ASCO GU 2022: CYCLONE 2: A Phase 2/3, Randomized, Placebo-Controlled Study of Abiraterone Acetate plus Prednisone with or Without Abemaciclib in Patients with mCRPC

( The 2022 GU ASCO Annual meeting included prostate cancer trials in progress session featuring the CYCLONE 2 trial, presented by Dr. Matthew Smith, a phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC). Despite recent advances, nearly all patients with mCRPC experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor signaling and/or activation of pathways in cross-talk with androgen receptor signaling are key drivers of mCRPC progression. Evidence suggests that androgen receptor signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer patients. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to androgen receptor targeted therapy may be an effective treatment for mCRPC patients.

CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone in patients with mCRPC. CYCLONE 2 is an adaptive study that is designed in three parts:

  • Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with abiraterone acetate (1000 mg, once daily) + prednisone (5 mg, twice daily)
  • In part 2, 150 patients are randomized 1:1 to abiraterone acetate plus prednisone with abemaciclib at the RP2D or placebo
  • The study expands to enroll an additional 170 patients in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee

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Patients with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible, and prior docetaxel for metastatic hormone sensitive prostate cancer is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Exploratory endpoints include PSA response rate, time to chemotherapy, biomarkers, and pain/quality of life. Currently, enrollment in Part 1 and 2 is completed. Based on the recommendation from the independent data monitoring committee, Part 3 was opened in June 2021 and enrolled patients from 112 sites across 12 countries:

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Presented by: Matthew R. Smith, MD, PhD, Massachusetts General Hospital, Boston, MA

Co-Authors: Neeraj Agarwal, Tilman Todenhöfer, Josep M. Piulats, Jae-Lyun Lee, Redas Trepiakas, Arpit Rao, Lisa Horvath, Andrew Lithio, Erica L. Johnston, Maarten Hulstijn, Karim Nacerddine, Christopher Sweeney 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022