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Options after progression on first-line CDK4/6 inhibitors in advanced breast cancer patients

Xiaomeng Jia1, Kainan Wang1, Xueqing Wang1

  • 1The Second Hospital of Dalian Medical University, Dalian, China.

Therapeutic Advances in Medical Oncology
|June 9, 2025
PubMed
Abstract

Insights

For advanced hormone receptor-positive breast cancer resistant to CDK4/6 inhibitors, the combination of CDK4/6 inhibitors and fulvestrant is the most effective second-line treatment. Other options like Bcl-2 inhibitors plus fulvestrant and selective estrogen receptor degraders show promise.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Optimal second-line treatment for advanced hormone receptor-positive (HR+) breast cancer with CDK4/6 inhibitor (CDK4/6i) resistance is not established.
  • CDK4/6 inhibitors have revolutionized HR+ advanced breast cancer treatment, but resistance necessitates effective subsequent therapies.

Purpose of the Study:

  • To identify the optimal second-line treatment for HR+ advanced breast cancer patients who have progressed on CDK4/6 inhibitors.
  • To evaluate the efficacy of various treatment regimens using network meta-analysis.
  • To explore how genetic background and clinical characteristics influence treatment efficacy through subgroup analyses.

Main Methods:

  • Systematic review and Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs).
  • Searched Medline, Embase, and Cochrane Library for relevant RCTs.
  • Primary outcome: progression-free survival (PFS); Secondary outcomes: overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR). Subgroup analyses focused on visceral metastasis and ESR1 mutations.

Main Results:

  • Analysis included 19 trials (6621 patients), with 14 studies (3876 patients) reporting on CDK4/6i-pretreated populations.
  • Combination of CDK4/6 inhibitors and fulvestrant (Ful) demonstrated superior PFS in CDK4/6i-pretreated HR+ advanced breast cancer.
  • Subgroup analyses for visceral metastasis and ESR1 mutations supported the efficacy of CDK4/6i + Ful. Bcl-2 inhibitor (Bcl-2i) + Ful showed favorable OS, while selective estrogen receptor degraders (SERD) and CDK4/6i + ET were beneficial for ORR and CBR, respectively.

Conclusions:

  • CDK4/6 inhibitor plus fulvestrant is the most effective second-line treatment for CDK4/6i-pretreated HR+ advanced breast cancer, especially in patients with visceral metastases or ESR1 mutations.
  • Bcl-2 inhibitor plus fulvestrant and selective estrogen receptor degraders represent potential alternative second-line strategies.
Keywords:
CDK4/6 inhibitorCDK4/6i resistanceHR-positivemetastatic/advanced breast cancer

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