Figure 6 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER<sup>+</sup> Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance

Enhanced efficacy of camizestrant in combination with PI3K/AKT/mTOR inhibitors as doublets in CDK4/6i-resistant models (2). A, 28-, 35- or 42-day efficacy studies using several ER⁺ breast cancer PDX harboring/not harboring alterations in PIK3CA/AKT/PTEN. Dark blue, mutations; light blue, deletions; orange, fusions. The rate of growth for each animal is estimated on the basis of fitting each tumor's growth curve to an exponential model: log₁₀(tumor volume) = a + b·time + error, where a and b correspond to the log initial volume and growth rate, respectively. The model assumes that the error terms are normally distributed. Tumor volumes less than 15 mm³ were replaced with a minimum value of 15 mm³. This growth rate summary metric was then used for statistical analysis to compare treatments with a user-specified reference group. Tumor growth inhibition was used to plot a heat map. Designed dosing: oral palbociclib 50 mg/kg daily, subcutaneous fulvestrant 5 mg weekly, oral camizestrant 10 mg/kg daily, oral capivasertib 130 mg/kg BID 4 days on/3 days off. Statistical analysis was performed by one-tailed, unequal variance t test versus log (change in tumor volume) at the final day of treatment. B, 28-, 35- or 42-day efficacy studies used in A; relative tumor volume plots displaying arms: control, standard-of-care hormone therapy + CDK4/6 inhibitor (fulvestrant + palbociclib), or triplet combination of hormone therapy + CDK4/6 inhibitor + AKTi (camizestrant + palbociclib + capivasertib). Designed dosing: oral palbociclib 50 mg/kg daily, subcutaneous fulvestrant 5 mg weekly, oral camizestrant 10 mg/kg daily, oral capivasertib 130 mg/kg BID 4 days on/3 days off. Statistical analysis was performed by one-tailed, unequal variance t test versus log (change in tumor volume) at the final day of treatment. C, Camizestrant fits centrally in the overall landscape of breast cancer as a backbone endocrine therapy. Estrogens (e.g., E2) bind to ERα, leading to its dimerization and translocation to the nucleus, where ERα dimers bind to coactivators to form transcriptionally active ERα complexes. Activated complexes regulate gene transcription in the nucleus or activate kinases in the cytoplasm to drive cell proliferation. Mutations in the ligand-binding domain of ESR1 drive resistance in advanced ER⁺ breast cancer and act independently of estrogens to activate transcription. Camizestrant is a next-generation SERD for the treatment of ER⁺ breast cancer, acting as a pure ER antagonist and selective ERα degrader. Camizestrant's mechanism of action stops the transcription of ER target genes in wild-type (blue) and mutant (green) ERα, impairing tumor cell proliferation. These properties position camizestrant as a central endocrine therapy partner along with CDK4/6 inhibitors (palbociclib and abemaciclib) in ER⁺ breast cancer. Other signaling pathways are essential to ER⁺ breast cancer proliferation and survival, and contribute to mechanisms of endocrine therapy resistance, including CDK4/6 and PI3K/AKT/mTOR pathways. Inhibitors of these signaling axes are currently approved targeted therapies (everolimus and alpelisib) or under investigation (e.g., capivasertib). *, P < 0.05; **, P < 0.005; ***, P < 0.0005. CAMI, camizestrant; CAPI, capivasertib; CDK, cyclin-dependent kinase; CoA, cytochrome C oxidase assembly; Del, deletion; E2, estradiol; E2F, E2F transcription factor; ERE, estrogen response element; FULV, fulvestrant; m, mutated; MET, metastatic; PALBO, palbociclib; PRIM, primary; RB1, retinoblastoma gene; TGI, tumor growth inhibition.