Lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 improves overall survival and progression-free survival in metastatic castration resistant prostate cancer (mCRPC), whereas immune checkpoint inhibitors (ICIs) have limited activity. Preclinical evidence suggests radioligand therapy might induce immunogenic cell death that can be enhanced with ICIs. This study evaluates the activity and adverse event profile associated with multiple doses of [177Lu]Lu-PSMA-617 with pembrolizumab.
PRINCE was a multicentre, single-arm, phase 1b/2 trial of [177Lu]Lu-PSMA-617 and pembrolizumab. Eligible participants were aged 18 years or older, had mCRPC, an Eastern Cooperative Oncology Group performance status of 0-1, previous androgen receptor pathway inhibitor therapy with previous docetaxel allowed, and high PSMA expression. Participants received up to six cycles of [177Lu]Lu-PSMA-617 intravenously every 6 weeks with 200 mg of pembrolizumab intravenously every 3 weeks for up to 24 months. Co-primary endpoints were safety and 50% prostate-specific antigen (PSA) response rate. All participants who received treatment were included in the analysis. The trial is registered with ClinicalTrials.gov, NCT03658447, and has been completed.
Between Aug 22, 2019 and Dec 16, 2020, 37 participants (median age 72 years, IQR 67-76; 27 [73%] docetaxel pretreated) received a median of six cycles (IQR 4-6) of [177Lu]Lu-PSMA-617 and a median of 12 cycles (IQR 6-24) of pembrolizumab. Median follow up was 30 months (IQR 28-31). A decline in PSA of 50% or greater from baseline was observed in 28 (76%, 95% CI 59-88) of the 37 participants. Common treatment-related adverse events were grade 1-2. Grade 3 adverse events included anaemia in one (3%) participant and immune-related adverse events in 11 (30%) participants, including two cases each of fatigue (5%), colitis (5%), and increased serum amylase (5%), and one case (3%) each of pancreatitis, pneumonitis, type 1 diabetes, nephritis, myasthenia gravis, and mucosal pemphigus attributable to pembrolizumab. One participant had co-occurring myasthenia gravis and colitis. There were no grade 4 adverse events or treatment-related deaths.
Multicycle [177Lu]Lu-PSMA-617 and pembrolizumab showed encouraging activity with manageable toxicity that was consistent with [177Lu]Lu-PSMA-617 or pembrolizumab, and the combination might provide durable clinical benefit in a subset of patients.
Victorian Cancer Agency, Merck Sharp & Dohme, and Novartis.
The Lancet. Oncology. 2026 Apr [Epub]
Shahneen Sandhu, Anthony M Joshua, Louise Emmett, Mathias Bressel, Angelyn Anton, Lavinia Spain, Lisa G Horvath, Anupama Pasam, Sofie H Tolmeijer, Timothy J Akhurst, Ramin Alipour, Patricia Banks, James P Buteau, Erin Cassidy, Megan Crumbaker, Nattakorn Dhiantravan, Wen Xu, Joanna Chan, Nadia Hitchen, Mark Scalzo, Aravind S Ravi Kumar, Grace Kong, Roslyn Wallace, Narelle Williams, Scott Williams, Nicole M Haynes, Paul Neeson, Alexander W Wyatt, Rodney J Hicks, Michael S Hofman
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia. Electronic address: ., St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia; Department of Medical Oncology, Kinghorn Cancer Centre, Sydney, NSW, Australia., Garvan Institute of Medical Research, Sydney, NSW, Australia; Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Department of Medical Oncology, Eastern Health, Melbourne, VIC, Australia; Eastern Clinical Research Unit, Monash University, Melbourne, VIC, Australia., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Eastern Clinical Research Unit, Monash University, Melbourne, VIC, Australia., Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Metastasis and Evolution Program, Cancer Metastasis and Personalised Immunotherapy Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Basic and Translational Research, BC Cancer, Vancouver, BC, Canada., Department of Medicine, St Vincent's Medical School, The University of Melbourne, Melbourne, VIC, Australia.