Safety and efficacy of [177Lu]Lu-SibuDAB in patients with progressive metastatic castration-resistant prostate cancer

Abstract

Purpose: Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy (RPT) is a safe and well-tolerated treatment option for metastatic, castration-resistant prostate cancer (mCRPC). A new radioligand, comprising ibuprofen as an albumin-binding entity, [177Lu]Lu-SibuDAB, demonstrated an increased tumour-absorbed dose and efficacy in preclinical studies while tumour-to-organ absorbed dose coefficient ratios were similar to conventional PSMA radiopharmaceuticals. We conducted a translational study to evaluate response rate, safety and efficacy, and quality of life of [177Lu]Lu-Sibu-DAB in progressive mCRPC patients. Methods: From July 2021 to January 2023 a total of seventeen eligible patients, sixteen (median age 71 years, range 63–83) were selected to receive up to four cycles of [177Lu]Lu-SibuDAB at an activity of 4.3 to 5.9 GBq (median 5.3 GBq). The response rate was assessed by serum prostate specific antigen (PSA) and by PET/CT using [18F]PSMA-1007, at baseline and post-therapeutic up to eight weeks, using RECIP 1.0 criteria. Safety and adverse events were investigated clinically by analyzing serial blood biomarkers and the recording of adverse events according to CTCAE v5.0. Quality of life was assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life (EORTC) questionnaires QLQ-C30 and QLQ-PR25. Results: Seven participants received 4 cycles of [177Lu]Lu-SibuDAB, 3 participants received 3 cycles and 6 participants received ≤ 2 cycles because of disease progression or advanced stage of the disease. A maximum PSA decline (median baseline PSA value: 49.1 ng/ml (min 0,84 ng/ml max 145,1 ng/ml) by at least ≥ 50%, was observed in four participants, while stable serum PSA was observed in five further participants. Longitudinal PET/CT was performed with 10 participants, showing partial remission in five, stable disease in two and progressive disease in three patients. We observed an association between the changes in PSA levels and PET/CT-image-based assessment of the response. Two participants experienced grade three anaemia, one of them also a grade four thrombocytopenia. Two patients, heavily pre-treated with chemotherapy, experienced grade 3 thrombocytopenia. Impairment of renal or liver function was not observed. Importantly, no xerostomia was recorded for any of the participants. No significant changes in the quality of life were reported. Median overall survival was 13.9 months in this cohort. Conclusion: Overall survival and response rates of patients are consistent with previous reports on PSMA-targeted RPT while the absence of xerostomia can be considered an improvement. Up to four cycles of [177Lu]Lu-SibuDAB were well tolerated and [177Lu]Lu-SibuDAB appears to be a valid option for effective treatment of patients with progressive mCRPC. Randomized clinical trials to assess efficacy compared to established RPT are warranted. © The Author(s) 2025.