Long-Term Follow-up and Outcomes of Retreatment in an Expanded 50-Patient Single-Center Phase II Prospective Trial of ¹⁷⁷Lu-PSMA-617 Theranostics in Metastatic Castration-Resistant Prostate Cancer

Abstract

Lu-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 177 Lu-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 177 Lu-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 177 Lu-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 5 0.001) and −1.0 (95% CI, −0.2 to −0.18; P 5 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 177 Lu-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 177 Lu-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 177 Lu-PSMA radioligand therapy. On progression, rechallenge 177 Lu-PSMA demonstrated higher response rates than other systemic t...

Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC

“…The mean absorbed dose to the salivary glands (0.86 Gy/ GBq) was similar for [ 177 Lu]Lu-PSMA-ALB-56 when compared with published data for [ 177 Lu]Lu-PSMA-617 (Table 4) [ [37][38][39]. Only two studies performed dosimetry fully based on 3D WB SPECT/CT for [ 177 Lu]Lu-PSMA-617, revealing higher (1.25 Gy/GBq) [36] or lower (0.51 Gy/GBq) [38] salivary gland doses.…”

“…The aim of increasing the accumulation of activity in tumor lesions was successfully achieved. It resulted in a 1.4-2.3-fold higher absorbed dose to tumor lesions (6.64 Gy/GBq) as compared with published values for [ 177 Lu]Lu-PSMA-617 (3.87 Gy/GBq [37], 4.60 Gy/GBq [38], and 2.80 Gy/GBq [39]) and [ 177 Lu]Lu-PSMA I&T (3.30 Gy/GBq [40] and 3.20 Gy/GBq [41]), respectively.…”

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting

“…TEAEs included lymphocytopenia (32%), thrombocytopenia (8%), anemia (10%), neutropenia (6%), and fatigue (2%). The only grade 4 TEAEs observed were thrombocytopenia (2%).Treatment with177 Lu-PSMA-617 improved quality of life measures including pain severity and pain interference 64. The higher response rates observed in the Australian trial compared with other trials/reports may reflect the stringent imaging selection criteria applied in this study that required patients to have highly PSMA avid disease without any FDG-positive/PSMA-negative lesions.…”

“…85,[92][93][94][95] In contrast, PSMA ligand-based RNT results in on-target, off-tumor radiation exposure to salivary glands and the digestive tract and possible late renal toxicity. [63][64][65]82,[84][85][86][87] Beta particle-emitting 90 Y-and 177 Lu-labeled J591 agents have demonstrated promise as theranostic agents in clinical studies. 85,[92][93][94][95][96][97] In SPECT imaging, 90 Y-(using 111 Indium imaging) and 177 111,112 The FDA has not allowed PSA changes to be considered as an indicator of clinical benefit in prostate cancer trials.…”

Novel therapies are changing treatment paradigms in metastatic prostate cancer

“…These data were reinforced in a follow-up analysis of the same cohort (with 20 additional patients) on later follow-up, with 64% of patients experiencing > 50% PSA decline. In patients treated with 177 Lu-PSMA, median PSA PFS was 6.9 months (95% CI 6.0–8.7) [ 57 ]. Patients predominantly had disease progression in the bone marrow and in the liver.…”