The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT.
TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete.
291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1).
These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease.
Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.
The Lancet. Oncology. 2023 Nov 30 [Epub ahead of print]
Michael S Hofman, Louise Emmett, Shahneen Sandhu, Amir Iravani, James P Buteau, 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 Yan Zhang, Martin R Stockler, Scott G Williams, Andrew J Martin, Ian D Davis, TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Prostate Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, Faculty of Medicine, The University of Melbourne, Melbourne, VIC, Australia. Electronic address: ., Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia., Prostate Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, Faculty of Medicine, The University of Melbourne, Melbourne, VIC, Australia., Prostate Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia., Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Queensland University of Technology, Brisbane, QLD, Australia., Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia., Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia., Department of Nuclear Medicine and PET, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia., Department of Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia., Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia., Department of Medical Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia., School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia; Department of Nuclear Medicine, Hunter New England Health, New Lambton, NSW, Australia., Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia., Department of Medicine, Faculty of Medicine, The 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., Department of Medical Oncology, Monash Health, Melbourne, VIC, Australia., Monash Health Imaging, Monash Health, Melbourne, VIC, Australia., Medical School, University of Western Australia, Perth, WA, Australia; Department of Medical Oncology, Fiona Stanley Hospital, Perth, WA, Australia., Medical School, University of Western Australia, Perth, WA, Australia; Department of Medical Oncology, Fiona Stanley Hospital, Perth, WA, Australia; Department of Nuclear Medicine, Fiona Stanley Hospital, Perth, WA, Australia., Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia., Department of Nuclear Medicine and PET, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia., Department of Medical Oncology, Liverpool Hospital, Sydney, NSW, Australia., Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, NSW, Australia., 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., NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia., Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia; NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia., Monash University Eastern Health Clinical School, Melbourne, VIC, Australia; Eastern Health Department of Cancer Services, Eastern Health, Melbourne, VIC, Australia.