A Signal-finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC).

Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg BID was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%.

At trial entry, forty (90.9%) of 44 patients had objective radiographic disease progression, four (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months (95% CI: 3.2, NA); median radiographic PFS; 2.7 months (95% CI: 1.9, 3.7); and median OS: 8.4 months (95% CI: 5.6, 12.7). Most frequent grade ≥3 TEAEs were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib.

Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Mar 21 [Epub ahead of print]

Neeraj Agarwal, Daniel Castellano, Teresa Alonso-Gordoa, Jose Angel Arranz Arija, Emeline Colomba, Gwenaelle Gravis, Loic Mourey, Stephane Oudard, Aude Fléchon, Macarena Gonzalez, Pablo M Maroto, Michael T Schweizer, Enrique Gallardo, Erica Johnston, Arjun Balar, Nadine Haddad, Adams K Appiah, Karim Nacerddine, Josep M Piulats

Huntsman Cancer Institute, Salt lake City, UT, United States., Hospital Universitario 12 De Octubre, Madrid, Spain., Hospital Universitario Ramón y Cajal, Madrid, Spain., Hospital General Universitario Gregorio Marañón, Madrid, Spain., Insitute Gustave Roussy, Villejuif, Ile de France, France., Institute Paoli-Calmettes, marseille, France., IUCT-Oncopole Claudius Regaud, Toulouse, France., Hopital Européen Georges Pompidou, Paris, Ile de France, France., Centre Léon Bérard, Lyon, France., Vall d'Hebron Hospital Universitari, Barcelona, Spain., Htal Sant Pau, Barcelona, Spain., University of Washington, Seattle, United States., Institute of Research and Innovation Parc Tauli, Sabadell, Spain., Eli Lilly and Company, Indianapolis, IN, United States., Perlmutter Cancer Center, NYU Langone Medical Center, United States., Eli Lilly (United States), United States., Eli Lilly and Company, United States., Institut Català d'Oncologia-IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.