September 30, 2023, PAL treatment was ongoing in 103/246 (41.9%) cases in Cohort A, 92/282 (32.6%) in Cohort B, and 11/65 (16.9%) in Cohort C. Dose reductions were required in 68/246 (27.6%), 59/282 (20.1%) and 15/65 (23.1%) patients, respectively. After a median follow-up of 22.5 months, the median PFS was 25.8 months (95% CI: 21.4-not reached) in Cohort A, 18.0 months (14.0-22.7) in Cohort B, and 12.0 months (7.7\u0026ndash;17.4) in Cohort C (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). CBR was 217/246 (88.2%) (95% CI 83.5\u0026ndash;92.0), 221/282 (78.4%) (95% CI 73.1\u0026ndash;83.0), and 46/65 (70.8%) (95% CI 58.2\u0026ndash;81.4) in Cohorts A, B and C, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The 90% CIs of PFS were 21.7\u0026ndash;41.4 for Cohort A, 14.5\u0026ndash;21.7 for Cohort B, and 8.1\u0026ndash;16.0 for Cohort C, all slightly narrower than the 95% CIs noted above. OS data was immature, with only 130 deaths (21.9%): 41 (16.7%) in Cohort A, 67 (23.8%) in Cohort B, and 22 (33.8%) in Cohort C. We do not report OS given the immaturity of the OS data and, as noted above, the absence of a significant OS benefit for PAL in the 1st- and 2nd-line RCTs (i.e., PALOMA 2 and 3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcomes in cohorts A, B and C\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo PD for 6 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCBR (%)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI (lower-upper limits)**\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA (N\u0026thinsp;=\u0026thinsp;246)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c4\"\u003e \u003cp\u003e83.5%-92.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB (N\u0026thinsp;=\u0026thinsp;282)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e78.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c4\"\u003e \u003cp\u003e73.1%-83.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC (N\u0026thinsp;=\u0026thinsp;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c4\"\u003e \u003cp\u003e58.2%-81.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*% of patients with CR, PR, or SD at 6 months based on imaging diagnosis\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e**Clopper-Pearson exact confidence intervals\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn Cohort A the median PFS2 was 36.4 (95% CI: 27.8-) months (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). In Cohort B, PFS2 was calculated in the 126/282 cases that relapsed during 1st-line endocrine monotherapy for metastases (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median PFS2, including the time on prior 1st-line endocrine monotherapy, was 57.9 (95% CI 45.2\u0026ndash;65.1) months (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). A post-hoc sensitivity analysis of PFS2 in Cohort B was performed as high risk patients who continued with chemotherapy instead of PAL after progressing on 1st-line endocrine monotherapy were excluded, and so data for these patients were not collected. In the SONIA trial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], 51/374 patients in the 2nd-line arm were unable to receive CDK4/6 inhibitors in the planned 2nd-line setting and ultimately received chemotherapy or other treatments. Assuming 20 similar cases, the same proportion as the SONIA trial in our Cohort B, we simulated PFS durations of 5, 10 and 15 months for these 20 patients. The Kaplan-Meier curves of the three \u0026ldquo;virtual B Cohorts\u0026rdquo; all lie between Cohorts A and B and more closely resemble PFS2 of Cohort A (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSafety\u003c/p\u003e \u003cp\u003eThe common AEs were neutropenia, leukopenia, fatigue, alopecia and stomatitis. Among non-hematologic events, fatigue, alopecia and stomatitis occurred in \u0026gt;\u0026thinsp;20% of patients in all cohorts (Supplementary Table\u0026nbsp;2). However, grade 3 events were rare. During the study-treatment period, there were 155 deaths: 149 due to disease progression and 6 with other causes, including one due to interstitial pneumonia. For hematological AEs, leukocytopenia and neutropenia were equally common in all 3 cohorts, with total rates of grade 3 or higher leukocytopenia and neutropenia of 41.3% and 73.5%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The dose was reduced in \u0026gt;\u0026thinsp;80% of cases, and \u0026lt;\u0026thinsp;20% were able to maintain the 125 mg dose at the 4th cycle (Supplementary Table\u0026nbsp;3). There were no other serious hematological toxicities, but there were a few cases of grade 3 or higher liver deterioration (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHematological adverse events of grade 3 or above\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGrade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCohort C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;246\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;593\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLeukocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89 (36.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120 (42.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 (41.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e236 (39.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91 (37.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e127 (45.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 (41.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e245 (41.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143 (58.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e179 (63.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e361 (60.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (11.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (14.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (12.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75 (12.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e170 (69.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e219 (77.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47 (72.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e436 (73.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (0.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLiver dysfunction: AST(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLiver dysfunction: ALT(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (0.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (10.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (6.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45 (7.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective study was conducted to assess the efficacy and safety of PAL with ET in postmenopausal patients in a real-world setting. The study overlapped in recruitment years with the SONIA RCT. PFS in Cohort A was similar to that in PALOMA-2 at 24.8 months in the 1st-line setting. Despite the similar entry criteria (i.e., patients who had not received prior ET in the metastatic setting and were \u0026gt;\u0026thinsp;1 year post-completion of adjuvant ET), PALOMA-2 included\u0026thinsp;~\u0026thinsp;20% of patients with recurrent breast cancer during and within 12 months after completion of adjuvant ET [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. PALOMA-2 also did not include patients who received chemotherapy after relapse, whereas Cohort A included 6.1% of such cases. However, taken together with other real-world retrospective studies [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], the median PFS is \u0026gt;\u0026thinsp;20 months when used in 1st-line treatment in a real-world setting.\u003c/p\u003e \u003cp\u003eThe median PFS periods in Cohorts B and C of 18.0 and 12.0 months, respectively, were longer than that reported in PALOMA 3 (median 9.5 months), but similar to 2nd-line studies of abemaciclib (Monarch 2; median 16.4 months) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and ribociclib (Monalessa 3; median 20.5 months) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The median PFS in Cohort B was almost double that in the PALOMA-3 trial [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. For comparison with PALOMA-3, a combined analysis of Cohorts B and C may be appropriate because PALOMA-3 included patients with 3rd-line treatment. PFS in Cohort C was also longer than that in PALOMA-3. It is not surprising that 2nd-line treatment outcomes vary more across trials compared to those for 1st-line treatment because of differences in patient background. For example, about 20% of patients in the PALOMA-3 and Monarch 2 studies were pre- or perimenopausal, whereas all patients in this study were postmenopausal. A large-scale retrospective study in Japanese patients reported PFS for 2nd-line PAL of 14.5 months [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Taken together with our prospective study, PFS of 2nd- or 3rd-line PAL may be more favorable in the real world setting in Japan compared with the PALOMA-3 trial.\u003c/p\u003e \u003cp\u003eRCTs on all three CDK4/6 inhibitors have shown clear evidence of improved PFS in 1st-line therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, none of these 1st-line studies allowed crossover to a CDK4/6 inhibitor in the control group after progression on 1st-line ET, despite evidence for a benefit from 2nd-line CDK 4/6 inhibitors from prior studies. As a result, these RCTs without crossover do not inform patients or caregivers about the optimal sequence of treatments that keep patients alive longest with the best possible QoL. In addition, from a societal perspective, it is likely that using expensive drugs early and for longer in PFS1 has higher costs. The SONIA study addressed this question, using a RCT of an aromatase inhibitor\u0026thinsp;\u0026plusmn;\u0026thinsp;CDK4/6 inhibitor in 1st-line therapy with a protocol that included crossover to fulvestrant in 2nd-line therapy with a CDK4/6 inhibitor for patients who had not received it as 1st-line [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The primary endpoint of the trial, median PFS2, showed no difference between the two arms (31.0 vs. 26.8 months), but with 72% higher Grade 3 or 4 side-effects and an increase of \u003cspan\u003e$\u003c/span\u003e200,000 per patient for use of the CDK 4/6 inhibitor as 1st-line therapy.\u003c/p\u003e \u003cp\u003eA recent presentation at ESMO 2025 suggested no difference in OS after median follow-up of 58.5 months, with median OS of 47.9 months for a 1st-line CDK 4/6 inhibitor and 48.1 months for a 2nd-line CDK 4/6 inhibitor (HR\u0026thinsp;=\u0026thinsp;0.91; 95% CI 0,77\u0026ndash;1.07; p\u0026thinsp;=\u0026thinsp;0.24) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our prospective observational study included only postmenopausal patients. In the SONIA trial 905 patients (87%) were postmenopausal, with no significant difference in this subgroup (HR 1.00; 99% CI 0.80\u0026ndash;1.25; P\u0026thinsp;=\u0026thinsp;0.01 vs. premenopausal subgroup). In addition to increased grade 3 or 4 side-effects with a 1st-line CDK 4/6 inhibitor, there is a significant financial disadvantage due to increased time on PAL in the 1st-line setting. All of these factors collectively indicate that early use of PAL does not benefit patients.\u003c/p\u003e \u003cp\u003eThe median PFS2 in our study was 36.9 and 57.9 months in Cohorts A and B, respectively, whereas the SONIA trial found PFS of 31.0 and 26.8 months for sequential use of a CDK 4/6 inhibitor in the 1st- and 2nd-lines, respectively. Thus, PFS 2 in Cohort A is similar to the results in the SONIA trial for 1st-line use of a CDK 4/6 inhibitor, whereas PFS2 in Cohort B is significantly greater than the 2nd-line results in SONIA. PFS2 may be overestimated due to the eligibility criteria for Cohort B, which allowed patients to receive 1st-line endocrine monotherapy followed by PAL as 2nd-line therapy. A potential selection bias may have arisen from clinicians\u0026rsquo; preference to administer chemotherapy rather than 2nd-line ET\u0026thinsp;+\u0026thinsp;CDK4/6 inhibitor for patients with a poor response to 1st-line ET, thereby excluding them from Cohort B. Thus, a post hoc sensitivity analysis was conducted with reference to the SONIA trial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], in which we modelled a similar percentage of patients in the SONIA trial who were unable to receive CDK4/6 inhibitors in the planned 2nd-line setting and ultimately received chemotherapy or other treatments. This reduced PFS2 for the group using PAL as 2nd-line therapy to closer to the median PFS2 for 1st-line PAL therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The result for Cohort B further supports the SONIA study and indicates the validity of 2nd-line treatment as an option for clinicians to use if they deem it appropriate.\u003c/p\u003e \u003cp\u003eRegarding side-effects, neutropenia was a frequent AE in all cohorts, with a 10% higher rate of grade 3 or higher neutropenia than in PALOMA-2 and \u0026minus;\u0026thinsp;3 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Thus, the dose was reduced in \u0026gt;\u0026thinsp;80% of cases. However, no febrile neutropenia occurred, and other AEs were reasonably tolerable, including non-hematological AEs. Based on the clinical outcomes of this trial, PAL treatment was considered to have been successfully implemented with appropriate dose reductions in response to neutropenia. Low grade symptoms such as fatigue, oral mucositis and lower GI symptoms (e.g., constipation and diarrhea) were common (i.e., 5\u0026ndash;10%) on the CDK 4\u0026ndash;6 inhibitor regimen.\u003c/p\u003e \u003cp\u003eThe main strength of this study is that it supports the findings of the SONIA RCT using real-world data. There are many patients in whom recurrence can be initially controlled for a significant period with endocrine monotherapy. Thus, use of ET, while observing the hormone sensitivity of each case and adding PAL if poor sensitivity to ET is determined, is a rational approach that provides effective early ET at lower cost and with less toxicity, while knowing that 2nd-line ET\u0026thinsp;+\u0026thinsp;CDK 4/6 inhibitor therapy will be available with no detriment to OS. A further strength of this study is that the real-life data is in patients drawn from a different geographic region and ethnic population than those in the SONIA RCT.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it is not randomized, which limits interpretation of the efficacy of adding PAL, particularly as 2nd line, since patients with poorer responses to 1st-line endocrine monotherapy might have been given chemotherapy rather than ET\u0026thinsp;+\u0026thinsp;PAL. This also means that patients included in Cohort B may have had a higher sensitivity to ET as the disease was well controlled with ET before PAL treatment, compared to the 2nd-line CDK 4\u0026ndash;6 inhibitor arm in the SONIA trial. However, we used a sensitivity analysis to try to account for this bias. A further limitation is that a longer observation period would have been useful to examine clinical outcomes for HR+/HER- MBC (e.g., OS), but enrollment was delayed from the initial protocol due to the Coronavirus pandemic. Thus, the median PFS2 was not observed, although the primary endpoint of median PFS1 was observed. Fourth, 91 cases were excluded from analyses because of a violation of adding PAL after starting anti-endocrine agents. In routine clinical practice, anti-endocrine agents could be started prior to PAL; however, the protocol did not allow for this in order to categorize the cohort rigorously in this prospective study.\u003c/p\u003e \u003cp\u003eIn conclusion, this study confirmed that real-world post-menopausal patients with HR+HER2- MBC have outcomes that are comparable to those observed in prior clinical trials. The results of the ongoing investigation of PROs/HRQoL are awaited, but PAL treatment was successfully implemented with appropriate dose reductions in response to neutropenia. Results with the use of PAL in the 2nd-line setting following the 1st-line endocrine monotherapy were as good as those with PAL in the 1st-line setting. Thus, we support the SONIA concept, which raises concerns about the current widespread 1st-line recommendation for PAL without randomized crossover trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthics approval and consent to participate:\u003c/h2\u003e \u003cp\u003e This study was approved by the protocol review committee of the Comprehensive Support Project for Oncological Research of Breast Cancer on March 10, 2018 (approval number T2018-0026) and registered in the UMIN Clinical Trials Registry as UMIN000035863 on February 20, 2019. Ethical approval was obtained from all institutions. The study was conducted in accordance with the legal and regulatory requirements and the general principles of the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), the Guidelines of Good Clinical Practice (International Conference on Harmonization 1996), and the Declaration of Helsinki (World Medical Association 1996 and 2008). Written informed consent was obtained from all participants.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.I., K.N., and H.M. conceived and designed the study.T.I., K.N., Y.K., H.M., and Y.U. analyzed the data.Y.U. performed the statistical analysis.H.S., T.I., M.K., T.S., K.M., S.T., D.T., T.Y., M.K., Y.K., A.Y., U.T., H.N., H.K., K.Y., R.N., N.T., and K.N. contributed to patient accrual.T.I. and H.M. wrote the original draft of the manuscript and were responsible for interpretation of the data and manuscript revisions.All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank all the patients who participated in this trial and their families; all members of the study committee; and the staff at all 69 hospitals and the CSPOR data center. We express our sincere and deepest gratitude to Dr. Gabe S. Sonke and Dr. John F.R. Robertson for their invaluable, insightful, and critical review of this manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData associated with the study will be made available upon request to the corresponding author, with appropriate restrictions to maintain patient privacy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFinn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol. 2015;16:25\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFinn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlamon DJ, Di\u0026eacute;ras V, Rugo HS, Harbeck N, Im SA, Gelmon KA, et al. Overall survival with palbociclib plus letrozole in advanced breast cancer. J Clin Oncol. 2024;42:994\u0026ndash;1000.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTurner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMukai H, Shimizu C, Masuda N, Ohtani S, Ohno S, Takahashi M, et al. Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients. Int J Clin Oncol. 2018;24:274\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasuda N, Inoue K, Nakamura R, Rai Y, Mukai H, Ohno S, et al. Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. Int J Clin Oncol. 2019;24:262\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024;636:474\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Ommen-Nijhof A, Konings IR, van Zeijl CJJ, Uyl-de Groot CA, van der Noort V, Jager A, et al. Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer \u0026ndash; the SONIA study: Study protocol for a randomized controlled trial. BMC Cancer. 2018;18:1146.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKish JK, Ward MA, Garofalo D, Ahmed HV, McRoy L, Laney J, et al. Real-world evidence analysis of palbociclib prescribing patterns for patients with advanced/metastatic breast cancer treated in community oncology practice in the USA one year post approval. Breast Cancer Res. 2018;20:37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVarella L, Eziokwu AS, Jia X, Kruse M, Moore HCF, Budd GT, et al. Real-world clinical outcomes and toxicity in metastatic breast cancer patients treated with palbociclib and endocrine therapy. Breast Cancer Res Treat. 2019;176:429\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeMichele A, Cristofanilli M, Brufsky A, Liu X, Mardekian J, McRoy L, et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US real-world clinical practice. Breast Cancer Res. 2021;23:37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshinami T, Nagai SE, Hattori M, Okamura T, Watanabe K, Nakayama T, et al. Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study. Breast Cancer. 2024;31:621\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagai SE, Hattori M, Yoshinami T, Masuda H, Okamura T, Watanabe K, et al. Overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- advanced breast cancer in the first-or second-line setting: a multicenter observational study (P-BRIDGE study). Breast cancer (Tokyo Japan). 2025;32:705\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;nez-Ja\u0026ntilde;ez N, Ezquerra MB, Manso Sanchez LM, Carrasco FH, Torres AA, Morales S, et al. First-line therapy with palbociclib in patients with advanced HR+/HER2- breast cancer: The real-life study PALBOSPAIN. Breast Cancer Res Treat. 2024;206:317\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, et al. Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2\u0026ndash;) advanced breast cancer (ABC) treated with endocrine therapy (ET) \u0026plusmn; ribociclib (RIB). Ann Oncol. 2021;32:S1290\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFinn RS, Rugo HS, Dieras VC, Harbeck N, Im SA, Gelmon KA, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL\u0026thinsp;+\u0026thinsp;LET) versus placebo plus letrozole (PBO\u0026thinsp;+\u0026thinsp;LET) in women with estrogen receptor\u0026ndash;positive/human epidermal growth factor receptor 2\u0026ndash;negative advanced breast cancer (ER+/HER2\u0026thinsp;\u0026ndash;\u0026thinsp;ABC): analyses from PALOMA-2. J Clin Oncol. 2022;40(17):LBA1003.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoetz MP, Toi M, Huober J, Sohn J, Tr\u0026eacute;dan O, Park IH, et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2\u0026thinsp;\u0026ndash;\u0026thinsp;advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024;35:718\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Sullivan CC, Clarke R, Goetz MP, Robertson J. Cyclin-dependent kinase 4/6 inhibitors for treatment of hormone receptor-positive, ERBB2-negative breast cancer: A review. JAMA Oncol. 2023;9:1273\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNarui K, Ishikawa T, Taira N, Uemura Y, Mukai H. Prospective cohort study of palbociclib treatment in postmenopausal patients with unresectable and metastatic hormone receptor-positive breast cancer: Study protocol for a CSPOR-BC palbociclib cohort trial. World J Oncol. 2022;13:190\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSledge GW, Masakazu Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017;35(25):2875\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWortelboer N, Ommen-Nijhof AV, Konings IR, Noort VVD, Pol EVD, P\u0026aacute;ez C, et al. Overall survival with first versus second-line use of CDK4/6 inhibitors in HR+/HER2- advanced breast cancer. Ann Oncol. 2025;36:S402\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026amp;#8729.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brcr","sideBox":"Learn more about [Breast Cancer Research](http://breast-cancer-research.biomedcentral.com)","snPcode":"13058","submissionUrl":"https://submission.nature.com/new-submission/13058/3","title":"Breast Cancer Research","twitterHandle":"@BCRJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, Palbociclib, Prospective cohort","lastPublishedDoi":"10.21203/rs.3.rs-8764760/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8764760/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePalbociclib (PAL), the first CDK4/6 inhibitor approved for breast cancer, improves progression-free survival (PFS) in hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) when added to an aromatase inhibitor or fulvestrant, but also increases toxicity compared to endocrine therapy alone. Use of PAL in 1st-line treatment increases the burden on patients and adds to costs compared to use as 2nd-line treatment, due to the longer period of 1st-line treatment. Therefore, data on use of PAL in a real-world setting are required to assess the merits of 1st- and 2nd-line therapy in the sequence of treatment for MBC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA prospective observational study was performed in patients with postmenopausal metastatic or unresectable breast cancer using PAL in 1st-, 2nd-, or 3rd-line treatment. The primary endpoint was PFS (start of PAL to progression or death). Secondary endpoints included PFS2 (start of 1st-line endocrine treatment to second progression) and adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study included 593 patients treated with PAL (246 1st-line, 282 2nd-line, 65 3rd-line) from April 2019 to January 2023. Median PFS was 25.8 (95%CI: 21.4), 18.0 (14.0-22.7), and 12.0 (7.7–17.4) months, for 1st-, 2nd- and 3rd-line use respectively. Median PFS2 was 36.9 (27.7-not reached) and 57.9 (43.4–65.3) months in the 1st- and 2nd-line cohorts. Neutropenia of grade ≥ 3 occurred in 70% of patients, and \u0026gt; 80% required dose reductions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePFS for the 1st-line cohort was similar to that in PALOMA-2, while the 2nd-line cohort had better outcomes than those in PALOMA-3, even when modelled for potential bias since some patients on 1st-line endocrine monotherapy would have received chemotherapy rather than 2nd-line PAL. Overall, the findings in this study of real-life treatment of patients with HR+/HER2- MBC support randomized control trial data that challenge the need to use a CDK4/6 inhibitor in the 1st-line setting for all patients.\u003c/p\u003e\n\u003cp\u003eClinical Trial Registration: UMIN000035863\u003c/p\u003e","manuscriptTitle":"Real-world data for a CDK4/6 inhibitor, Palbociclib, as 1st- or 2nd-line therapy in HR+/HER2− metastatic breast cancer: A multicenter prospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 10:33:22","doi":"10.21203/rs.3.rs-8764760/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-25T14:14:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-27T14:05:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73452105438767434245810678536232973502","date":"2026-02-10T21:58:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-10T21:00:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T02:05:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-05T22:30:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research","date":"2026-02-02T11:40:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brcr","sideBox":"Learn more about [Breast Cancer Research](http://breast-cancer-research.biomedcentral.com)","snPcode":"13058","submissionUrl":"https://submission.nature.com/new-submission/13058/3","title":"Breast Cancer Research","twitterHandle":"@BCRJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"959ef6a5-aed5-4db2-9986-5e9b5894681b","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T19:08:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-16 10:33:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8764760","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8764760","identity":"rs-8764760","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}