Prostate-Specific Membrane Antigen (PSMA)-targeted radionuclide therapy is emerging as a promising approach for managing metastatic castration-resistant prostate cancer (mCRPC). This article reviews recent advancements and clinical data supporting the efficacy and safety of PSMA-targeted therapies, particularly focusing on 177Lu-PSMA-617.
PSMA-PET Imaging
PSMA-PET imaging has become a crucial tool for identifying and staging prostate cancer. Small molecule PSMA-PET imaging, utilizing positron-emitting radionuclides, offers convenience for patients with same-day imaging. Gallium-68 conjugated to PSMA-11 (68Ga-PSMA-11) is a well-studied tracer, demonstrating high effectiveness in defining both intra-prostatic and metastatic disease, especially at low PSA levels (under 2 ng/mL). Other imaging ligands, such as fluorine-conjugated DCFPyL, PSMA-1007, and PSMA-7, are also under investigation.
Early TRT Experiences with 131I-MIP-1095
Initial trials of targeted radionuclide therapy (TRT) used beta-emitter iodine-131 conjugated to the small molecule MIP-1095. A retrospective study involving mCRPC patients treated with a single dose (average 4.8 GBq) showed a PSA decline of over 50% in 60.7% of patients. However, 131I-MIP-1095 TRT faced challenges due to high levels of co-emitted gamma radiation and difficulties in production.
177Lu-PSMA-617: A Promising Agent
177Lu-PSMA-617, a urea-based small molecule with a DOTA chelator, exhibits high affinity for PSMA and rapid plasma clearance. Dosimetric studies indicate that the kidneys (mean 0.75 Gy/GBq) and parotid glands (1.28 Gy/GBq) absorb the highest doses, while the bone marrow receives a lower dose (0.02 Gy/GBq).
Clinical Evidence for 177Lu-PSMA-617
Early retrospective studies of 177Lu-PSMA-617 showed encouraging results, with approximately 50% of patients experiencing a PSA decline of over 50%. The first prospective study, reported by Hofman et al. in 2018, involved 30 patients receiving four cycles of therapy. Results showed that 57% of patients had a PSA decline over 50%, with 20% experiencing a decline exceeding 96%. The median biochemical progression-free and overall survival were 7.6 months and 13.5 months, respectively. High grade toxicities included 13% with grade 3/4 thrombocytopenia and anemia, and 7% with grade 3 neutropenia.
Individualized Dosing and Dose Escalation
While individualized dosing based on predicted dosimetry is hypothesized to be optimal, some studies suggest that higher doses may be warranted due to the relatively low toxicity profile. A phase I/II dose-escalation study (NCT03042468) of fractionated dose 177Lu-PSMA-617 showed that 59.1% of patients experienced >50% PSA decline, with no dose-limiting toxicity at the highest planned dose of 22.2 GBq.
TheraP Trial: A Randomized Study
The ANZUP investigators reported results of the TheraP study, a randomized trial comparing 177Lu-PSMA-617 (dosed at 8.5 GBq for the first cycle, reduced by 0.5 GBq each following cycle) versus cabazitaxel chemotherapy in mCRPC patients. The primary endpoint of PSA response was met, with 66% in the 177Lu-PSMA-617 arm versus 37% in the cabazitaxel arm achieving >50% PSA decline. While high grade adverse events were more common with cabazitaxel, 177Lu-PSMA-617 was associated with more all-grade xerostomia, dry eye, and thrombocytopenia.
VISION Trial: A Phase III Study
The VISION trial is a phase III, multi-institution study enrolling 750 patients, comparing standard of care plus 177Lu-PSMA-617 against best standard of care alone. The study population includes patients with progressive mCRPC who have received prior treatment with both taxane chemotherapy and ARPI. The dual primary endpoints are radiographic progression-free and overall survival. Results are awaited.
Ongoing and Future Studies
Additional randomized studies in earlier disease states have been initiated or planned, including the UpfrontPSMA study (NCT04343885), which is evaluating 177Lu-PSMA-617 in combination with docetaxel for metastatic castration-sensitive prostate cancer.
