Abstract
Introduction: A novel radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), 177Lu-rhPSMA-10.1, for the treatment of metastatic prostate cancer (mCRPC) has been developed with optimized pharmacokinetics and is currently under investigation in a Phase 1/2 clinical trial (NCT05413850). Early clinical data suggest that rhPSMA-10.1 improves the therapeutic index compared with first-generation PSMA-targeted therapies, with a more efficient delivery of radiation to tumor deposits versus the kidney. An improved therapeutic index may improve patient outcomes. One of the key objectives of the Phase 1 study was to characterize the distribution and dosimetry of 177Lu-rhPSMA-10.1 in organs and tumors, and use these data alongside safety data, to inform the dosing regimen for Phase 2. Methods: Patients with PSMA-positive mCRPC underwent 1 3 cycles (at 6-week intervals) of 177Lu-rhPSMA-10.1 (5.5 7.40 GBq/cycle). Sequential blood samples and SPECT-CT images were collected after every administration of 177Lu-rhPSMA-10.1. SPECT-CT acquisitions were performed at 3, 24, 48, and 168-hours (h) post injection. Pharmacokinetics and absorbed dose estimates for organs at-risk and tumors were assessed. Two approaches were used for tumor selection and delineation (Cycle 1 only). The first approach was an anatomy-based method; up to 5 tumors were selected in a blinded fashion on CT per Response Evaluation Criteria in Solid Tumors. Tumor delineation and volume was determined using CT only. For the second approach, an activity-based method was used; up to 3 tumors were selected according to their relative uptake on SPECT-CT, and tumor volume was determined using PSMA PET-CT. All absorbed dose estimates were calculated using MIRD S-value methodology and expressed as mean absorbed dose per unit activity (Gy/GBq) alongside standard deviation (SD). Results: Thirteen patients were enrolled and received 177Lu-rhPSMA-10.1: 3 received 5.55 GBq/cycle and 10 received 7.40 GBq/cycle. In total, 34 cycles of dosimetry data were available for analysis. Across all patients and cycles, the mean absorbed dose, Gy/GBq, was 0.299 (SD: 0.10) in kidneys, 0.130 (SD: 0.08) in salivary glands, and 0.011 (SD: 0.02) in the bone marrow; estimates remained consistent across cycles. Absorbed doses in other organs were in line with values reported previously for other PSMA RLT. Cumulative absorbed doses remained well below the limits applied in external beam radiotherapy. 177Lu-rhPSMA-10.1 was rapidly cleared from the blood with a mean effective half-life of 2.2 (SD: 0.5) h. For activity-based tumor dosimetry, a total of 36 lesions were analyzed after Cycle 1; a mix of bone (n=27) and lymphatic (n=9) tumor sites were included. The mean (range) tumor absorbed dose was 8.9 (2.3 25.7) Gy/GBq, resulting in tumor-to-kidney (T:K) and tumor-to-salivary gland (T:S) ratios of 32 and 73, respectively. Tumor dose estimates across 57 lesions from anatomy-based dosimetry were lower, resulting in T:K and T:S ratios of 9 and 19, respectively. Eighteen lesions were common across both methods used. Tumor absorbed doses decreased with each cycle. Conclusions: 177Lu-rhPSMA-10.1 delivers high radiation doses to tumors compared with normal organs, and this dataset suggests it has an improved therapeutic index compared with previously reported values for first generation PSMA-targeted RLT. Importantly, tumor selection and delineation methods have a significant impact on reported tumor doses and standardization of methods across trials should be targeted. The observed normal organ absorbed doses will allow administration of a high cumulative therapeutic activity. Decline in tumor absorbed dose with subsequent cycles suggests that a fixed dosing regimen may not be optimal for PSMA RLT; higher cumulative absorbed tumor dose can be achieved by administering a higher proportion of radioactivity during earlier cycles. The impact of this on the efficacy and safety of 177Lu-rhPSMA-10.1 will be explored in Phase 2.