[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial

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; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

doi:10.1016/S0140-6736(21)00237-3

[¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial

Lancet. 2021 Feb 27;397(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3. Epub 2021 Feb 11.

Authors

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; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Collaborators

TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group:
Arun A Azad, Wei Chua, Ian D Davis, Nattakorn Dhiantravan, Louise Emmett, Kate Ford, Michael S Hofman, Roslyn J Francis, Craig Gedye, Jeffrey C Goh, Alex Guminski, Edward Hsiao, Amir Iravani, Anthony M Joshua, Ian D Kirkwood, Ailsa Langford, Nicola Lawrence, Sze-Ting Lee, Peter Lin, Andrew J Martin, William McDonald, Margaret M McJannett, Siobhan Ng, David A Pattison, Shakher Ramdave, Nisha Rana, Andrew D Redfern, Natalie K Rutherford, Shahneen Sandhu, Andrew M Scott, Martin R Stockler, Shalini Subramaniam, Thean Hsiang Tan, John A Violet, Andrew Weickhardt, Scott G Williams, Sonia Yip, Alison Y Zhang

Affiliations

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.

PMID: 33581798
DOI: 10.1016/S0140-6736(21)00237-3

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.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intravenous
Aged
Antigens, Surface / genetics
Dipeptides / therapeutic use*
Glutamate Carboxypeptidase II / genetics
Heterocyclic Compounds, 1-Ring / therapeutic use*
Humans
Lutetium / therapeutic use*
Male
Positron Emission Tomography Computed Tomography
Prostate-Specific Antigen / blood*
Prostate-Specific Antigen / therapeutic use
Prostatic Neoplasms, Castration-Resistant / blood
Prostatic Neoplasms, Castration-Resistant / drug therapy*
Prostatic Neoplasms, Castration-Resistant / radiotherapy
Radioisotopes / therapeutic use*
Taxoids / therapeutic use*
Treatment Outcome

Substances

Antigens, Surface
Dipeptides
Heterocyclic Compounds, 1-Ring
PSMA-617
Radioisotopes
Taxoids
cabazitaxel
Lutetium
Lutetium-177
FOLH1 protein, human
Glutamate Carboxypeptidase II
Prostate-Specific Antigen

Associated data

ClinicalTrials.gov/NCT03392428