In this P-BRIDGE study, real-world, multi-center, observational study conducted in nearly 700 patients with HR+/HER2− ABC in Japan, the median OS with palbociclib treatment was over 5 years in 1L treatment after 48-months follow-up; the respective 5-year survival rate was 56.5%. Recently, the PALOMA-2 study, one of the pivotal studies of palbociclib, reported the median OS of 53.9 months (95% CI: 49.8-60.8) [11]. Several patient characteristics were similar between the PALOMA-2 and P-BRIDGE (1L population) studies, such as the presence of visceral metastasis (48.2% and 50.2%). However, there were differences in ECOG status (0, 1: 63.1%, 15.7% and 57.9%, 40.1%, respectively) and pre/perimenopausal status (0% and 20.1%) and in TFI. Notably, 20% of patients in the PALOMA-2 study had a TFI of ≤ 12 months, whereas 40% of patients in the P-BRIDGE study had a TFI of ≤ 12 months, indicating a different patient population in P-BRIDGE. Additionally, in P-BRIDGE, the combination of palbociclib with fulvestrant was the most frequently selected therapy. This choice may reflect its use in treating patients with a TFI < 12 months. This finding contrasts with the PALOMA-2 study, which was designed to examine letrozole as the sole hormone therapy combined with palbociclib. Another recent study, PARSIFAL-LONG [16], reported a median OS of 65.4 months (95% CI: 57.8-72.0) in the 5-year extended follow-up of PARSIFAL [17]. The main difference between the PARSIFAL-LONG and P-BRIDGE studies was the TFI population; PARSIFAL-LONG did not include patients with a TFI of < 12 months, focusing only on hormone-sensitive patients (ie. TFI > 12 months or de novo). In the P-BRIDGE study, the comparative population for hormone sensitivity included patients with a TFI ≥ 12 months and those with de novo metastatic disease. Although the median OS was not reached in our study, the 60-month survival rates were 72.9% (TFI ≥ 12 months) and 60% (de novo stage IV). Despite including 40% of patients with a TFI of ≤ 12 months, the median OS in the P-BRIDGE study exceeded five years, comparable to the PARSIFAL-LONG study.

Several studies have demonstrated the real-world effectiveness of palbociclib in clinical practice. In the P-REALITY X study [14], the real-world study in routine US clinical practice to date, the median PFS and OS were 19.8 months (95% CI, 17.9-21.7) and 49.1 months (95% CI, 45.2-57.7), respectively, in patients receiving first-line palbociclib (n = 1,572). The 2-year OS rate was 76.6%. When comparing patient backgrounds between P-BRIDGE and P-REALITY X, patients in P-BRIDGE tended to be younger (median age: 60 versus 70 years) and had a better ECOG Performance Status (0-1: 80% and 53%). More patients in P-BRIDGE had visceral (54% and 34%) and de novo metastatic disease at diagnosis (54% and 34%). Similarly, the PALBOSPAIN study, a retrospective, multi-center, observational, study evaluating real-world patterns and outcomes with first-line palbociclib in men and women with advanced HR+/HER2– breast cancer in Spain, reported a median real-world PFS and OS of 24 and 42 months, respectively [18]. The patient backgrounds were similar between P-BRIDGE and PALBOSPAIN, including frequencies of premenopausal patients (20.1% versus 15.6%), visceral metastasis (50.2% versus 54.9%), and TFI ≤ 12 months (45.8% versus 31.8%). Acknowledging caution in any comparison of rwPFS across different real-world studies, the respective median values in P-BRIDGE and PALBOSPAIN were similar (26.2 months [95% CI, 21.4-30.4] and 24 months [95% CI, 21-27]). However, median OS was longer in the P-BRIDGE study (68.2 months [95% CI, 60.8-NE]) compared to the PALBOSPAIN study (42 months [95% CI, 40-NE]), suggesting a potential contribution of differences in subsequent treatments between these two studies.

In the P-BRIDGE study, the proportion of subsequent therapies after palbociclib plus ET was similar to the PALOMA-2 study, including endocrine-based therapy (61.7% in the P-BRIDGE study and 60.8% in PALOMA-2 study, respectively) and chemotherapy (34.2% and 36.6%, respectively). However, 24.4% of patients in the P-BRIDGE study received CDK4/6 inhibitors plus ET as subsequent therapy after palbociclib plus ET, which differs from PALOMA-2 (0%). Positive results have recently been presented regarding post-CDK4/6 inhibitor treatments, including postMONARCH and CAPItello-291 [19, 20]. Such new treatment strategies might have impacted the OS outcome, underlining the requirement to further consider treatment strategies, such as combination therapy with molecular target drugs, to improve patients' lives.

Interestingly, a Japanese phase 2 study demonstrated a median OS of 85.4 months with a median follow-up of 89.7 months, investigating the efficacy and safety of first-line palbociclib combined with letrozole in postmenopausal Japanese women with ER+/HER2− ABC [21]. This phase 2 follow-up study also indicated a numerically longer median OS, and the reasons for this extended OS are being investigated, including factors such as subsequent therapy and other related aspects. Further, factors unique to Japan, such as subsequent treatment patterns, the medical environment, and the insurance system, might contribute to this OS result. The reason for the median OS over 5 years requires further investigation with RWD from Japan and other countries.

In the 1L treatment setting, patients without liver metastasis had longer OS compared with patients with liver metastasis (NR [68.0-NE] months and 46.4 [37.2-NE] months, respectively). This trend was also observed in rwPFS. As shown in Supplementary Tables 3-6, we could not find any differences in patients’ backgrounds as well as treatment patterns and dose modifications between those with/without liver metastasis (Supplementary Tables 3-6). These findings suggest a poorer prognosis for 1L patients with liver metastases; therefore, it is crucial to carefully consider the strategy of subsequent therapy in this population.

In 2L treatment group, some of the patient backgrounds were similar between PALOMA-3 and P-BRIDGE study such as ECOG PS 0 (59.7% and 57.3%) and incidence of visceral metastases (59.4% and 59.9%). Although PALOMA-3 study included multiple treatment lines (1L 24.2%, 2L 38.0%, 3L 25.9%, and more than 3L 11.8%), the median PFS was 11.2 months and OS was 34.8 months. Of note, the median OS was 38.0 months among the patient with only one prior line of therapy for metastatic disease [12]. In the P-BRIDGE study, rwPFS was 14.9 months and OS was 50.7 months in the 2L treatment group after 48.1 months follow-up, confirming the effectiveness of palbociclib as 2L treatment in Japanese routine clinical practice.

This real-world study has several potential limitations. This study is a retrospective data retrieval from electronic medical records, which may include missing or erroneous data. Some subgroups analysed had small sample sizes, which may have influenced the results. Short duration of follow-up, and lack of a control arm cause limitations especially in the assessment of time-to-event outcomes. Moreover, this study did not collect data on adverse events, given the challenges of reliable and consistent safety reporting in a retrospective chart review. Therefore, conclusions regarding the safety of palbociclib in the Japanese real-world setting cannot be directly drawn from this study. Disease progression was not based on standard criteria (e.g., Response Evaluation Criteria in Solid Tumors), but instead on the individual treating physician’s clinical assessment and interpretation of radiographic or pathologic results. Findings presented here may not be generalizable to patient populations in other country. Nevertheless, real-world data may be more representative of the effectiveness of treatment in the general population, and our study extends upon our understanding of outcomes associated with palbociclib combined with ET in Japanese patients.

In conclusion, the findings from this P-BRIDGE study derived from routine clinical practice in Japan further underline the clinical benefits observed thus far with palbociclib plus ET in the real-world setting. More than 5 years of median OS was observed in the 1L palbociclib plus ET treatment group, supporting the use of palbociclib plus ET as a 1L standard of care for HR+/HER2– ABC.