Abstract 1423TiP
Background
Landmark trials led to the integration of docetaxel (D) or novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) into the treatment paradigm for mHSPC. Recent data showed survival benefit for treatment intensification with ADT+D+NHA triplet therapy vs ADT+D in selected patients (pts). Yet, there is a significant medical need to expand therapeutic options especially for pts 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 NHA therapy. In preclinical models, abemaciclib induces cell cycle arrest and prostate tumor growth inhibition.
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 metastasis and/or visceral disease will be randomised in a 1:1 ratio to the AP + abemaciclib or placebo arm. Up to 3 months of prior ADT alone, or up to 6 cycles of prior D+ADT, is permitted in the absence of radiographic or PSA progression. Pts who have not undergone orchiectomy will continue ADT. Stratification factors are de novo mHSPC, visceral metastases and prior docetaxel use. 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. Enrollment is open at approximately 270 sites across 25 countries.
Clinical trial identification
NCT05288166.
Editorial acknowledgement
Scientific writing support was provided by Garreth Lawrence, employee of Eli Lilly and Company.
Legal entity responsible for the study
Eli Lilly and Company.
Funding
Eli Lilly and Company.
Disclosure
R.R. McKay: Financial Interests, Personal, Advisory Role: Astellas Medivation, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Tempus, Vividion Therapeutics; Financial Interests, Institutional, Funding: Bayer, Pfizer, Tempus. N. Agarwal: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly and Company, EMD Serono, Exelixis, Genentech, Foundation Medicine, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, Seattle Genetics; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, Bavarina Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly and Company, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, Tracon. N. Matsubara: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bayer, Chugai Pharma, Janssen, Merck Sharp Dohme; Financial Interests, Personal, Advisory Role: AstraZeneca, Janssen, Eli Lilly and Company, Sanofi; Financial Interests, Institutional, Funding: Astellas Pharma, AstraZeneca, Bayer, Bayer Yakuhin, Chugai Pharma, Janssen, MSD. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati. M.R. Smith: Financial Interests, Personal, Advisory Role: Amgen, Astellas Pharma, Bayer, Janssen Oncology, Eli Lilly and Company, Novartis, Pfizer; Financial Interests, Institutional, Funding: Bayer, Gilead Sciences, Janssen Oncology, Eli Lilly and Company; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Bayer, Janssen, Eli Lilly and Company. T. Todenhöfer: Financial Interests, Personal, Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp Dohme, Roche. T. Zhang: Financial Interests, Personal, Advisory Board: Merck, Exelixis, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Amgen, BMS, Pharmacyclics, SeaGen, Calithera, Dendreon, QED Therapeutics, Eisai, Aveo, Bayer, Eli Lilly; Financial Interests, Personal, Other, Consulting: MJH Associates, Vanaiam, Aptitude Health, PeerView, Clinical Care Options; Financial Interests, Institutional, Invited Speaker: Novartis, Merrimack, AbbVie, Merck, Regeneron, Mirati Therapeutics, Janssen, AstraZeneca, Pfizer, Astellas; Financial Interests, Institutional, Research Grant: OmniSeq, PGDx; Non-Financial Interests, Advisory Role, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Advisory Role, Scientific Advisory Board: KCCure; Non-Financial Interests, Advisory Role: Myrovlytis Trust. A.V. Balar: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests, Personal, Full or part-time Employment: Loxo Oncology at Eli Lilly and Company. C. Schaverien, S. Sherwood, A. Lithio, K. Nacerddine: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. E. Johnston: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests, Personal, Other, Travel, Accommodation and Expenses: Eli Lilly and Company. C.J. Sweeney: Financial Interests, Personal, Advisory Role: Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, Pfizer, Eli Lilly and Company, Janssen Biotech, Astellas Pharma, Sanofi; Financial Interests, Institutional, Funding: Bayer, Sotio, Dendreon; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Patrhenolide (Indiana University), dimethylaminoparthenolide (Leuchemix), Abiraterone plus cabozantinib combination (Exelixis), FRAS1 SNP and tristetraprolin as biomarkers of lethal prostate cancer.