PSMA PET and FDG PET as predictors of response and prognosis in metastatic, castration-resistant prostate cancer
The TheraP trial previously demonstrated that 177Lu-PSMA-617 (Lu-PSMA) improved PSA=50% response rate compared with cabazitaxel in metastatic castration-resistant prostate cancer progressing after docetaxel. Biomarker analysis now indicate that PSMA SUVmean ≥10 is predictive of a higher likelihood of favourable response to Lu-PSMA, whilst a high volume of disease on FDG PET was associated with a worse prognosis, regardless of randomly assigned treatment.
177Lu-PSMA-617 (Lu-PSMA) is a novel, radiolabeled, small molecule enabling the delivery of high doses of tumour-killing irradiation to sites of metastases. TheraP was the first randomised trial comparing Lu-PSMA to the current standard-of-care chemotherapy cabazitaxel in men with metastatic castration-resistant prostate cancer (mCRPC). All men had disease that had already progressed after standard chemotherapy. The trial met its primary endpoint by demonstrating a significantly higher PSA-50% response rate (PSA-50RR) in those men randomised to Lu-PSMA. Study inclusion required high PSMA uptake (SUVmax ≥20) and no sites of metastatic disease with discordant 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG)-positive and PSMA-negative findings. At ASCO GU 2022, Prof. Hofman reported on PSMA PET and FDG PET as potential predictive and prognostic biomarkers.
Study design
Investigators prospectively analysed semi-automated quantitative PET parameters in centrally- collected 68Ga-PSMA-11 PET and 18F-FDG PET in 200 eligible men. SUVmean ≥10 on PSMA PET was evaluated as a predictive biomarker for response to Lu-PSMA vs. cabazitaxel. Metabolic tumour volume (MTV) ≥ 200 ml on FDG PET was tested as a prognostic biomarker accounting for the randomly assigned treatment. Hypothesis of the study was that as the PSMA tumour intensity increased, we would see a higher response rate to Lu-PSMA vs. cabazitaxel. In contrast, upon increasing FDG volume, a decreased response to either treatment would be observed. Responses were defined according to PSA50-RR (primary endpoint), PSA-progression-free survival (PFS) and radiographic PFS (rPFS).
Results
Very high PSMA uptake on PSMA PET (SUVmean ≥ 10) was seen in 35/99 patients (35%) assigned Lu-PSMA and 30/101 patients (30%) assigned cabazitaxel. PSMA intensity was found to be a predictive biomarker. The odds of a response to Lu-PSMA vs. cabazitaxel were significantly higher for men with SUVmean ≥10 (OR[95%CI]: 12.2[3.4-59]) than in men with SUVmean < 10 (OR[95%CI]: 2.2[ 1.1-4.5; p= 0.03). Important to note is that in both groups the odds ratio defines a higher likelihood of response to Lu-PSMA. Furthermore, in men with SUVmean ≥10, the PSA50-RR for Lu-PSMA vs. cabazitaxel were 32/35 (91%) vs. 14/30 (47%). In men with PSMA SUVmean < 10, the PSA50-RR were 33/62 (52%) vs. 23/71 (32%). The HR for PSA-PFS for Lu-PSMA vs. cabazitaxel was 0.45 (95%CI: 0.25-0.80) for SUVmean ≥10 vs. 0.77 (95%CI: 0.53-1.12) for SUVmean < 10 (p= 0.2).
High-volume metabolic disease on FDG PET (MTV ≥ 200 ml) was seen in 30% of patients in both the Lu-PSMA and cabazitaxel arms. The PSA50-RR in these men was 17/30 (57%) for Lu-PSMA vs. 6/30 (20%) for cabazitaxel. In comparison, the PSA50-RR for men with MTV < 200 ml on FDG PET was 70% for Lu-PSMA vs. 44% for cabazitaxel. After accounting for treatment, the odds of a PSA50-response was lower among men with high MTV (OR 0.44; p= 0.01), demonstrating the prognostic value of FDG PET. The HRs for high MTV on FDG PET adjusted for treatment were 1.44 (95%CI 1.03-2.02) for PSA-PFS (p= 0.03); and 1.79 (95%CI 1.28-2.52) for rPFS (p< 0.001).
Conclusion
In men with mCRPC, high PSMA expression (SUVmean ≥ 10) was predictive of a higher likelihood of favourable response to Lu-PSMA than cabazitaxel. Furthermore, a high volume of disease on FDG PET (MTV > 200 ml) was associated with worse prognosis regardless of randomly assigned treatment.
Reference
Buteau JP, et al. PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic, castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603). Presented at ASCO GU 2022; Abstract 10.
