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

Buteau, JP; Martin, AJ; Emmett, L; Iravani, A; Sandhu, S; Joshua, AM; Francis, RJ; Zhang, AY; Scott, AM; Lee, ST; Azad, AA; McJannett, MM; Stockler, MR; Williams, SG; Davis, ID; Hofman, MS; TheraP Trial Investigators; Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Author(s): Buteau, JP; Martin, AJ; Emmett, L; Iravani, A; Sandhu, S; Joshua, AM; Francis, RJ; Zhang, AY; Scott, AM; Lee, ST; Azad, AA; McJannett, MM; Stockler, MR; Williams, SG; Davis, ID; Hofman, MS; TheraP Trial Investigators; Australian and New Zealand Urogenital and Prostate Cancer Trials Group;
Details: Publication Year 2022-11,Volume 23,Issue #11,Page 1389-1397
Journal Title: Lancet Oncology
Publication Type: Research article
Abstract: BACKGROUND: Previously, results from the TheraP trial showed that treatment with lutetium-177 [(177)Lu]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 [(68)Ga]Ga-PSMA-11 PET (PSMA-PET) and 2-[(18)F]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/m(2) intravenously every 3 weeks for up to ten cycles) or [(177)Lu]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 [(177)Lu]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 [(177)Lu]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 [(177)Lu]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 [(177)Lu]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 [(177)Lu]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 [(177)Lu]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 [(177)Lu]Lu-PSMA-617 than cabazitaxel, which provides guidance for optimal [(177)Lu]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.
Keywords: Male; Humans; Adolescent; Adult; *Prostate-Specific Antigen/therapeutic use; Fluorodeoxyglucose F18; *Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/drug therapy; Prognosis; Australia; Treatment Outcome
Department(s): Cancer Imaging; Radiation Oncology; Medical Oncology
PubMed ID: 36261050
Publisher's Version: https://doi.org/10.1016/S1470-2045(22)00605-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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