We investigated the AD-response relationship on both the patient and lesion levels. Voxelwise dosimetry was performed on data from serial [177Lu]Lu-PSMA-617 SPECT/CT scans. Treatment response was evaluated based on percentage change in: (i) PSA before and after cycle 1 (patient-level); or (ii) maximum standardized uptake value (SUVmax) between baseline and follow-up [68Ga]Ga-PSMA-11 PET/CT (lesion-level).
Baseline PET and SPECT lesion SUVmax were strongly correlated (Pearson’s r=0.74; N=1364 lesions), despite PSMA PET being performed 52±24 days before cycle 1, during which time PSA values on average nearly doubled. Abundant intravenous hydration resulted in relatively low kidney doses (0.28±0.12 Gy/GBq) and no significant decreases in estimated glomerular filtration rate at 1-year post-therapy.
A moderate AD-response relationship was observed on both patient (Spearman’s ρ=-0.33; N=63 patients) and lesion level (ρ=-0.30; N=681 lesions in N=37 patients). Patient-level correlation was stronger if substituting volume-weighted mean AD with a metric that additionally incorporates PSA doubling time before RPT. Patients receiving higher volume-weighted mean AD (>7.5 Gy; N=33) had significantly deeper best PSA response (median=70% vs -5%; p<0.001), longer biochemical progression-free survival (median=4.1 months vs. 1.6 months; p=0.005) and longer overall survival (median = 16.0 months vs. 9.5 months; p=0.048) compared to patients whose volume-weighted mean AD was <7.5 Gy (N=32). Some lesions exhibited good initial responses despite receiving relatively low A, with such cases more likely to be observed in patients who presented with a limited disease burden.
The association of higher AD with better biochemical or image-based responses supports the hypothesis that higher AD for a given lesion would result in improved outcome, although the evidence for causality is not definitive (disease phenotype might be a primary driver of response). Increasing the effective dose to a lesion could be achieved by, e.g., higher administered activities, upregulating PSMA expression, or delayed co-administration of radiosensitizers such as DNA damage response inhibitors. Extended [177Lu]Lu-PSMA-617 RPT might be a feasible treatment option in patients with high-volume residual tumor burden. Further improving the efficacy of RPT for metastatic prostate cancer will likely require novel combinatorial approaches and additional radionuclides. Treatment personalization will be crucial for the safe implementation of these strategies.
Written by: Milan Grkovski,1 Simone S Krebs,2,3 Joseph A O'Donoghue,4 Jonathan Kuten,2 Audrey Mauguen,5 Parnian Shobeiri,2 Daniel Lafontaine,4 Maria Thor,4 Finn Augensen,4 Josef J Fox,2 Neeta Pandit-Taskar,2,6 Mark P Dunphy,2 Lisa Bodei,2 John L Humm,4 Heiko Schöder,7
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Nuclear Medicine, Division of Diagnostic Imaging, University of Texas M.D. Anderson Cancer Center, Houston, Texas
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
- Nuclear Medicine Division, Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York