Long-Term Follow-up and Outcomes of Retreatment in an Expanded 50-Patient Single-Center Phase II Prospective Trial of 177 Lu-PSMA-617 Theranostics in Metastatic Castration-Resistant Prostate Cancer
Open accessAbstract
177Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted β-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%–77%), including 22 patients (44%; 95% CI, 30%–59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177Lu-PSMA were self-limiting G1–G2 dry mouth (66%), transient G1–G2 nausea (48%), G3–G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of −1.2 (95% CI, −0.5 to −1.9; P = 0.001) and −1.0 (95% CI, −0.2 to −0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5–18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8–23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177Lu-PSMA radioligand therapy. On progression, rechallenge 177Lu-PSMA demonstrated higher response rates than other systemic therapies.
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In a phase 2 study of 28 patients who underwent 51Cr-EDTA GFR measurement before and 3 months after completion of 4 cycles of 177Lu-PSMA, a very modest decline of approximately 12 mL/min in GFR was noted.
“In a phase 2 study of 28 patients who underwent 51 Cr-EDTA GFR measurement before and 3 mo after completion of 4 cycles of 177 Lu-PSMA, a very modest decline of approximately 12 mL/min in GFR was noted ( 39 , 68 , 69 ).”
From Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns (2021) · cites this paper as [68]
The Biochemical and Imaging Response section reports that 28 patients had 51Cr-EDTA measurements before and three months after treatment, with a mean GFR decline of 11.7 mL/min. The Results section says the median was four cycles, but 21 patients received fewer; it does not establish that all 28 patients with paired measurements completed four cycles. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDisease progression on 177Lu-PSMA-617 is inevitable even in patients who are strongly PSMA-positive on imaging, with patients either having no response or progressing long-term despite having an excellent initial response.
“Disease progression on 177Lu-PSMA-617 is inevitable even in patients who are strongly PSMA-positive on imaging, with patients either having no response or progressing long-term despite having an excellent initial response258.”
From The evolving landscape of antibody-drug conjugates (ADCs) for treatment of prostate cancer (2025) · cites this paper as [258]
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- Authors
- Violet, J., Sandhu, S., Iravani, A., Ferdinandus, J., Thang, S.-P., Kong, G., Kumar, A. R., Akhurst, T., Pattison, D., Beaulieu, A., Mooi, J., Tran, B., Guo, C., Kalff, V., Murphy, D. G., Jackson, P., Eu, P., Scalzo, M., Williams, S., Hicks, R. J., & Hofman, M. S.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2019-11-15
- Volume
- 61
- Issue
- 6
- Pages
- 857-865
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- PMC
- PMC7262220
- OpenAlex
- W2988034537
- Cited by
- 292
- References
- 32
- Citations by year
- 2026: 30 · 2025: 29 · 2024: 39 · 2023: 39 · 2022: 56 · 2021: 63 · 2020: 35 · 2017: 1
- FWCI
- 25.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Peter MacCallum Cancer Centre
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- 177Lu-PSMA-617, radioligand therapy, castration-resistant prostate cancer, metastatic prostate cancer, PSMA-targeted therapy, long-term outcomes, progression-free survival, overall survival, PSA response, treatment toxicity, thrombocytopenia, pain, quality of life, retreatment, salvage therapy, docetaxel, cabazitaxel
- MeSH terms
- Theranostic Nanomedicine, Aged, Aged, 80 and over, Dipeptides, Follow-Up Studies, Heterocyclic Compounds, 1-Ring, Humans, Lutetium, Male, Middle Aged, Prospective Studies, Quality of Life, Prostate-Specific Antigen, Retreatment, Radiopharmaceuticals, Prostatic Neoplasms, Castration-Resistant
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