To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen-receptor inhibitors.
In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400mg daily [QD]) plus rucaparib (400 or 600mg twice daily [BID]) to assess safety and identify a recommended phase 2 dose (RP2D). A Part 1 dose-escalation phase was followed by a Part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on tumor mutational status.
Fifty-one patients were enrolled (Part 1=21; Part 2=30). Ipatasertib 400mg QD plus rucaparib 400mg BID was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per RECIST 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months (95% CI, 4.0-8.1), and median overall survival was 13.3 months (95% CI, 10.9-not evaluable).
Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Jun 20 [Epub ahead of print]
David Pook, Daniel M Geynisman, Joan Carles, Filippo de Braud, Anthony M Joshua, Jose Luis Perez-Gracia, Casilda Llácer Pérez, Sang Joon Shin, Bruno Fang, Minal Barve, Marco Maruzzo, Sergio Bracarda, Miso Kim, Yannick Kerloeguen, Jorge Daniel Gallo, Sophia L Maund, Adam Harris, Kuan-Chieh Huang, Victor Poon, Dhruvitkumar S Sutaria, Howard Gurney
Monash University, Melbourne, VIC, Australia., Fox Chase Cancer Center, Philadelphia, PA, United States., Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Fondazione IRCCS Istituto Nazionale dei Tumori and Università degli Studi Milan of Milan, Milan, Italy., The Kinghorn Cancer Centre, Sydney, NSW, Australia., University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008, Navarra, Spain., Regional and Virgen de la Victoria University Hospitals, IBIMA, Malaga, Malaga, Spain., Yonsei University College of Medicine, Seoul, Korea(South), Republic of, Korea (South), Republic of., Astera Cancer Care, East Brunswick, NJ 08816, United States., Mary Crowley Cancer Research Center, Dallas, United States., Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Azienda Ospedaliera S.Maria, Terni, TR, Italy., Seoul National University Hospital, Seoul, Korea (South), Republic of., F. Hoffmann-La Roche Ltd, Basel, Switzerland., Genentech, South San Francisco, California, United States., 6129813500, Macquarie University, New South Wales, Australia.