However, investigations are ongoing to improve therapy efficacy and limit patient selection to candidates highly likely to benefit from treatment. In our state-of-the-art article published in the Journal of Nuclear Medicine, we examined a clinical question that practicing physicians, particularly urologists and oncologists, face with increasing frequency: what is the role of continuing [177Lu]Lu-PSMA RPT beyond the standard approved cycles in patients with mCRPC who have responded to initial treatment but retain residual disease or experience disease progression later on?
We synthesized evidence from the current literature evaluating two distinct approaches: 1) Extended therapy: Radiopharmaceutical therapy continuation beyond six cycles without interruption, and 2) Rechallenge therapy: Re-administration of [177Lu]Lu-PSMA after a treatment-free interval (i.e., therapy break). Based on the findings, extended therapy demonstrated PSA50 response (a decrease of at least 50% in serum PSA) rates of 62-88%, with median overall survival ranging from 18 to 29 months. Importantly, response rates often increased with successive treatment cycles, suggesting cumulative benefit in selected patients, while managing potential toxicities. Rechallenge therapy showed PSA50 response rates of 26-80%, with a median overall survival of 23-31 months. These are clinically significant therapeutic outcomes, given that these patients exhausted multiple lines of therapy.
Safety profiles were also generally acceptable. Low-grade adverse events predominated across both approaches. Approximately one-third of patients experienced grade 3 toxicities, with, importantly, no grade 4 events reported in the majority of the cohorts. Hematotoxicity, particularly anemia and thrombocytopenia, emerged as the most prominent concern. Additionally, renal function declined progressively through consecutive cycles, though severe nephrotoxicity remained infrequent. Notably, baseline hematologic and renal function strongly predicted toxicity risk, and patients having prior low-grade toxicities on standard therapy faced a substantially higher risk for high-grade events during extended or rechallenge cycles.
What does this mean for patient management?
Patient selection matters most, as [177Lu]Lu-PSMA therapy is not a one-size-fits-all approach. Patients with insufficient treatment effect from the initial six cycles of [177Lu]Lu-PSMA therapy (partial response with high-volume residual disease) who have adequate organ function (e.g., acceptable bone marrow reserve and estimated GFR) and preserved performance status are potential candidates for extended therapy. Patients with a favorable initial response to [177Lu]Lu-PSMA therapy (PSA50 response plus imaging favorable response showing small-volume residual disease), adequate organ function following initial treatment or complete recovery, and good performance status are reasonable candidates for rechallenge therapy.
However, important uncertainties persist. Heterogeneity across studies, in patient selection, treatment protocols/timelines, response assessment criteria, and follow-up duration, limited firm conclusions. Furthermore, selection bias in retrospective cohorts made it challenging to isolate the actual treatment effect from patient-related factors predicting favorable outcomes. Results from ongoing prospective trials may offer clearer insights into the efficacy and safety of rechallenge and extended [177Lu]Lu-PSMA therapy.
Written by: Seyed Ali Mirshahvalad, MD1,2 & Mohsen Beheshti, MD1
- Division of Molecular Imaging & Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria
- Department of Medical Imaging, Health Sciences North, Northern Ontario School of Medicine, Sudbury, ON, Canada