In a phase III study (CYCLONE 2) reported in The Lancet Oncology, Smith et al found that the addition of abemaciclib to abiraterone did not significantly improve radiographic progression–free survival in men with metastatic castration-resistant prostate cancer (mCRPC).
Study Details
In the double-blind trial, 393 patients from sites in 12 countries were randomly assigned between November 2018 and July 2022 to receive abiraterone at 1,000 mg once daily (n = 206) or placebo (n = 187), both with prednisone or prednisolone at 5 mg twice daily and abemaciclib at 150 or 200 mg twice daily. Previous receipt of docetaxel for metastatic castration-sensitive disease was permitted; previous receipt of abiraterone, apalutamide, enzalutamide, darolutamide, and CDK4 or CDK6 inhibitors were not permitted. The primary endpoint of the trial was investigator-assessed radiographic progression–free survival in the intention-to-treat population.
Key Findings
Median follow-up was 26.3 months (interquartile range [IQR] = 22.1–48.2 months) in the abemaciclib group and 25.6 months (IQR = 22.1–40.8 months) in the control group. Radiographic progression–free survival events were observed in 92 patients (45%) in the abemaciclib group vs 95 patients (51%) in the control group (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.62–1.11, P = .21). Median radiographic progression–free survival was 22.0 months (95% CI = 19.3–27.5 months) in the abemaciclib group vs 20.3 months (95% CI = 16.5–24.4 months) in the control group.
For the abemaciclib group vs the control group, median overall survival was 38.0 vs 33.2 months (HR = 0.93, P = .65), median time to symptomatic progression was 51.4 vs 35.7 months (HR = 0.77, P = .18), median time to prostate-specific antigen progression was 22.2 vs 16.6 months (HR = 0.64, P = .0026), and median time to worst pain progression was 41.5 vs 24.8 months (HR = 094, P = .70).
Grade 3 or higher adverse events occurred in 68% of the abemaciclib group vs 51% of the control group; the most common in the abemaciclib group were anemia (14%), neutropenia (13%), and increased alanine aminotransferase (9%), and the most common in the control group was hypertension (9%). Serious adverse events occurred in 44% vs 37% of patients. Treatment-related deaths occurred in three patients in the abemaciclib group, all due to interstitial lung disease.
The investigators concluded: “Dual inhibition of CDK4 and CDK6 and the androgen receptor pathway with abemaciclib plus abiraterone did not improve radiographic progression–free survival compared with abiraterone alone in the CYCLONE 2 study population with mCRPC. Safety of the combination was consistent with the previously reported safety of the individual drugs. Additional research is required to identify effective combination therapies for patients with mCRPC, especially in those presenting with adverse prognostic characteristics.”
Matthew Smith, MD, PhD, of Massachusetts General Hospital Cancer Center, Boston, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Eli Lilly. For full disclosures of all study authors, visit thelancet.com.
