PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial

James P Buteau; Andrew J Martin; Louise Emmett; Amir Iravani; Shahneen Sandhu; Anthony M Joshua; Roslyn J Francis; Alison Y Zhang; Andrew M Scott; Sze-Ting Lee; Arun A Azad; Margaret M McJannett; Martin R Stockler; Scott G Williams; Ian D Davis; Michael S Hofman; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

doi:10.1016/S1470-2045(22)00605-2

PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial

Lancet Oncol. 2022 Nov;23(11):1389-1397. doi: 10.1016/S1470-2045(22)00605-2. Epub 2022 Oct 16.

Authors

James P Buteau¹, Andrew J Martin², Louise Emmett³, Amir Iravani¹, Shahneen Sandhu⁴, Anthony M Joshua⁵, Roslyn J Francis⁶, Alison Y Zhang⁷, Andrew M Scott⁸, Sze-Ting Lee⁸, Arun A Azad⁴, Margaret M McJannett⁹, Martin R Stockler¹⁰, Scott G Williams¹¹, Ian D Davis¹², Michael S Hofman¹³; 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:
Tim Akhurst, Ramin Alipour, Arun A Azad, Patricia Banks, Alexis Beaulieu, James P Buteau, Wei Chua, Ian D Davis, Nattakorn Dhiantravan, Louise Emmett, Kate Ford, Michael S Hofman, Roslyn J Francis, Craig Gedye, Jeffrey C Goh, Alex Guminski, Anis Hamid, Mohammad B Haskali, Rodney J Hicks, Edward Hsiao, Amir Iravani, Anthony M Joshua, Ian D Kirkwood, Grace Kong, Edmond M Kwan, Ailsa Langford, Nicola Lawrence, Sze-Ting Lee, Jeremy Lewin, Peter Lin, Andrew J Martin, William McDonald, Margaret M McJannett, Kate Moodie, Declan G Murphy, Siobhan Ng, David A Pattison, Izabella Pokorski, Shakher Ramdave, Aravind S Ravi Kumar, Andrew D Redfern, Natalie K Rutherford, Javad Saghebi, Shahneen Sandhu, Andrew M Scott, Lavinia Spain, Martin R Stockler, Shalini Subramaniam, Thean Hsiang Tan, Sue Ping Thang, Ben Tran, Roslyn Wallace, 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.
² NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
³ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.
⁴ Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia.
⁵ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
⁶ Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia.
⁷ 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.
⁸ Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
⁹ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia.
¹⁰ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
¹¹ Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
¹² Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia; Eastern Health, Melbourne, VIC, Australia.
¹³ 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@petetermac.org.

PMID: 36261050
DOI: 10.1016/S1470-2045(22)00605-2

Abstract

Background: Previously, results from the TheraP trial showed that treatment with lutetium-177 [¹⁷⁷Lu]Lu-PSMA-617 improved frequency of prostate-specific antigen (PSA) response rate and progression-free survival compared with cabazitaxel in men with metastatic castration-resistant prostate cancer. In this study, we aimed to analyse gallium-68 [⁶⁸Ga]Ga-PSMA-11 PET (PSMA-PET) and 2-[¹⁸F]fluoro-2-deoxy-D-glucose PET (FDG-PET) imaging parameters as predictive and prognostic biomarkers in this patient population.

Methods: TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m² intravenously every 3 weeks for up to ten cycles) or [¹⁷⁷Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles). The primary study endpoint, analysed previously, was PSA response rate. The prespecified tertiary study endpoint was association between total tumour quantitative parameters on PSMA-PET, FDG-PET, and baseline characteristics with clinical outcomes. A SUVmean of 10 or higher on PSMA-PET was evaluated as a predictive biomarker for response to [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel. A metabolic tumour volume (MTV) of 200 mL or higher on FDG-PET was tested as a prognostic biomarker. Both cutoff points were prespecified. The analysis was intention-to-treat, using logistic regression. This trial is registered with ClinicalTrials.gov, NCT03392428.

Findings: 200 patients were randomly assigned between Feb 6, 2018, and Sept 3, 2019. 101 men were assigned to the cabazitaxel group and 99 were assigned to the [¹⁷⁷Lu]Lu-PSMA-617 group. The median follow-up at data cutoff of July 20, 2020, was 18·4 months (IQR 12·8-21·8). 35 (35%) of 99 men who were assigned [¹⁷⁷Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel had high PSMA uptake (SUVmean of ≥10). Odds of PSA response to [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel were significantly higher for men with SUVmean of 10 or higher compared with those with SUVmean of less than 10 (odds ratio [OR] 12·19 [95% CI 3·42-58·76] vs 2·22 [1·11-4·51]; p_adj=0·039 for treatment-by-SUVmean interaction). PSA response rate for [¹⁷⁷Lu]Lu-PSMA-617 compared with cabazitaxel was 32 (91% [95% CI 76-98]) of 35 men versus 14 (47% [29-65]) of 30 men in patients with SUVmean of 10 or higher, and 33 (52% [39-64]) of 64 men versus 23 (32% [22-45]) of 71 men in those with SUVmean of less than 10. High-volume disease on FDG-PET (MTV ≥200 mL) was seen in 30 (30%) of 99 men who were assigned [¹⁷⁷Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel. PSA response rate for both treatment groups combined for FDG-PET MTV of 200 mL or higher versus FDG-PET MTV of less than 200 mL was 23 (38% [95% CI 26-52]) of 60 men versus 79 (56% [48-65]) of 140 men (OR 0·44, 95% CI 0·23-0·84; p_adj=0·035).

Interpretation: In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [¹⁷⁷Lu]Lu-PSMA-617 than cabazitaxel, which provides guidance for optimal [¹⁷⁷Lu]Lu-PSMA-617 use. High FDG-PET MTV was associated with lower responses regardless of randomly assigned treatment, warranting further research for treatment intensification. A strength of this analysis is the validation of pre-specified cutpoints within a multicentre, randomised, controlled trial. Quantitative PET parameters used, however, require specialised software and are not yet routinely available in most clinics.

Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride.

Publication types

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

MeSH terms

Adolescent
Adult
Australia
Fluorodeoxyglucose F18
Humans
Male
Prognosis
Prostate-Specific Antigen* / therapeutic use
Prostatic Neoplasms, Castration-Resistant* / diagnostic imaging
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Treatment Outcome

Substances

PSMA-617
Prostate-Specific Antigen
cabazitaxel
Fluorodeoxyglucose F18

Associated data

ClinicalTrials.gov/NCT03392428