[¹⁷⁷Lu]Lu-PSMA-617 Versus Cabazitaxel in Patients with Metastatic Castration-Resistant Prostate Cancer (TheraP): A Randomised, Open-Label, Phase 2 Trial

Background Lutetium-177 [¹⁷⁷Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [¹⁷⁷Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.

Methods We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [⁶⁸Ga]Ga-PSMA-11 and 2-flourine-18[¹⁸F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [¹⁷⁷Lu] Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m² intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428.

Findings Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [¹⁷⁷Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [¹⁷⁷Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the [¹⁷⁷Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [¹⁷⁷Lu]Lu-PSMA-617.

Interpretation [¹⁷⁷Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [¹⁷⁷Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.


Authors: Michael S Hofman, Louise Emmett, Shahneen Sandhu, Amir Iravani, Anthony M Joshua, Jeffrey C Goh, David A Pattison, Thean Hsiang Tan, Ian D Kirkwood, Siobhan Ng, Roslyn J Francis, Craig Gedye, Natalie K Rutherford, Andrew Weickhardt , Andrew M Scott, Sze-Ting Lee, Edmond M Kwan, Arun A Azad, Shakher Ramdave, Andrew D Redfern, William Macdonald, Alex Guminski, Edward Hsiao, Wei Chua, Peter Lin, Alison Y Zhang, Margaret M McJannett, Martin R Stockler, John A Violet*, Scott G Williams, Andrew J Martin, Ian D Davis, for the TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (Prof M S Hofman MBBS, S Sandhu MBBS, A Iravani MD, A A Azad PhD, J A Violet PhD, Prof S G Williams MD); Sir Peter MacCallum Department of Oncology (Prof M S Hofman, S Sandhu, A A Azad, J A Violet, Prof S G Williams), and Department of Medicine (Prof A M Scott MD, S-T Lee PhD), University of Melbourne, Melbourne, VIC, Australia;Department of Theranostics and Nuclear Medicine (Prof L Emmett MD), and Department of Medical Oncology, Kinghorn Cancer Centre (Prof A M Joshua PhD), St Vincent’s Hospital, Sydney, NSW, Australia; Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia (Prof L Emmett, Prof P Lin MBBS);Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA (A Iravani); Department of Nuclear Medicine & Specialised PET Services(D A Pattison MBBS), and Medical Oncology (J C Goh MBBS), Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, St Lucia, Brisbane, QLD, Australia (D A Pattison); Department of Oncology (T H Tan MBBS, I D Kirkwood MBBS) and Department of Nuclear Medicine and PET (I D Kirkwood), Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA Australia (T H Tan, I D Kirkwood); Department of Oncology (S Ng MBBS) and Department of Nuclear Medicine (R J Francis PhD), Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School (R J Francis, A D Redfern MBChB, S Ng), University of Western Australia, Perth, WA, Australia; Department of Medical Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia (C Gedye PhD); Department of Nuclear Medicine (N K Rutherford MD), Hunter New England Health, Newcastle, NSW, Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia (C Gedye, N K Rutherford); Olivia Newton-John Cancer and Wellness Centre (A Weickhardt PhD) and Department of Molecular Imaging and Therapy (Prof A M Scott, S-T Lee), Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia (A Weickhardt, Prof A M Scott, S-T Lee); Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia (Prof A M Scott, S-T Lee); Department of Medical Oncology (E M Kwan PhD) and Monash Health Imaging (S Ramdave MD), Monash Health, Melbourne, VIC, Australia; Department of Medical Oncology (A D Redfern) and Department of Nuclear Medicine (W Macdonald MPH), Fiona Stanley Hospital, Perth, WA, Australia; Department of Medical Oncology (A Guminski PhD) and Department of Nuclear Medicine and PET (E Hsiao MBChB), Royal North Shore Hospital, Sydney, NSW, Australia; Northern Clinical School (A Guminski), NHMRC; Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (A Y Zhang PhD, Prof M R Stockler MBBS, A J Martin PhD); Department of Medical Oncology (W Chua PhD) and Department of Nuclear Medicine and PET (P Lin), Liverpool Hospital, Sydney, NSW, Australia; Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia (M M McJannett); Department of Medical Oncology, Macquarie University Hospital, Sydney, NSW, Australia (A Y Zhang); Department of Medical Oncology, Chris O’Brien Lifehouse, Sydney, NSW, Australia (A Y Zhang, Prof M R Stockler); Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia (Prof I D Davis PhD); Eastern Health, Melbourne, VIC, Australia (Prof I D Davis)

Source: Hofman M, Emmett L, Sandhu S et al. "[¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial." The Lancet. 2021. S0140-6736(21)00237-3.

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Clinical Trial Information: NCT03392428