TY - JOUR
T1 - [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP)
T2 - a randomised, open-label, phase 2 trial
AU - TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group
AU - Hofman, Michael S.
AU - Emmett, Louise
AU - Sandhu, Shahneen
AU - Iravani, Amir
AU - Joshua, Anthony M.
AU - Goh, Jeffrey C.
AU - Pattison, David A.
AU - Tan, Thean Hsiang
AU - Kirkwood, Ian D.
AU - Ng, Siobhan
AU - Francis, Roslyn J.
AU - Gedye, Craig
AU - Rutherford, Natalie K.
AU - Weickhardt, Andrew
AU - Scott, Andrew M.
AU - Lee, Sze Ting
AU - Kwan, Edmond M.
AU - Azad, Arun A.
AU - Ramdave, Shakher
AU - Redfern, Andrew D.
AU - Macdonald, William
AU - Guminski, Alex
AU - Hsiao, Edward
AU - Chua, Wei
AU - Lin, Peter
AU - Zhang, Alison Y.
AU - McJannett, Margaret M.
AU - Stockler, Martin R.
AU - Violet, John A.
AU - Williams, Scott G.
AU - Martin, Andrew J.
AU - Davis, Ian D.
AU - Dhiantravan, Nattakorn
AU - Ford, Kate
AU - Langford, Ailsa
AU - Lawrence, Nicola
AU - McDonald, William
AU - Rana, Nisha
AU - Subramaniam, Shalini
AU - Yip, Sonia
N1 - Funding Information:
TheraP is a partnership between the ANZUP Cancer Trials Group and the Prostate Cancer Foundation of Australia with support from the Australian Nuclear Science and Technology Organization; Endocyte, a Novartis Company; Movember; The Distinguished Gentleman's Ride; It's a Bloke Thing; and CAN4CANCER. MSH is supported by grants from the Prostate Cancer Foundation and the Peter MacCallum Foundation. AMS is supported by a NHMRC investigator fellowship (1177837). ID is supported by an NHMRC practitioner fellowship (1102604). ANZUP acknowledges funding from Cancer Australia through its Support for Cancer Clinical Trials programme. We thank the men and their partners and carers who volunteered to take part in this trial and the trial teams and investigators at each site for their contributions. Findings were presented at major congresses (ASCO 2020 and ASCO GU 2020). This investigator-initiated trial was designed and conducted by ANZUP in collaboration with the NHMRC Clinical Trials Centre at the University of Sydney, and the Australasian Radiopharmaceutical Trials Network. 177 Lu was supplied by the Australian Nuclear Science and Technology Organization. Endocyte, a Novartis Company, provided PSMA-11 and PSMA-617, and additional funding support. ANZUP receives infrastructure support from the Australian Government through Cancer Australia.
Funding Information:
TheraP is a partnership between the ANZUP Cancer Trials Group and the Prostate Cancer Foundation of Australia with support from the Australian Nuclear Science and Technology Organization; Endocyte, a Novartis Company; Movember; The Distinguished Gentleman's Ride; It's a Bloke Thing; and CAN4CANCER. MSH is supported by grants from the Prostate Cancer Foundation and the Peter MacCallum Foundation. AMS is supported by a NHMRC investigator fellowship (1177837). ID is supported by an NHMRC practitioner fellowship (1102604). ANZUP acknowledges funding from Cancer Australia through its Support for Cancer Clinical Trials programme. We thank the men and their partners and carers who volunteered to take part in this trial and the trial teams and investigators at each site for their contributions. Findings were presented at major congresses (ASCO 2020 and ASCO GU 2020). This investigator-initiated trial was designed and conducted by ANZUP in collaboration with the NHMRC Clinical Trials Centre at the University of Sydney, and the Australasian Radiopharmaceutical Trials Network. 177Lu was supplied by the Australian Nuclear Science and Technology Organization. Endocyte, a Novartis Company, provided PSMA-11 and PSMA-617, and additional funding support. ANZUP receives infrastructure support from the Australian Government through Cancer Australia.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/2/27
Y1 - 2021/2/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101171240&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(21)00237-3
DO - 10.1016/S0140-6736(21)00237-3
M3 - Article
C2 - 33581798
AN - SCOPUS:85101171240
SN - 0140-6736
VL - 397
SP - 797
EP - 804
JO - The Lancet
JF - The Lancet
IS - 10276
ER -