Editorial Note: The results of studies such as postMONARCH and Young-PEARL presented at the 2024 ASCO Annual Meeting have sparked a new round of discussions on treatment strategies for patients with HR+/HER2- advanced breast cancer. To gain deeper insights into the significance of these studies and their implications for clinical practice, Professor Shaohua Zhang from The Fifth Medical Center of PLA General Hospital provided a detailed analysis of the relevant research at the 2024 BOC/BOA Annual Meeting.

Oncology Frontier: In the postMONARCH study, what treatment advantages did abemaciclib + fulvestrant show over placebo + fulvestrant for patients with disease progression after CDK4/6 inhibitor + endocrine therapy (ET)?

Professor Shaohua Zhang: The postMONARCH study is a prospective, Phase III, randomized controlled trial that included pre- and post-menopausal women and men with HR+/HER2- advanced breast cancer. These patients initially received AI + CDK4/6 inhibitor therapy and later progressed or relapsed in the advanced stage without receiving other treatments.

The study showed that approximately 62% of patients had visceral metastases and about 20% had bone-only metastases. Nearly all patients had previously received CDK4/6 inhibitors, with a median duration of about 20 months, and approximately one-quarter of patients had a treatment duration of less than 12 months. Previous CDK4/6 inhibitors used included palbociclib in 59% of patients, ribociclib in 34%, and abemaciclib in 8%.

In contrast to other studies, the uniqueness of the postMONARCH study lies in its inclusion of only patients who progressed immediately after initial treatment and did not cover patients who had received late-stage chemotherapy, making it a true second-line study. In other studies, the proportion of patients who received chemotherapy was approximately 20%, covering second- and third-line treatments.

In the postMONARCH study, the abemaciclib + fulvestrant group demonstrated a significant improvement in PFS. The statistical hypothesis hazard ratio (HR) was 0.7, with an actual HR of 0.73, and median PFS was 6.0 months vs. 5.3 months, showing statistical significance (P=0.02). Additionally, the objective response rate (ORR) also improved, with rates of 17% vs. 7% (P=0.0145). Therefore, abemaciclib in combination with fulvestrant is a viable treatment option for HR+/HER2- breast cancer patients who experience disease progression after CDK4/6 inhibitor therapy, regardless of PI3K/AKT pathway or ESR1 mutation status.

In subgroup analyses, patients without visceral metastases showed a significant PFS improvement with abemaciclib, with a difference of 5.5 months (5.6 months vs. 11.1 months) and an HR of 0.53. In the subgroup with visceral metastases, the difference in PFS between the two groups was approximately 2 months (3.7 months vs. 5.4 months). For patients who had previously received CDK4/6 inhibitors for more than 12 months, PFS improved from 5.4 months to 7.0 months in the abemaciclib group, with an HR of 0.7, which was significant. Therefore, patients without visceral metastases and those who have been treated with CDK4/6 inhibitors for a longer period may benefit more from abemaciclib + fulvestrant treatment. In terms of safety, abemaciclib’s safety profile was consistent with what is known, with a low discontinuation rate (6%).

Oncology Frontier: With multiple options available post-CDK4/6 inhibitor therapy, and considering the results of the postMONARCH study, what is the role of switching to another CDK4/6 inhibitor + ET in the treatment strategy for patients with HR+/HER2- advanced breast cancer who experience disease progression after CDK4/6 inhibitor therapy?

Professor Shaohua Zhang: Multiple authoritative breast cancer guidelines both domestically and abroad uniformly recommend CDK4/6 inhibitor combined with endocrine therapy as the first-line standard treatment regimen for patients with HR+/HER2-MBC. However, the standard treatment after CDK4/6 inhibitor therapy is still unclear.

In general, treatment selection is based on individual factors such as the patient’s previous treatment history, genetic mutation status, and tumor burden. For example, for patients with abnormal PI3K pathways, PI3K inhibitors or AKT inhibitors may be considered; for patients with ESR1 mutations, oral SERD drugs may be an option; and for patients with BRCA1/2 gene mutations, PARP inhibitors such as olaparib are also viable. In addition, ADC drugs have shown good data in late-stage treatment, such as the DB-06 study presented at this year’s ASCO conference, which reconfirmed the efficacy of trastuzumab deruxtecan in HR+/HER2-low and HER2-ultralow mBC patients who have received ≥1 line of endocrine therapy.

In HR+/HER2- advanced breast cancer patients after CDK4/6 inhibitor therapy, treatment options are becoming increasingly diversified. In a gradually personalized treatment mode, switching to another CDK4/6 inhibitor, even for patients without specific target detection or due to drug economics, is an effective and reasonable treatment choice.

Based on previous evidence-based medicine, there is still no consensus on the advantages and disadvantages of switching to another CDK4/6 inhibitor + ET in patients with HR+/HER2- advanced breast cancer after CDK4/6 inhibitor therapy. The MAINTAIN study showed that switching to PAL + AI significantly prolonged PFS in patients after CDK4/6 inhibitor therapy. Whether switching to AL + AI has clinical significance in patients after CDK4/6 inhibitor therapy needs further exploration in future clinical trials.

Oncology Frontier: What impact does CDK4/6 inhibitor + ET have on median survival in patients with disease progression after treatment?

Professor Shaohua Zhang: Mid-term analysis results from the postMONARCH study show that abemaciclib in combination with fulvestrant does not significantly increase median survival in patients with HR+/HER2- advanced breast cancer who progressed after treatment. However, extended median survival can still be observed in patients who showed low or no sensitivity to endocrine therapy during first-line treatment.

For patients who demonstrated low or no sensitivity to endocrine therapy during first-line treatment, the study showed: PFS with PAL + AI was approximately 9.0 months, with an HR of 0.8. In patients with disease progression, PFS with abemaciclib + AI/AL was approximately 5.0 months, with an HR of 0.7, showing significant differences. In patients with disease progression, PFS with abemaciclib + AI/AL was approximately 5.0 months, with an HR of 0.7, showing significant differences.

Professor Shaohua Zhang

The Fifth Medical Center, PLA General Hospital Doctor of Medicine, Associate Chief Physician Deputy Director, Department of Oncology, PLA General Hospital Council Member, Chinese Society of Clinical Oncology (CSCO) Executive Committee Member and Deputy Secretary-General, CSCO Breast Cancer Expert Committee Director, Breast Disease Channel, Medical Reference News