ESMO 2022: CYCLONE 3: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Abemaciclib in Combination With Abiraterone Plus Prednisone in Men With High-risk mHSPC

( The 2022 European Society of Medical Oncology (ESMO) annual meeting featured a prostate cancer session, including a presentation by Dr. Rana McKay discussing the trial protocol for CYCLONE 3, a phase 3, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone + prednisone in men with high-risk metastatic hormone-sensitive prostate cancer (mHSPC).

Landmark trials previously led to the integration of docetaxel or novel hormonal agents added to androgen deprivation therapy (ADT) into the treatment paradigm for mHSPC. Recent data showed survival benefit for treatment intensification with ADT + docetaxel + novel hormonal agent triplet therapy vs ADT + docetaxel in selected patients.1 Yet, there is a significant medical need to expand therapeutic options, especially for patients with poor prognoses, including those not candidates for chemotherapy. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 & 6) dosed on a continuous schedule, approved for the treatment of advanced or metastatic and certain types of high-risk early stage 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 novel hormonal agent therapy. In preclinical models, abemaciclib induces cell cycle arrest and prostate tumor growth inhibition. Additionally, ongoing studies are investigating the role of abemaciclib as a single agent and in combination with abiraterone in patients with mCRPC (CYCLONE 1: NCT04408924; CYCLONE 2: NCT03706365)

CYCLONE 3 is a global, randomized, double-blind, placebo-controlled study evaluating the addition of abemaciclib to abiraterone + prednisone in patients with high-risk mHSPC. Approximately 900 patients with high-risk mHSPC defined by ≥4 bone metastasis and/or visceral disease will be randomized in a 1:1 ratio to the abiraterone + prednisone + abemaciclib or placebo arm. Patients will be stratified based on: (i) de novo metastatic prostate (ii) visceral metastasis, and (iii) prior docetaxel use for mHSPC. Up to 3 months of prior ADT alone, or up to 6 cycles of prior docetaxel + ADT, is permitted in the absence of radiographic or PSA progression. Patients who have not undergone orchiectomy will continue ADT. The trial schema for CYCLONE 3 is as follows:


ESMO 2022_CYCLONE 3_Rana R. McKay-0 


The 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
  • Time to deterioration in health-related quality of life
  • Safety
  • Pharmacokinetics


Enrollment is open at approximately 270 sites across 25 countries:


ESMO 2022_CYCLONE 3_Rana R. McKay-1 


Clinical trial identification: NCT05288166.


Presented by:  Rana R. McKay, MD, Moores Cancer Center, University of California San Diego, La Jolla, CA

Co-Authors: N. Agarwal2, N. Matsubara3, J.M. Piulats Rodriguez4, M.R. Smith5, T. Todenhöfer6, T. Zhang7, A.V. Balar8, C. Schaverien9, S. Sherwood8, E. Johnston8, A. Lithio9, K. Nacerddine8, C.J. Sweeney10


  1. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142.


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