Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) remains a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib (for PIK3CA-mutated tumors), established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in the setting of acquired resistance. Multiple randomized studies have demonstrated that the addition of targeted agents to endocrine therapy results in significantly improved progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression. Current evidence strongly supports that in hormone receptor–positive metastatic breast cancer progressing after CDK4/6 inhibitors, combination therapy with endocrine agents and targeted treatments should be favored over single-agent hormonal therapy, except in carefully selected patients with low disease burden, indolent biology, or frailty where treatment tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib demonstrated significant benefit when combined with fulvestrant in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. These findings consistently reinforce that endocrine therapy combined with pathway-targeted agents provides superior clinical outcomes compared with endocrine therapy alone, particularly in patients previously treated with CDK4/6 inhibitors. Real-world analyses further confirm the effectiveness of these combination strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which frequently co occur in up to one third of tumors and contribute to reduced sensitivity to endocrine monotherapy, further emphasizing the importance of combination treatment strategies. Notably, while ESR1 and PI3K pathway alterations guide approved therapies, FGFR alterations remain early-phase targets without integrated standard-of-care options, though ongoing trials are evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can guide early therapeutic modification, extending endocrine-based disease control by approximately 5 to 7 months when ESR1 mutations are detected prior to radiographic progression. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC.

Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) represents a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with the SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward molecularly selected combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in acquired resistance. Multiple randomized studies have demonstrated that adding targeted agents to endocrine therapy improves progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression, except in carefully selected patients with low disease burden, indolent biology, or frailty where tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. Real-world analyses further support the effectiveness of these biomarker-directed strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms, including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which may co-occur and reduce sensitivity to endocrine monotherapy. While ESR1 and PI3K pathway alterations now guide approved therapies, FGFR alterations remain investigational targets, with ongoing trials evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can detect emergent ESR1 mutations before radiographic progression, providing a clinically actionable lead time for early therapeutic modification and extending endocrine-based disease control by approximately 5 to 7 months. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC.