Michael S Hofman1, Louise Emmett2, Shahneen Sandhu3, Amir Iravani4, Anthony M Joshua5, Jeffrey C Goh6, David A Pattison7, Thean Hsiang Tan8, Ian D Kirkwood9, Siobhan Ng10, Roslyn J Francis11, Craig Gedye12, Natalie K Rutherford13, Andrew Weickhardt14, Andrew M Scott15, Sze-Ting Lee15, Edmond M Kwan16, Arun A Azad3, Shakher Ramdave17, Andrew D Redfern18, William Macdonald19, Alex Guminski20, Edward Hsiao21, Wei Chua22, Peter Lin23, Alison Y Zhang24, Margaret M McJannett25, Martin R Stockler26, John A Violet3, Scott G Williams3, Andrew J Martin27, Ian D Davis28. 1. 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, University of Melbourne, Melbourne, VIC, Australia. Electronic address: michael.hofman@petermac.org. 2. Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia. 3. 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, University of Melbourne, Melbourne, VIC, Australia. 4. Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA. 5. Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia. 6. Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. 7. Department of Nuclear Medicine & Specialised PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, St Lucia, Brisbane, QLD, Australia. 8. Department of Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA Australia. 9. Department of Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia; Department of Nuclear Medicine and PET, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA Australia. 10. Department of Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia. 11. Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia. 12. Department of Medical Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia. 13. Department of Nuclear Medicine, Hunter New England Health, Newcastle, NSW, Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia. 14. Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia. 15. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia. 16. Department of Medical Oncology, Monash Health, Melbourne, VIC, Australia. 17. Monash Health Imaging, Monash Health, Melbourne, VIC, Australia. 18. Medical School, University of Western Australia, Perth, WA, Australia; Department of Medical Oncology, Fiona Stanley Hospital, Perth, WA, Australia. 19. Department of Nuclear Medicine, Fiona Stanley Hospital, Perth, WA, Australia. 20. Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia; Northern Clinical School, University of Sydney, Sydney, NSW, Australia. 21. Department of Nuclear Medicine and PET, Royal North Shore Hospital, Sydney, NSW, Australia. 22. Department of Medical Oncology, Liverpool Hospital, Sydney, NSW, Australia. 23. Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, NSW, Australia. 24. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Macquarie University Hospital, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia. 25. Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia. 26. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia. 27. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. 28. Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia; Eastern Health, Melbourne, VIC, Australia.
Abstract
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. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
RCT Entities:
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. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
Authors: Jeremie Calais; Andrei Gafita; Matthias Eiber; Wesley R Armstrong; Jeannine Gartmann; Pan Thin; Kathleen Nguyen; Vincent Lok; Laura Gosa; Tristan Grogan; Rouzbeh Esfandiari; Martin Allen-Auerbach; Andrew Quon; Shadfar Bahri; Pawan Gupta; Linda Gardner; David Ranganathan; Roger Slavik; Magnus Dahlbom; Ken Herrmann; Ebrahim Delpassand; Wolfgang P Fendler; Johannes Czernin Journal: J Nucl Med Date: 2021-05-20 Impact factor: 10.057
Authors: Oliver Sartor; Johann de Bono; Kim N Chi; Karim Fizazi; Ken Herrmann; Kambiz Rahbar; Scott T Tagawa; Luke T Nordquist; Nitin Vaishampayan; Ghassan El-Haddad; Chandler H Park; Tomasz M Beer; Alison Armour; Wendy J Pérez-Contreras; Michelle DeSilvio; Euloge Kpamegan; Germo Gericke; Richard A Messmann; Michael J Morris; Bernd J Krause Journal: N Engl J Med Date: 2021-06-23 Impact factor: 91.245
Authors: Sazan Rasul; Tim Wollenweber; Lucia Zisser; Elisabeth Kretschmer-Chott; Bernhard Grubmüller; Gero Kramer; Shahrokh F Shariat; Harald Eidherr; Markus Mitterhauser; Chrysoula Vraka; Werner Langsteger; Marcus Hacker; Alexander R Haug Journal: Cancers (Basel) Date: 2021-05-20 Impact factor: 6.639
Authors: Jeremie Calais; Johannes Czernin; Pan Thin; Jeannine Gartmann; Kathleen Nguyen; Wesley R Armstrong; Martin Allen-Auerbach; Andrew Quon; Shadfar Bahri; Pawan Gupta; Linda Gardner; Magnus Dahlbom; Beilei He; Rouzbeh Esfandiari; David Ranganathan; Ken Herrmann; Matthias Eiber; Wolfgang P Fendler; Ebrahim Delpassand Journal: J Nucl Med Date: 2021-07-16 Impact factor: 10.057