Prostate Specific Membrane Antigen as a Diagnostic and Therapeutic Target

Abstract

Prostate specific membrane antigen (PSMA) based imaging could improve clinical outcomes in men with metastatic castration resistant prostate cancer treated with 177Lutetium-PSMA-617. This thesis aimed to identify imaging biomarkers from pre-treatment 68Ga-PSMA and 18F-fluorodeoxygluose (18F-FDG) positron emission tomography (PET) that could be used to optimise patient selection; and, to characterise responses to treatment using PET and 177Lu SPECT (single photon emission computed tomography).

PET and 177Lu SPECT imaging studies were acquired within a prospective single arm trial (LuPIN). Quantitative analysis derived imaging biomarkers including measures of total tumour volume (TTV), and of intensity of 68Ga-PSMA and 18F-FDG uptake.

The baseline 68Ga-PSMA and 18F-FDG imaging and clinical markers associated with PSA response and overall survival were identified. Higher PSMA SUVmean was associated with increased odds of PSA response; and higher PSMA TTV was associated with decreased odds of PSA response. Higher PSMA TTV was associated with worse overall survival.

Analysis of post-treatment PET imaging demonstrated that 12/37 participants had an increase in PSMA TTV, and this was associated with poorer overall survival. Those with an increase in TTV also had persistently high PSMA expression.

Quantitative analysis of interim imaging with 177Lu SPECT was also examined. Analysis of post cycle 1 and cycle 3 177Lu SPECT showed that an increase in 177Lu SPECT TTV was associated with worse PSA PFS.

Patterns of treatment response on 68Ga-PSMA PET were explored using a novel Traffic Light Workflow (TLW). Complex responses were common, with 16/37 having a reduction in PSMA TTV despite the presence of low-volume disease progression. TLW overall response category was prognostic for overall survival.

The findings reported in this thesis support the use of quantitative analysis of PSMA based imaging to personalise the use of 177Lu-PSMA-617 therapy and improve clinical outcomes.