This chapter reviews current standards of care, emerging therapeutic options, and evolving combination strategies across biomarker-defined subgroups. We also highlight how ongoing clinical trials and advances in molecular profiling are informing personalized approaches to overcome endocrine resistance and improve patient outcomes.

P1, N=28, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2026 --> Jun 2026

P=N/A, N=2758, Completed, Pfizer | Active, not recruiting --> Completed

The most common adverse effect was neutropenia (68%), which was manageable with appropriate dose reductions. Conclusion Our retrospective data support the notion that ribociclib-based therapy is effective and safe in patients with HR+/HER2- ABC/MBC; however, as it is a retrospective study with a small sample size, further prospective studies are necessary to further prove these results in the local population, and efforts should be taken in society at large to make this treatment available to all patients who require this treatment.

Combination of Echinacoside effectively overcome resistance to palbociclib in breast cancer treatment. These findings highlight targeting PTEN neddylation as a promising strategy for restoring tumor suppressor activity and overcoming resistance.

Extended analysis from PARSIFAL confirmed no difference between fulvestrant and letrozole when combined with palbociclib for patients with endocrine-sensitive, HR-positive/HER2-negative ABC. Efficacy results were consistent with those reported in the pivotal first-line trials involving CDK4/6i. Progression within the first year on CDK4/6i may indicate a poorer prognosis.

P3, N=674, Recruiting, Celcuity Inc | Not yet recruiting --> Recruiting

P1/2, N=100, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Jun 2025 --> Jun 2027

Twenty-five systematic reviews and meta-analyses, RCTs, pooled safety analysis and observational studies were included in this narrative review to evaluate the incidence rate of palbociclib, ribociclib and abemaciclib induced hepatoxicity. Ribociclib seems to be associated with the highest risk of drug-induced hepatotoxicity. More studies need to be done to confirm and quantify this finding.

P2, N=180, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting | N=130 --> 180 | Trial completion date: Aug 2030 --> Aug 2031 | Trial primary completion date: Aug 2027 --> Aug 2028

P2, N=45, Recruiting, Eli Lilly and Company | Trial primary completion date: Jul 2027 --> Nov 2027

The results from this large real-world database study indicate that 30.6% of patients with HR+/HER2- EBC met the eligibility criteria for NATALEE versus 14.5% for monarchE, presenting the opportunity to improve outcomes in nearly one-third of patients with HR+/HER2- EBC at high risk of recurrence.

P=N/A, N=733, Completed, Pfizer | Not yet recruiting --> Completed | N=1300 --> 733 | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

The effect of early treatment discontinuation showed no significant differences between ribociclib + NSAI + OFS and tamoxifen ± OFS (TT-a: HR = 1.2 [95% CI: 0.71; 2.01], p = 0.48; TTtox-a: HR = 0.54 [95% CI 0.22; 1.30], p = 0.23). In this retrospective analysis, ribociclib + NSAI + OFS demonstrated advantages across all effectiveness endpoints, including OS, in premenopausal women with HR+, HER2- early BC, without increasing overall treatment discontinuation rates compared to tamoxifen ± OFS.

Synthetic compounds like STAT3-IN-1 and CDDO-Me demonstrated superior binding in most targets, except for CDDO-Me with HIF-1α, suggesting unique structural incompatibilities. Natural products such as zerumbone and umbelliferone displayed moderate activity, while palbociclib highlighted synthetic-drug advantages. These results underscore the importance of ligand-receptor structural complementarity, particularly for HIF-1α's confined binding site, where helenalin's terminal Michael acceptor system proved optimal. The findings advocate for integrating computational and experimental approaches to develop cysteine-targeted therapies, balancing synthetic precision with natural product versatility for context-dependent cancer treatment strategies.

P3, N=1903, Not yet recruiting, Fudan University

The combination of Palbociclib plus letrozole has a favorable toxicity profile and appears to have clinical activity in recurrent hormone receptor-positive high-grade ovarian cancer.

CDK4/6i therapy is feasible in patients with pre-existing AD. Interestingly, the onset or flaring of AD during treatment is associated with improved PFS, suggesting a potential immune activation induced by CDK4/6i. However, further robust and prospective studies are required to validate these findings and explore the underlying mechanisms.

In our data set, univariate analyses suggest age and visceral metastases to be potential factors influencing outcomes in patients with ABC treated with palbociclib plus an AI. Comorbidities, did not significantly impact survival, suggesting that palbociclib is well-tolerated in patients with varying health profiles.

HERMIONE-7 study showed that 2nd-line treatment with Abemaciclib + AIs is a feasible option in MBC patients who progressed on Fulvestrant in 1st-line setting and could be an alternative especially in terms of optimizing the cost-benefit ratio in some Countries.

Although the primary endpoint was not met, the NEOLBC trial (NCT03283384) showed a similar CCCA and pathological response for RL vs. CT with less toxicity. Therefore, RL as an alternative for NAC merits further investigation.

In this study, the induction of senescence in human melanoma cells by palbociclib is found to lead to a senescent phenotype characterized by overexpression of the membrane protein dipeptidyl peptidase 4 (DPP4), previously identified only in ageing contexts...The nanoparticle based on mesoporous silica is loaded with the senolytic navitoclax, coated with disulfide-containing poly(ethylene glycol) to generate a redox-sensitive gatekeeper (S-S-PEG), and functionalized with an antibody against the DPP4 protein...The DPP4-targeted nanoparticle effectively reduces tumor growth and selectively removes senescent cells. Taken together, this study highlights the potential of surfaceome-targeted nanoparticles, as a clinically relevant strategy for improving senolytic therapies.

P1, N=12, Terminated, Novartis Pharmaceuticals | Phase classification: P1/2 --> P1 | N=231 --> 12 | Trial completion date: Jan 2028 --> Feb 2025 | Recruiting --> Terminated | Trial primary completion date: Oct 2027 --> Feb 2025; Study halted early due to high toxicity risk (from BHLRM model) in combo treatment and inability to identify recommended Phase 2 dose in initial phase (Phase 1-Part A), making continuation to next phase (Phase 1-Part B and Phase 2) unfeasible.

P2, N=33, Recruiting, The First Affiliated Hospital of Xiamen University | Not yet recruiting --> Recruiting

Here, we report on ratiometric codelivery of FLT3 and CDK4/6 dual inhibitors, gilteritinib and palbociclib, by daratumumab-decorated polymersomes (GIPA@DP) for high-efficacy targeted therapy of acute myeloid leukemia (AML). Selective AML-targeting in conjunction with ratiometric drug codelivery and synergistic anti-AML effects of GIPA@DP collectively led to significant survival benefits in CD38-upregulated MV-4-11 and Molm-13-Luc AML models, outperforming the nontargeted control (GIPA@P) and a mixture of two targeted single drug formulations (GI@DP + PA@DP). This targeted ratiometric delivery of dual inhibitors provides a new treatment strategy for AML and other malignancies.

P=N/A, N=700, Recruiting, Roswell Park Cancer Institute | N=400 --> 700 | Trial completion date: Jul 2025 --> Jul 2030 | Trial primary completion date: Jul 2025 --> Jul 2030

P2, N=45, Recruiting, Massachusetts General Hospital | Trial completion date: Sep 2026 --> Sep 2027 | Trial primary completion date: Sep 2025 --> Sep 2026

P=N/A, N=300, Active, not recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

P=N/A, N=33, Not yet recruiting, The First Affiliated Hospital of Xiamen University; The First Affiliated Hospital of Xiamen University

P1/2, N=72, Not yet recruiting, Sun Yat sen University Cancer Center; Sun Yat-sen University Cancer Center

P2, N=61, Active, not recruiting, Stemline Therapeutics, Inc. | Recruiting --> Active, not recruiting

P2, N=33, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jul 2025 --> Jul 2026

P=N/A, N=50, Recruiting, Yale University | Trial completion date: May 2027 --> Jan 2028 | Trial primary completion date: May 2025 --> Jan 2026

P2, N=80, Not yet recruiting, UNICANCER | Initiation date: Mar 2025 --> Jul 2025

P2, N=9, Completed, Stanford University | Active, not recruiting --> Completed

P2, N=29, Recruiting, Case Comprehensive Cancer Center | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Jun 2025 --> Dec 2025

In this series of patients relapsing on adjuvant abemaciclib plus ET, 50% showed ER loss, 90% had P53 pathway alterations, and median first-line metastatic treatment lasted 3 months.

P1/2, N=71, Recruiting, Sun Yat-sen University | Not yet recruiting --> Recruiting | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

We designed 43 hybrid compounds by combining the pyrido[3,4-d]pyrimidine moiety from palbociclib with the phthalazinone ring from olaparib. We checked the binding affinities using docking methods and the stability of the protein-ligand complex using molecular dynamics simulations with Desmond module in Maestro Schrödinger suite (v13.5). Quantum mechanical analyses at the B3LYP/6-31G** level were conducted to elucidate the DFT/TD-DFT, molecular electrostatic potential, Mulliken charges, chemical descriptors, NBO, and NLO properties.

We report a case of a 55-year-old woman on abemaciclib and fulvestrant who developed painful, erythematous nodules that progressed to hyperpigmented plaques with skin retraction, including on the breasts. This case expands the known spectrum of skin toxicities linked to CDK4/6 inhibition. It underscores the importance of recognizing panniculitis as a potential immune-mediated adverse event, which, in select cases, may be managed conservatively without interrupting oncologic therapy.

These findings suggest a promising synergistic effect of C + P in overcoming cisplatin resistance in HCC. However, further research is needed to fully elucidate the complex interactions between these drugs.