Abemaciclib, a potent CDK4 and CDK6 inhibitor, has shown antitumour activity in prostate cancer models and in patients with metastatic castration-resistant prostate cancer (mCRPC) who have been heavily treated. We aimed to evaluate the safety and efficacy of abemaciclib in combination with abiraterone in patients with mCRPC.

CYCLONE 2 was a randomised, double-blind, placebo-controlled, phase 3 study done in 89 hospitals and academic and private research centres in 12 countries. All study parts had identical eligibility criteria, and used block randomisation with the same stratification factors (previous docetaxel treatment, presence of measurable disease, and type of progression). Participants were adults aged 18 years and older with histologically confirmed adenocarcinoma of the prostate and metastatic disease as documented by bone scans, CT scans, or MRI scans, and radiographic or PSA progression during continuous androgen deprivation therapy. Previous docetaxel for metastatic castration-sensitive prostate cancer was permitted; previous abiraterone, apalutamide, enzalutamide, darolutamide, or CDK4 and CDK6 inhibitors were exclusionary. The trial was conducted in three parts. Part 1 was a four-arm, placebo-controlled safety and dose-finding lead-in to determine the recommended phase 2 dose of abemaciclib with abiraterone. Participants were randomly assigned (2:2:1:1) to receive abiraterone (1000 mg orally once daily) and prednisone or prednisolone (5 mg orally twice daily) with either abemaciclib at 150 mg or 200 mg orally twice daily or with matching placebo (150 mg or 200 mg twice daily). In part 2 and part 3, patients were randomly assigned (1:1) to standard abiraterone and prednisone or prednisolone plus either abemaciclib at the recommended phase 2 dose or matching placebo. Patients, investigators, and sponsor were masked to treatment assignment. The primary outcome, investigator-assessed radiographic progression-free survival, was analysed in the intention-to-treat (participants from all study parts) population. Patients who received at least one dose of abiraterone, abemaciclib, or placebo were included in the safety population. This trial is registered at ClinicalTrials.gov , NCT03706365 , and is completed.

Between Nov 26, 2018, and July 20, 2022, 515 patients were screened for eligibility, 393 of whom were randomly assigned, 206 patients to abemaciclib plus abiraterone and 187 to placebo plus abiraterone. The median age was 70·0 years (IQR 63·0–76·0). 289 (74%) of 393 patients identified as White, 80 (20%) as Asian, 17 (4%) as Black or African American, and seven (2%) as multiple race or not reported. The highest tested dose of 200 mg abemaciclib administered twice daily was chosen as the recommended phase 2 dose. The median follow-up time was 26·3 months (IQR 22·1–48·2) for the abemaciclib plus abiraterone group and 25·6 months (22·1–40·8) for the placebo plus abiraterone group. The primary endpoint of radiographic progression-free survival was not met: radiographic progression-free survival events were reported in 92 (45%) of 206 patients in the abemaciclib plus abiraterone group and 95 (51%) of 187 patients in the placebo plus abiraterone group (HR 0·83 [95% CI 0·62–1·11]; p=0·21). Median radiographic progression-free survival was 22·0 months (95% CI 19·3–27·5) for abemaciclib plus abiraterone and 20·3 months (16·5–24·4) for placebo plus abiraterone. The most common grade 3 or higher adverse events reported in the abemaciclib plus abiraterone group were anaemia (28 [14%] of 206 vs eight [4%] of 185 in the placebo plus abiraterone group), neutropenia (26 [13%] vs one [1%]), and alanine aminotransferase increase (18 [9%] vs 12 [6%]). Serious adverse events occurred in 91 (44%) of 206 patients in the abemaciclib plus abiraterone group and in 68 (37%) of 185 patients in the placebo plus abiraterone group. There were three treatment-related deaths due to interstitial lung disease in the abemaciclib plus abiraterone group.

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.

Eli Lilly.