PURPOSE: Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor–positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455 ). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone–releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA–evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

Background: There is a male predominance of acute myeloid leukemia (AML) incidence, but survival data are conflicting. The objective of this study is to carry out a comprehensive analysis of sex differences in AML, and to investigate the impact of sex disparities in survival.Methods: The cohort included patients ≥18 years diagnosed with AML (2010–2022). Demographics, treatment patterns, treatment adverse events, and survival were analyzed. The population was described and compared by sex, and sex‐based risks and associations were obtained via Cox proportional‐hazards regression.Results: In total, 1020 AML patients were analyzed (57.4% males), with lower risk of death for females (aHR = 0.41, 95% CI 0.26–0.66). Among females, BMT (aHR = 0.51, 95% CI 0.27–0.97), hospitalization record (aHR = 0.65, 95%CI 0.45–0.93), and higher appointment completion rates (aHR = 0.98, 95% CI 0.98–0.98) were associated with lower risk of death. Overall, and similarly in males, higher age at diagnosis (aHR = 1.03, 95% CI 1.02–1.04) and a TP53 mutation (aHR = 2.24, 95% CI 1.69–2.97) were associated with higher risk of death.Conclusion: Sex differences exist in both AML incidence and overall survival. Treatment and health care factors should be addressed by caregivers and public policies developed to reduce mortality rates and mitigate existing sex differences.

Background: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1‐point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown. Methods and Results: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010–2019) and followed up at a large, hybrid academic‐community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0–11). Adjusted Fine–Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2‐year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1‐point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06–1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12–1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08–1.19]). When considering AL as a time‐varying exposure, the peak associated MACE risk occurred with a 1‐point AL rise between 6 and 12 months post‐ breast cancer, lung cancer, and colorectal cancer diagnosis. Conclusions: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.