TY - JOUR
T1 - Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP)
T2 - secondary outcomes of a randomised, open-label, phase 2 trial
AU - Hofman, Michael S.
AU - Emmett, Louise
AU - Sandhu, Shahneen
AU - Iravani, Amir
AU - Buteau, James P.
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 Yan
AU - Stockler, Martin R.
AU - Williams, Scott G.
AU - Martin, Andrew J.
AU - Davis, Ian D.
AU - for the TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group
N1 - Funding Information:
The TheraP trial (ANZUP 1603) is a collaboration between the ANZUP Trials Group, the NHMRC Clinical Trials Centre, University of Sydney, and the Australasian Radiopharmaceutical Trials Network in partnership with the Prostate Cancer Foundation of Australia with support from ANSTO, Endocyte (a Novartis company), Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER. ANZUP receives infrastructure support from the Australian Government through Cancer Australia (Support for Cancer Clinical Trials Program). MSH acknowledges philanthropic and government grant support from the Prostate Cancer Foundation funded by Canica, the Peter MacCallum Foundation, MRFF, an NHMRC Investigator Grant, and Movember. 177 Lu was supplied by ANSTO. Endocyte, a Novartis Company, provided PSMA-11 and PSMA-617, and additional funding support. We thank the patients who volunteered to take part in this trial, their partners and carers, and the trial teams and investigators at each site for their contributions.
Funding Information:
The TheraP trial (ANZUP 1603) is a collaboration between the ANZUP Trials Group, the NHMRC Clinical Trials Centre, University of Sydney, and the Australasian Radiopharmaceutical Trials Network in partnership with the Prostate Cancer Foundation of Australia with support from ANSTO, Endocyte (a Novartis company), Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER. ANZUP receives infrastructure support from the Australian Government through Cancer Australia (Support for Cancer Clinical Trials Program). MSH acknowledges philanthropic and government grant support from the Prostate Cancer Foundation funded by Canica, the Peter MacCallum Foundation, MRFF, an NHMRC Investigator Grant, and Movember. 177Lu was supplied by ANSTO. Endocyte, a Novartis Company, provided PSMA-11 and PSMA-617, and additional funding support. We thank the patients who volunteered to take part in this trial, their partners and carers, and the trial teams and investigators at each site for their contributions.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2024/1
Y1 - 2024/1
N2 - Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: 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.
AB - Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: 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.
UR - http://www.scopus.com/inward/record.url?scp=85178568744&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(23)00529-6
DO - 10.1016/S1470-2045(23)00529-6
M3 - Article
C2 - 38043558
AN - SCOPUS:85178568744
SN - 1470-2045
VL - 25
SP - 99
EP - 107
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 1
ER -
