1841TiP - Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase III, randomized, double-blind, placebo-controlled study (ARASTEP)

Background

Patients (pts) with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR, defined as a prostate-specific antigen (PSA) increase without evidence of metastases on conventional imaging. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), a more effective and precise imaging method, may detect small lesions in patients with BCR. Patients with BCR at high risk of metastatic progression and who have lesions identified by PSMA PET/CT need effective treatment to delay this progression. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor, which significantly improved metastasis-free survival (MFS) and overall survival (OS) in pts with nonmetastatic castration-resistant prostate cancer (CRPC). The ARASTEP study (NCT05794906) is designed to evaluate whether DARO plus ADT improves radiological progression-free survival (rPFS) by PSMA PET/CT vs placebo (PBO) plus ADT in pts with BCR following primary therapy and PSMA PET/CT-positive lesions.

Trial design

Eligible pts have prostate cancer treated by primary RT or RP followed by adjuvant RT (ART) or salvage RT (SRT), or RP alone if ART/SRT was not appropriate, with BCR (defined as PSA doubling time [PSADT] <12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), ≥1 PSMA PET/CT-positive lesion without visible lesions on conventional imaging, and serum testosterone >150 ng/dL. Approximately 750 pts from 184 sites worldwide will be randomized to oral DARO 600 mg twice daily or PBO, both with ADT, for 24 months. Image-guided radiotherapy or surgery is allowed within 12 weeks from randomization. Randomization is stratified by PSADT <6 vs ≥6–<12 months, prior RP vs primary RT, and distant ± locoregional vs locoregional-only metastases. The primary endpoint is rPFS by PSMA PET/CT, assessed by blinded independent central review (BICR). Secondary endpoints include MFS by BICR, time to CRPC, OS, quality of life, and safety. Enrollment began in April 2023.

Clinical trial identification

NCT05794906.

Editorial acknowledgement

Medical writing support was provided by Nancy Niguidula, of OPEN Health Communications (London, UK).

Legal entity responsible for the study

Bayer AG and Orion Pharma.

Funding

Bayer AG and Orion Pharma.

Disclosure

A.K. Morgans: Financial Interests, Institutional, Research Funding: Bayer, Seattle Genetics, Sanofi, Astellas, Pfizer, Myovant; Financial Interests, Personal, Other, Honoraria: Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Clovis, Exelixis, Genentech, Janssen, Merck, Myovant, Pfizer, Sanofi, Telix; Financial Interests, Personal, Other, Travel, accommodations or expenses: Sanofi. J.E. Gschwend: Financial Interests, Personal, Advisory Board: BMS. N.D. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Propella, PreView, Sanofi Genzyme, Speciality Networks, Sesen Bio, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Photocure, Vaxiion, Asieris, Alessa Therapeutics, GConcology, Akido, Arquer, Fize medical, Genentech, Guardant, Ferring, Foundation Medicine, Immunitybio, Incyte, Minomic, NGM, Nonagen, Novartis, PlatformQ, Profound, Promaxo, Protara, Vessi; Financial Interests, Personal, Member of Board of Directors: Photocure. A. Ross: Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Speaker’s Bureau: Tempus; Financial Interests, Personal, Other, Honoraria: Bayer, Janssen Biotech, Blue Earth Diagnostics, Decipher Biosciences, Astellas Pharma, Myovant Pharma, Lantheus Medical Imaging. F. Feng: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Myovant, SerImmune, Bayer, Novartis, Tempus, Varian, Blue Earth Diagnostics, Exact Sciences; Financial Interests, Personal, Advisory Role: Artera; Financial Interests, Personal, Stocks or ownership: Artera. T. Hope: Financial Interests, Institutional, Research Funding: Clovis Oncology, Philips, GE Healthcare, Lantheus, the Prostate Cancer Foundation, National Cancer Institute; Financial Interests, Personal, Other, personal fees: Bayer, BlueEarth Diagnostics; Financial Interests, Personal, Stocks or ownership: RayzeBio, Curium. L. Trandafir, M. Le Berre, I. Kuss: Financial Interests, Personal, Full or part-time Employment: Bayer. H. Joensuu: Financial Interests, Personal, Advisory Board, Chair of the Scientific Advisory Board: Orion Pharma, Neutron Therapeutics, Maud Kuistila Foundation; Financial Interests, Personal, Invited Speaker: Deciphera Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment, Until Aug. 31, 2020: Orion Pharma; Financial Interests, Personal, Stocks/Shares: Orion Pharma, Sartar Therapeutics. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis.