Editor's Note: Hormone receptor-positive (HR+) breast cancer accounts for about 70% of all breast cancers. With endocrine therapy as the foundation, chemotherapy, targeted therapy, novel antibody-drug conjugates (ADCs), and immune checkpoint inhibitors (ICIs) provide a wealth of treatment options for HR+ advanced breast cancer patients, also offering more potential combinations for clinical practice. In this "Man Talks Breast Cancer: ASCO Special," Professor Man Li's team from The Second Affiliated Hospital of Dalian Medical University has selected the latest ASCO studies on HR+ advanced breast cancer, covering topics such as cross-line treatment with CDK4/6 inhibitors, novel ADCs combined with ICIs, and comparing CDK4/6 inhibitors + ET with chemotherapy in premenopausal women. These can provide more valuable insights for clinical practice.

The “ET vs. CT” Debate in Premenopausal Women—First OS Results from the Young-PEARL Study

Study Overview

Background The phase II Young-PEARL (KCSG-BR 15-10) study compared palbociclib combined with endocrine therapy (ET) to chemotherapy in premenopausal HR+/HER2- advanced breast cancer patients. Initial PFS results were presented at the 2019 ASCO Annual Meeting. The 2024 ASCO meeting reported extended follow-up results, providing important references for the use of palbociclib combined with ET in HR+/HER2- advanced breast cancer.

Design This prospective, multicenter, randomized phase II study enrolled 189 premenopausal HR+/HER2- advanced breast cancer patients, with 178 included in the final analysis. First-line advanced patients must have received tamoxifen treatment before enrollment. Patients were randomized 1:1 to receive CDK4/6 inhibitor palbociclib + exemestane + goserelin or capecitabine. The primary endpoint was investigator-assessed PFS; secondary endpoints included DCR, OS, AE, QoL, and biomarkers.

Enrollment Young-PEARL enrolled 50% first-line advanced treatment patients and 33% second-line advanced treatment patients, with about 20% having received first-line chemotherapy for advanced disease. 94% of patients had only received tamoxifen endocrine therapy, with no AI usage.

Results With a median follow-up of 54 months, the primary endpoint analysis showed that palbociclib combined with ET had a median PFS of 19.5 months vs. 14.0 months for capecitabine (HR 0.744, 95% CI: 0.567-0.975, P=0.0357). Subgroup analysis showed similar trends. The first OS results showed median OS of 54.8 months vs. 57.8 months (HR 1.021, 95% CI: 0.689-1.511, P=0.919). OS analysis excluding post-progression CDK4/6 inhibitor usage showed a trend favoring palbociclib combined with ET: 49.0 months vs. 38.8 months (P=0.065). Most patients in the capecitabine group received endocrine therapy post-progression (80.3%), while the palbociclib + ET group received more chemotherapy (63.4%) with only 28.2% receiving endocrine therapy.

Expert Commentary

Young-PEARL is the first study exclusively enrolling premenopausal women to compare CDK4/6 inhibitor palbociclib combined with ET to single-agent capecitabine. Initial results from 2019 showed significant PFS benefit for palbociclib + exemestane + goserelin over capecitabine. The 2024 extended follow-up data show similar PFS trends and report new OS results (54.8 months vs. 57.8 months, HR 1.021, 95% CI: 0.689-1.511). Although there was no significant OS benefit, evaluating OS in HR+/HER2- advanced patients requires a multi-dimensional approach. Subgroup analysis suggests that palbociclib combined with ET is more beneficial for patients without prior advanced chemotherapy. While no OS difference was seen, the rapid development of targeted therapies and new endocrine agents suggests that maximizing each treatment’s PFS is crucial for providing more opportunities for patients to benefit from new drugs.

The study also highlighted treatment choices post-progression. Most patients in the palbociclib + ET group did not continue endocrine therapy but switched to chemotherapy, while the capecitabine group mostly continued with endocrine therapy, including CDK4/6 inhibitors. Excluding post-progression CDK4/6 inhibitor use, OS analysis showed a more pronounced benefit for palbociclib combined with ET. This emphasizes the importance of strategic treatment planning to maximize overall survival benefits for HR+/HER2- advanced breast cancer patients.

OS benefits are the sum of multi-line treatment efficacy, and achieving PFS benefits in each line leads to OS benefits. In the era of rapidly evolving new drugs, considering the OS impact of the first drug is crucial, especially for advanced cancers with good prognosis and multiple lines of treatment.