The prostate-specific membrane antigen (PSMA)-targeted radioligand [¹⁷⁷Lu]Lu-PSMA-617 is a new standard treatment for metastatic castration-resistant prostate cancer (mCRPC), but predictive genomic biomarkers informing its rational use are unknown. We performed detailed dissection of prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with mCRPC from the randomized TheraP trial of [¹⁷⁷Lu]Lu-PSMA-617 (n = 97) versus cabazitaxel chemotherapy (n = 83). The primary endpoint was PSA50 biochemical response, with secondary endpoints of progression-free survival (PFS) and overall survival (OS). In this post-hoc biomarker analysis, a low pretreatment circulating tumor DNA (ctDNA) fraction predicted a superior biochemical response (100% versus 58%, P = 0.0067) and PFS (median 14.7 versus 6.0 months; hazard ratio 0.12, P = 2.5 × 10-4) on [¹⁷⁷Lu]Lu-PSMA-617 independent of predictive PSMA-positron emission tomography imaging parameters, although this benefit did not extend to OS. Deleterious PTEN alterations were associated with worse PFS and OS on cabazitaxel, whereas ATM defects were observed in select patients with favorable [¹⁷⁷Lu]Lu-PSMA-617 outcomes. Comparing pretreatment and progression ctDNA revealed population flux but no evidence that alterations in individual mCRPC genes (or FOLH1) are dominant causes of acquired [¹⁷⁷Lu]Lu-PSMA-617 or cabazitaxel resistance. Our results nominate new candidate biomarkers for [¹⁷⁷Lu]Lu-PSMA-617 selection and ultimately expand the mCRPC predictive biomarker repertoire. We anticipate our ctDNA fraction-aware analytical framework will aid future precision management strategies for [¹⁷⁷Lu]Lu-PSMA-617 and other PSMA-targeted therapeutics. ClinicalTrials.gov identifier: NCT03392428 .
Nature medicine. 2025 May 27 [Epub ahead of print]
Edmond M Kwan, Sarah W S Ng, Sofie H Tolmeijer, Louise Emmett, Shahneen Sandhu, James P Buteau, Amir Iravani, Anthony M Joshua, Roslyn J Francis, Vinod Subhash, Sze-Ting Lee, Andrew M Scott, Andrew J Martin, Martin R Stockler, Gráinne Donnellan, Matti Annala, Cameron Herberts, Ian D Davis, Michael S Hofman, Arun A Azad, Alexander W Wyatt, TheraP Investigators and the ANZUP Cancer Trials Group
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia., Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia., Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia., Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia., Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia., NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia., Centre for Clinical Research, University of Queensland, Brisbane, Queensland, Australia., Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland., Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia. ., Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. ., Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. ., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. .