284TiP - CYCLONE 3: A phase III, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone plus prednisone in men with high-risk metastatic hormone-sensitive prostate cancer

Background

Landmark trials have established a survival benefit for novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC). Yet, there is a significant medical need to expand therapeutic options, especially for pts with high-risk mHSPC who experience poorer outcomes. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6) dosed on a continuous schedule and approved for the treatment of node-positive high-risk early-stage and advanced or metastatic HR+, HER2− breast cancer. Analogous to the estrogen receptor signaling pathway in breast cancer, there is evidence that the androgen receptor axis activates CDK4/6 to sustain prostate cancer cell proliferation, and upregulation of cyclin D1 is a potential mechanism of resistance to NHA therapy. In preclinical models, abemaciclib induces cell cycle arrest and inhibition of prostate tumor growth.

Trial design

CYCLONE 3 is a global, randomized, double-blind, placebo-controlled study evaluating the addition of abemaciclib to abiraterone+prednisone (AP) in pts with high-risk mHSPC. Approximately 900 pts with high-risk mHSPC defined by ≥4 bone metastases and/or visceral disease will be randomised in a 1:1 ratio to the AP + abemaciclib or AP + placebo arm. Up to 3 months of ADT prior to randomization is permitted; prior docetaxel for mHSPC is excluded. Pts who has not undergone orchiectomy will continue ADT. Stratification factors are de novo mHSPC and visceral metastases. Primary endpoint is investigator-assessed radiographic progression-free survival (rPFS). Key secondary endpoints include rPFS assessed by blinded independent central review, castration-resistant prostate cancer-free survival, overall survival, time to pain progression, safety and pharmacokinetics. Approximately 270 sites across 24 countries are participating, including in Asia. Updated from abstract previously presented at European Society for Medical Oncology (ESMO) 2022, FPN (Final Publication Number): 2189, Rana McKay et al. Reused with permission.

Clinical trial identification

NCT05288166.

Editorial acknowledgement

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

N. Matsubara: Other, Personal and Institutional, Advisory Role, Honoraria, Speakers’ bureau, Research funding: Janssen, MSD; Other, Personal and Institutional, Research Funding, Honoraria: Taiho; Other, Personal and Institutional, Advisory Role, Research funding: Bayer, Roche; Other, Personal and Institutional, Advisory Role, Speakers’ bureau: Sanofi; Other, Personal and Institutional, Speaker’s Bureau: AstraZeneca. N. Agarwal: Other, Personal and Institutional, Advisory Role: Eli Lilly & Company, Janssen, Pfizer, Bayer, Amgen, Novartis, Bristol Myers Squibb, Astellas Pharma, AstraZeneca, ORIC Pharmaceuticals, Nektar, Pharmacyclics, Foundation Medicine, Eisai, AVEO; Other, Personal, Advisory Role: Calithera Biosciences, MEI Pharma, Gilead Sciences, Takeda. M.R. Smith: Other, Personal and Institutional, Advisory Role, Honoraria, Research Funding: Astellas Pharma, Bayer, Pfizer, Janssen, Lilly; Other, Personal and Institutional, Research Funding: Arvinas. R.R. McKay: Financial Interests, Personal, Research Funding, Consulting or Advisory Role: Bayer, Pfizer, Tempus; Financial Interests, Personal, Advisory Role: Astellas Medivation, AstraZeneca, Aveo, Bristol Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Janssen, Merck, Myovant, Novartis, Sanofi. T. Todenhöfer: Financial Interests, Personal, Advisory Role: Eli Lilly and Company, Janssen, Pfizer, Bayer, Novartis, Amgen, Bristol Myers Squibb, Astellas Pharma, AstraZeneca, Roche, Ipsen, Basilea. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Role: Pfizer, Janssen, Bristol Myers Squibb, Merck, Roche, AstraZeneca, Astellas Pharma, Clovis Oncology, VCN Biosciences, Incyte, EMD Serono, BeiGene. K.L. Chung, D. Heirich, S. Sherwood, C. Schaverien, N. Fasnacht, A. Lithio, K. Nacerddine: Financial Interests, Personal, Other, Employee and Shareholder: Eli Lilly and Company. All other authors have declared no conflicts of interest.