Combination cancer drugs extend survival for thousands of breast cancer patients

<p><strong>BACKGROUND: </strong>CDK4/6 inhibitors have shown clinical benefits in patients with hormone receptor-positive, HER2-negative advanced breast cancer. This meta-analysis aims to evaluate their effect on survival outcomes across clinically relevant subgroups.</p><p><strong>METHODS:</strong> For this reconstructed individual patient-level meta-analysis, we searched PubMed, Web of Science, the Cochrane Library, and Scopus on June 2, 2025, for phase 3 trials that compared CDK4/6 inhibitors plus endocrine therapy with endocrine monotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer. Kaplan-Meier curves were reconstructed with the use of a time-to-event algorithm to retrieve survival data for individual patients. A series of pooled analyses for the reconstructed individual patient data were conducted with the use of a stratified Cox regression model. A pairwise random-effects meta-analysis was also conducted. Patients were stratified by endocrine sensitivity into endocrine-sensitive and endocrine-resistant, as well as by age, ethnicity, progesterone receptor status, menopausal status, Eastern Cooperative Oncology Group performance status, bone-only disease, and visceral metastasis. Primary outcomes analysed were progression-free survival and overall survival. The protocol is registered in PROSPERO (CRD420251073444).</p><p><strong>FINDINGS: </strong>11 phase 3 trials, including 6035 patients and four agents-abemaciclib, ribociclib, palbociclib, and dalpiciclib-were included. CDK4/6 inhibitors plus endocrine therapy significantly improved progression-free survival in both endocrine-sensitive (HR 0·57, 95% CI 0·52-0·63; p&lt;0·0001) and endocrine-resistant cancers (0·51, 0·45-0·57; p&lt;0·0001). Overall survival was also improved with CDK4/6 inhibitors plus endocrine therapy in both subgroups: endocrine-sensitive (0·83; 0·74-0·92; p=0·0005) and endocrine-resistant (0·77; 0·67-0·89; p=0·0003). All individual agents, when combined with endocrine therapy showed progression-free survival benefits: abemaciclib (HR 0·53, 95% CI 0·46-0·61; p&lt;0·0001), ribociclib (0·60, 0·52-0·68; p&lt;0·0001), palbociclib (0·56, 0·49-0·65; p&lt;0·0001), and dalpiciclib (0·49, 0·40-0·61; p&lt;0·0001). However, only abemaciclib (0·79, 0·67-0·92; p=0·0031) and ribociclib (0·73, 0·64-0·84; p&lt;0·0001) showed significant overall survival benefits; palbociclib did not reach statistical significance (0·89, 0·77-1·02; p=0·0920), and data for dalpiciclib remain immature. Other clinically relevant subgroups, stratified by age, ethnicity, progesterone receptor status, menopausal status, Eastern Cooperative Oncology Group performance status, bone-only disease, and visceral metastasis, showed progression-free survival and overall survival benefits in patients with endocrine-sensitive and endocrine-resistant tumours.</p><p><strong>INTERPRETATION: </strong>CDK4/6 inhibitors plus endocrine therapy significantly improved survival in hormone receptor-positive, HER2-negative advanced breast cancer. Benefits in progression-free survival and overall survival were consistent across major clinical subgroups. Although all agents improved progression-free survival, only ribociclib and abemaciclib showed statistically significant overall survival benefits, whereas palbociclib did not, and data for dalpiciclib remain immature. Further head-to-head comparisons and assessments of toxicity profiles, as well as patient-reported outcomes, are needed. FUNDING: None.</p>