A recent study published in Scientific Reports has shed light on the real-world safety profile of Lutetium-177-PSMA-617 (177Lu-PSMA-617) in patients with metastatic castration-resistant prostate cancer (mCRPC). The pharmacovigilance study, utilizing data from the FDA Adverse Event Reporting System (FAERS), analyzed 6266 reports of adverse events associated with the radiopharmaceutical drug between Q1 2022 and Q2 2024.
The research aimed to supplement existing safety data from the VISION trial and the European Union Summary of Product Characteristics (EUSmPC) by identifying potential adverse events in real-world clinical use. While the study acknowledged that death was the most frequently reported outcome (60.82%), researchers attributed this primarily to disease progression given the advanced stage of mCRPC in the patient population.
Hematological Abnormalities
The study highlighted significant signals for hematological abnormalities, including anemia, decreased full blood count, decreased hemoglobin, pancytopenia, decreased platelet count, and thrombocytopenia. These findings align with observations from the VISION trial, where blood cell abnormalities were commonly reported. Researchers suggest that the bone marrow, a dose-limiting organ for therapeutic radiopharmaceuticals, may be particularly susceptible to the effects of 177Lu-PSMA-617 due to its targeting of prostate tumors with high PSMA expression and the proximity of radiation to the bone marrow.
"We should pay extra attention to hematological abnormalities during the use of 177Lu-PSMA-617, not only because of their relatively high incidence rate but also because hematological AEs are more often grades 3–4," the authors noted.
Comparison with Clinical Trials
Interestingly, some adverse events highlighted in clinical trials and the EU SmPC, such as gastrointestinal toxicity, nervous system disorders, and urinary tract infections, were not identified as significant signals in this study. The researchers suggest this discrepancy may be due to the high prevalence of these AEs across all drugs in the FAERS database, diluting the specificity of the signal values for 177Lu-PSMA-617.
Addressing Indication Bias
To mitigate potential indication bias, where adverse events may be related to the patient population or disease rather than the drug itself, the researchers performed a disproportionality analysis using reports of other drugs for treating mCRPC as background data. This analysis reinforced the significance of "Full blood count decreased," "General physical health deterioration," and "Laboratory test abnormal," consistent with findings from the VISION trial and the EU SmPC. Renal toxicity warnings, prominent in the VISION trial and EU SmPC, were represented in the FAERS data as "Laboratory test abnormal."
Time to Adverse Events
The study also examined the time intervals between drug administration and the occurrence of adverse events. A significant proportion of patients (21.0%) reported AEs within one day of using 177Lu-PSMA-617, and over half (53.6%) reported AEs within one month. This suggests that AEs are more likely to occur shortly after administration, with the likelihood decreasing as the duration of medication increases. The study authors noted that prolonged exposure to 177Lu-PSMA-617 does not appear to increase the risk of toxicity, and most AEs are manageable and do not significantly affect patients' quality of life.
Limitations
The authors acknowledged several limitations of the study, including the voluntary nature of the FAERS reporting system, which may introduce missing values and non-professional reports, affecting the accuracy of AE identification and attribution. They also noted that the FAERS database does not distinguish between disease progression and drug toxicity as reasons for severe outcomes. Despite these limitations, the study provides valuable real-world evidence to supplement clinical trial data and inform clinical practice.
"Clinicians should provide appropriate examinations and preventive interventions based on the actual situation of patients, and this study offers additional references for clinical practice based on previous research," the authors concluded.
